Details of a Researcher - Yasuda, Hiroyuki

Papers - Yasuda, Hiroyuki

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Initial single-institutional experience with salvage surgery for stage IV non-small-cell lung cancer.

Tomoyuki Hishida, Naoyuki Oka, Kaito Yano, Seiji Omura, Yu Okubo, Kyohei Masai, Kaoru Kaseda, Keiko Ohgino, Hideki Terai, Hiroyuki Yasuda, Keisuke Asakura

Interdisciplinary cardiovascular and thoracic surgery 40 ( 3 ) 2025.03

The purpose of this study was to assess surgical outcomes of salvage surgery for clinical stage IV non-small-cell lung cancer. A total of 14 patients who underwent lung resection following systemic therapy between 2010 and 2022 were included in this study. Systemic therapy prior to surgery included agents including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in eight patients and non-TKI agents in six (chemotherapy alone: four, chemotherapy plus immune checkpoint inhibitors: two). During a median follow-up of 5.2 years, the EGFR-TKI group showed a favourable 5-year overall survival of 83%; however, it was due to treatment after relapse, and there were no 4-year relapse-free survivors. The non-EGFR-TKI group showed a 5-year relapse-free survival of 33%, and 2 patients have survived more than 3 years without any relapse and further treatment. When considering the role of surgery in multimodal treatment for initial c-stage IV non-small-cell lung cancer, salvage surgery following non-TKI therapy (chemotherapy with or without immune checkpoint inhibitor) can be regarded as genuine salvage surgery.

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Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE<inf>2</inf> signaling pathway in mice

Sakurai K., Chubachi S., Miyata J., Hamamoto J., Naganuma T., Shimada T., Otake S., Nakayama S., Irie H., Tsutsumi A., Kameyama N., Hegab A.E., Shimoda M., Terai H., Yasuda H., Kanai Y., Arita M., Fukunaga K.

Frontiers in Immunology 16 1557790 2025

Introduction: Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2’s role in lipid metabolism. Methods: Male A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors. Results: Intermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE2) production in the airway. PGE2 increased LA-4 cell viability via the EP4 receptor and promoted colony formation. Discussion: Celecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.

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Real-World Efficacy and Safety of Atezolizumab for Advanced Non-Small Cell Lung Cancer in Japan: A Retrospective Multicenter Analysis.

Masahiko Okada, Keiko Ohgino, Kohei Horiuchi, Koichi Sayama, Daisuke Arai, Mayuko Watase, Keigo Kobayashi, Takeshi Terashima, Kota Ishioka, Masayoshi Miyawaki, Fumio Sakamaki, Keita Masuzawa, Hideki Terai, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga

Journal of clinical medicine 13 ( 24 ) 2024.12

ISSN 2077-0383

Background/Objectives: Atezolizumab, an immune checkpoint inhibitor (ICI), was used in a phase III clinical trial, i.e., the OAK trial, of previously treated patients with non-small cell lung cancer. We aimed to evaluate the real-world efficacy and safety of atezolizumab in a non-selected population and identify the clinical characteristics that influence its efficacy. Methods: This was a multicenter, retrospective, single-arm observational study. Seventy-four patients with advanced non-small cell lung cancer, who received atezolizumab monotherapy at Keio University and affiliated hospitals in Japan between April 2018 and March 2019, were enrolled. The follow-up period was until 28 February 2024. The efficacy of treatment and adverse events were reviewed retrospectively. Statistical analyses using Pearson's χ2 test, Fisher's exact test, log-rank test, and Student's t-test were performed. Results: The median age of patients was 70 (range, 45-85) years. The overall survival duration was 7.54 (95% confidence interval [CI], 5.14-11.3) months, and the median time to treatment failure (TTF) was 2.00 (95% CI, 1.75-2.54) months. Patients treated with atezolizumab as their first ICI had a longer TTF than those treated with atezolizumab as their second or subsequent ICI (p = 0.04). Conclusions: Atezolizumab may be more effective when used as the first ICI for previously treated patients and may be safely used in elderly patients with non-small cell lung cancer in real-world settings.

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Therapeutic Efficacy of IL7/CCL19-Expressing CAR-T Cells in Intractable Solid Tumor Models of Glioblastoma and Pancreatic Cancer

Keisuke Ohta, Yukimi Sakoda, Keishi Adachi, Taro Shinozaki, Masao Nakajima, Hiroyuki Yasuda, Hiroaki Nagano, Koji Tamada

Cancer Research Communications (American Association for Cancer Research (AACR)) 4 ( 9 ) 2514 - 2524 2024.09

Abstract

Cancer immunotherapy using immune checkpoint inhibitors and its combination with other anticancer therapies has emerged as a new standard of care because of the encouraging therapeutic effects in various solid cancers. Nonetheless, glioblastoma and pancreatic cancer remain resistant to immunotherapy and represent intractable cancers with the poorest prognosis. We investigated the therapeutic effects of next-generation chimeric antigen receptor (CAR) T cells producing IL7 and chemokine (C–C motif) ligand 19 (CCL19; referred to as 7 × 19 CAR-T) in these intractable cancers. Cytotoxic activities and therapeutic effects of 7 × 19 CAR-T were evaluated in vitro and in vivo, in a model using EGFR variant III (EGFRvIII)–positive glioblastoma and anti-EGFRvIII CAR-T generated from healthy donor peripheral blood mononuclear cells (PBMC), or a model using HER2-positive pancreatic cancer organoids and anti-HER2 CAR-T generated from the same patient’s PBMC. Anti-EGFRvIII 7 × 19 CAR-T exhibited cytotoxic activity specific to EGFRvIII-positive tumor, induced complete rejection of glioblastoma with massive T-cell infiltration and tumor cell death in the tumor tissues, and consequently prolonged mouse survival. Anti-HER2 7 × 19 CAR-T demonstrated a potent cytotoxic activity against autologous HER2-positive pancreatic cancer organoids and induced complete rejection of autologous tumor along with prolonged mouse survival. Our results suggest that 7 × 19 CAR-T could become a therapeutic option for glioblastoma and pancreatic cancer. To the best of our knowledge, this is the first study to demonstrate the therapeutic efficacy of next-generation CAR-T in an autologous model using patient-derived tumor organoids and CAR-T generated from the same patient’s PBMC, in which unwanted allogeneic immune responses are fully excluded.

Significance:

Despite the clinical development of CAR T-cell therapy, its efficacy in solid cancers has yet to be established. This study explored the therapeutic potential and immunologic mechanisms of IL7/CCL19-producing CAR-T therapy in preclinical solid cancer models of glioblastoma and pancreatic cancer. We found that IL7/CCL19-producing CAR-T cells generated from the patient’s PBMC showed potent therapeutic effects against the solid cancer model established by inoculating organoids from the autologous tumor tissue.

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Development of a Machine Learning-Based Model for Predicting the Incidence of Peripheral Intravenous Catheter-Associated Phlebitis.

Yasuda H, Rickard CM, Mimoz O, Marsh N, Schults JA, Drugeon B, Kashiura M, Kishihara Y, Shinzato Y, Koike M, Moriya T, Kotani Y, Kondo N, Sekine K, Shime N, Morikane K, Abe T

Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures) 10 ( 3 ) 232 - 244 2024.07

ISSN 2393-1809

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Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

Kikuchi Y, Shimada H, Yamasaki F, Yamashita T, Araki K, Horimoto K, Yajima S, Yashiro M, Yokoi K, Cho H, Ehira T, Nakahara K, Yasuda H, Isobe K, Hayashida T, Hatakeyama S, Akakura K, Aoki D, Nomura H, Tada Y, Yoshimatsu Y, Miyachi H, Takebayashi C, Hanamura I, Takahashi H

International journal of clinical oncology 29 ( 5 ) 512 - 534 2024.05

ISSN 1341-9625

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Clinical utility of the Oncomine Dx Target Test multi-CDx system and the possibility of utilizing those original sequence data.

Ayaka Saito, Hideki Terai, Tae-Jung Kim, Katsura Emoto, Ryutaro Kawano, Kohei Nakamura, Hideyuki Hayashi, Hatsuyo Takaoka, Akihiko Ogata, Katsuhito Kinoshita, Fumimaro Ito, Lisa Shigematsu, Masahiko Okada, Takahiro Fukushima, Akifumi Mitsuishi, Taro Shinozaki, Keiko Ohgino, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Hiroshi Nishihara, Koichi Fukunaga

Cancer medicine 13 ( 4 ) e7077 2024.02

BACKGROUND: Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non-small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi-CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. AIMS: This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. MATERIALS AND METHODS: We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. RESULTS: Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction-based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). CONCLUSION: Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next-generation sequencing.

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Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis.

Kohei Horiuchi, Shinnosuke Ikemura, Takashi Sato, Keitaro Shimozaki, Satoshi Okamori, Yoshitake Yamada, Yoichi Yokoyama, Masahiro Hashimoto, Masahiro Jinzaki, Ikuko Hirai, Takeru Funakoshi, Ryuichi Mizuno, Mototsugu Oya, Kenro Hirata, Yasuo Hamamoto, Hideki Terai, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga

The oncologist 29 ( 1 ) E108 - E117 2024.01

ISSN 10837159

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. MATERIALS AND METHODS: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. RESULTS: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). CONCLUSION: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

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Prognostic factors affecting survival in patients with non-small cell lung cancer treated with salvage surgery after drug therapy: a multi-institutional retrospective study.

Shigeki Suzuki, Keisuke Asakura, Masayuki Okui, Naoko Izawa, Makoto Sawafuji, Hiroyuki Sakamaki, Takao Shigenobu, Atsushi Tajima, Naoyuki Oka, Kyohei Masai, Kaoru Kaseda, Tomoyuki Hishida, Hiroyuki Yasuda, Koichi Fukunaga, Hisao Asamura

World journal of surgical oncology 21 ( 1 ) 290 - 290 2023.12

BACKGROUND: The prevalence of salvage surgeries after drug therapy for non-small cell lung cancer (NSCLC) has risen, mainly due to recent progress in molecular-targeted drugs and immune checkpoint inhibitors for NSCLC. While the safety and effectiveness of salvage surgery after drug therapy for NSCLC have been studied, its indications remain unclear. We aimed to identify the prognostic factors affecting survival in patients with advanced-stage (stages III-IV) NSCLC treated with salvage surgery after drug therapy. METHODS: A retrospective investigation was conducted on patients who received salvage surgery after drug therapy at four hospitals between 2007 and 2020. Salvage surgery was defined as surgery after drug therapy for local progression, tumor conversion to resectable status, and discontinuation of prior drug therapy owing to serious complications. RESULTS: Thirty-two patients received cytotoxic agents alone (n = 12 [38%]), tyrosine kinase inhibitors (TKIs; n = 16 [50%]), or immune checkpoint inhibitors (n = 4 [13%]) as prior drug therapy. In 11 (34%) and 21 (66%) patients, the clinical stage before treatment was III or IV, respectively. The median initial and preoperative serum carcinoembryonic antigen (CEA) levels were 10.2 (range, 0.5-1024) ng/mL and 4.2 (range, 0.6-92.5) ng/mL, respectively. Among the patients, 28 (88%) underwent lobectomy, 2 (6%) underwent segmentectomy, and 2 (6%) underwent wedge resection. Complete resection of the primary lesion was accomplished in 28 (88%) patients. Postoperative complications were documented in six (19%) patients. Mortality rates were 0% at 30 days and 3% at 90 days post-operation. The 5-year overall survival rate stood at 66%, while the 5-year progression-free survival rate was 21%. Multivariate analyses showed that prior TKI therapy and preoperative serum CEA level < 5 ng/mL were prognostic factors influencing overall survival (hazard ratio [95% confidence interval]: 0.06 [0.006-0.68] and 0.03 [0.002-0.41], respectively). The 5-year overall survival in the 11 patients with both favorable prognosticators was 100%. CONCLUSIONS: In this study, prior TKI therapy and preoperative serum CEA level < 5 ng/mL were favorable prognostic factors for overall survival in patients with NSCLC treated with salvage surgery. Patients with these prognostic factors are considered good candidates for salvage surgery after drug therapy.

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Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

Rishu Takimoto, Takashi Kamigaki, Hisao Ito, Masashi Saito, Ken Takizawa, Kenzo Soejima, Hiroyuki Yasuda, Keiko Ohgino, Hideki Terai, Katsuro Tomita, Miyabi Miura, Eishiro Mizukoshi, Tomoharu Miyashita, Yasunari Nakamoto, Katsuhiro Hayashi, Shinji Miwa, Masaaki Kitahara, Akihiko Takeuchi, Hiroaki Kimura, Takafumi Mochizuki, Hiroki Sugie, Ken-Ichiro Seino, Tomonori Yamada, Syuhei Takeuchi, Kaori Makita, Keiko Naitoh, Kosei Yasumoto, Yoichiro Yoshida, Hiroyuki Inoue, Katsuhiro Kotake, Kihachi Ohshima, Shin-Ei Noda, Masahiko Okamoto, Yuya Yoshimoto, Sachiko Okada, Hiroshi Ibe, Eri Oguma, Shigenori Goto

Cytotherapy 25 ( 11 ) 1229 - 1235 2023.11

ISSN 14653249

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αβT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αβT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

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Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study

Terai H., Ishii M., Takemura R., Namkoong H., Shimamoto K., Masaki K., Tanosaki T., Chubachi S., Matsuyama E., Hayashi R., Shimada T., Shigematsu L., Ito F., Kaji M., Takaoka H., Kurihara M., Nakagawara K., Tomiyasu S., Sasahara K., Saito A., Otake S., Azekawa S., Okada M., Fukushima T., Morita A., Tanaka H., Sunata K., Asaoka M., Nishie M., Shinozaki T., Ebisudani T., Akiyama Y., Mitsuishi A., Nakayama S., Ogawa T., Sakurai K., Irie M., Yagi K., Ohgino K., Miyata J., Kabata H., Ikemura S., Kamata H., Yasuda H., Kawada I., Kimura R., Kondo M., Iwasaki T., Ishida N., Hiruma G., Miyazaki N., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Haraguchi M., Kagyo J., Shiomi T., Lee H., Sugihara K., Omori N., Sayama K., Otsuka K., Miyao N., Odani T., Watase M., Mochimaru T., Satomi R., Oyamada Y., Masuzawa K., Asakura T., Nakayama S., Suzuki Y., Baba R., Okamori S., Arai D., Nakachi I., Kuwahara N., Fujiwara A., Oakada T., Ishiguro T., Isosno T., Makino Y., Mashimo S., Kaido T., Minematsu N., Ueda S., Minami K., Hagiwara R., Manabe T., Fukui T.

Respiratory Investigation 61 ( 6 ) 802 - 814 2023.11

ISSN 22125345

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. Methods: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. Results: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41–64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. Conclusions: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

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CGP検査の結果により遺伝カウンセリング推奨となった胸部悪性腫瘍症例の考察

福島貴大, 寺井秀樹, 中村康平, 川野竜太郎, 江本桂, 石川麻倫, 緒方暁彦, 高岡初誉, 齋藤彩夏, 扇野圭子, 安田浩之, 川田一郎, 副島研造, 西原広史, 福永興壱

肺癌 ((NPO)日本肺癌学会) 63 ( 5 ) 461 - 461 2023.10

ISSN 0386-9628

CGP検査の結果により遺伝カウンセリング推奨となった胸部悪性腫瘍症例の考察

肺癌 ((NPO)日本肺癌学会) 63 ( 5 ) 461 - 461 2023.10

ISSN 0386-9628

EGFR遺伝子変異陽性肺腺癌に対するEGFR-TKI治療後,小細胞肺癌への形質転化と肺腺癌成分の再増大を繰り返し交互に認め,両組織型への治療を組み合わせる必要があった1例

渡邊素子, 小山薫, 木下雄仁, 緒方暁彦, 高岡初誉, 扇野圭子, 寺井秀樹, 安田浩之, 川田一郎, 福永興壱

肺癌 ((NPO)日本肺癌学会) 63 ( 2 ) 135 - 135 2023.04

ISSN 0386-9628

Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma.

Toshiki Ebisudani, Junko Hamamoto, Kazuhiro Togasaki, Akifumi Mitsuishi, Kai Sugihara, Taro Shinozaki, Takahiro Fukushima, Kenta Kawasaki, Takashi Seino, Mayumi Oda, Hikaru Hanyu, Kohta Toshimitsu, Katsura Emoto, Yuichiro Hayashi, Keisuke Asakura, Todd A Johnson, Hideki Terai, Shinnosuke Ikemura, Ichiro Kawada, Makoto Ishii, Tomoyuki Hishida, Hisao Asamura, Kenzo Soejima, Hidewaki Nakagawa, Masayuki Fujii, Koichi Fukunaga, Hiroyuki Yasuda, Toshiro Sato

Cell reports 42 ( 3 ) 112212 - 112212 2023.03

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

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Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

Emi Ishikawa, Yuta Yokoyama, Haruna Chishima, Hidefumi Kasai, Ouki Kuniyoshi, Motonori Kimura, Jun Hakamata, Hideo Nakada, Naoya Suehiro, Naoki Nakaya, Hideo Nakajima, Shinnosuke Ikemura, Ichiro Kawada, Hiroyuki Yasuda, Hideki Terai, Aya Jibiki, Hitoshi Kawazoe, Kenzo Soejima, Hiroshi Muramatsu, Sayo Suzuki, Tomonori Nakamura

Investigational new drugs 41 ( 1 ) 122 - 133 2023.02

ISSN 01676997

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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Successful Steroid Treatment of Pembrolizumab-induced Agranulocytosis that Developed after Splenectomy in a Patient with Non-small-cell Lung Cancer: A Case Report.

Shinichi Okuzumi, Hirofumi Kamata, Katsura Emoto, Takayuki Shimizu, Shiro Otake, Hidehiro Irie, Shotaro Chubachi, Shinnosuke Ikemura, Hiroyuki Yasuda, Koichi Fukunaga

Internal medicine (Tokyo, Japan) 62 ( 14 ) 2113 - 2121 2023

ISSN 09182918

Neutropenia, a rare immune-related adverse event, affects patients receiving treatment with immune checkpoint inhibitors (ICIs). We herein report a case of pembrolizumab-induced agranulocytosis. An 83-year-old man was diagnosed with advanced-stage lung carcinoma concomitant with splenomegaly complicated by hypersplenism, causing pancytopenia. To avoid the risk of bone marrow suppression due to cytotoxic chemotherapy, pembrolizumab monotherapy was chosen. However, the patient developed agranulocytosis despite the resolution of pancytopenia through splenectomy performed after the fourth pembrolizumab cycle. Neutrophil counts improved after steroid treatment but not after granulocyte colony-stimulating factor treatment. This case demonstrated that neutropenia can sometimes develop abruptly after several ICI therapy cycles.

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Most Important Things and Associated Factors With Prioritizing Daily Life in Patients With Advanced Lung Cancer.

Naofumi Kameyama, Takashi Sato, Daisuke Arai, Daisuke Fujisawa, Mari Takeuchi, Ichiro Nakachi, Ichiro Kawada, Hiroyuki Yasuda, Shinnosuke Ikemura, Hideki Terai, Shigenari Nukaga, Yasushi Nakano, Toshiyuki Hirano, Naoto Minematsu, Takanori Asakura, Takashi Kamatani, Kyuto Tanaka, Shoji Suzuki, Masayoshi Miyawaki, Katsuhiko Naoki, Koichi Fukunaga, Kenzo Soejima

JCO oncology practice 18 ( 12 ) E1977 - E1986 2022.12

ISSN 26881527

PURPOSE: Patients' values and priorities in their lives should be appreciated from an early phase of incurable diseases such as advanced cancer. However, studies examining these characteristics have been lacking. This study attempted to determine what patients with advanced lung cancer valued most, once they had been diagnosed, and any associated factors. METHODS: Patients with newly diagnosed advanced lung cancer (N = 248) were enrolled in a questionnaire survey conducted at 16 hospitals in Japan. Their priorities were assessed using a free-text response to the question what is the most important thing to you now? at the time of diagnosis and 3 months after diagnosis. The free-text responses were classified into 10 categories for quantification. The clinical characteristics associated with the category describing daily life were further examined. RESULTS: Free-text comments were obtained from 103 (44.0%) and 66 (42.6%) patients at the time of diagnosis and at 3 months, respectively. The most frequent categories were family (at diagnosis: 50.5%; at 3 months: 50.0%) and daily life (at diagnosis: 33.0%; at 3 months: 36.4%), followed by health (at diagnosis: 32.0%; at 3 months: 27.3%) at both time points. The patients mentioning daily life, the issues related to how to spend daily life, showed significantly higher total scores and functional well-being subscale scores on the Functional Assessment of Cancer Therapy-Lung scale at both time points and lower depression scores at diagnosis and lower anxiety scores at 3 months on the Hospital Anxiety and Depression Scale. CONCLUSION: Family and daily life were highly valued by patients with advanced lung cancer at diagnosis. A better quality of life and better mood were associated with mentioning daily life, which should be taken into account in care planning to maintain patients' involvement in daily life even with incurable diseases.

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Comparison of the effects of lidocaine and amiodarone for out-of-hospital cardiac arrest patients with shockable rhythms: a retrospective observational study from a multicenter registry.

Kishihara Y, Kashiura M, Amagasa S, Fukushima F, Yasuda H, Moriya T

BMC cardiovascular disorders 22 ( 1 ) 466 2022.11

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A burden of fluid, sodium, and chloride due to intravenous fluid therapy in patients with respiratory support: a post-hoc analysis of a multicenter cohort study.

Sakuraya M, Yoshihiro S, Onozuka K, Takaba A, Yasuda H, Shime N, Kotani Y, Kishihara Y, Kondo N, Sekine K, Morikane K, AMOR-VENUS study group

Annals of intensive care 12 ( 1 ) 100 2022.10

ISSN 2110-5820

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Real-world clinical practice for advanced non-small-cell lung cancer in the very elderly: A retrospective multicenter analysis.

Takahiro Fukushima, Yoshitaka Oyamada, Shinnosuke Ikemura, Shigenari Nukaga, Takashi Inoue, Daisuke Arai, Keiko Ohgino, Aoi Kuroda, Kota Ishioka, Fumio Sakamaki, Yusuke Suzuki, Hideki Terai, Hiroyuki Yasuda, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima

Clinical lung cancer 23 ( 6 ) 532 - 541 2022.09

ISSN 15257304

BACKGROUND: The optimal treatment for advanced non-small cell lung cancer (NSCLC) in very elderly patients is unclear. We aimed to evaluate their treatment in real-world clinical practice and identify suitable therapy that can improve their prognosis. MATERIALS AND METHODS: The medical records of 132 Japanese patients aged 80 years and older with advanced NSCLCs who were enrolled at a university hospital and its 9 affiliates were retrospectively analyzed. Clinical characteristics and overall survival (OS) were compared based on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) and biomarker statuses. Patients were defined as biomarker-positive if programmed death-ligand 1 tumor proportion score (PD-L1 TPS) was ≥ 50% or activating mutations were present in epidermal growth factor receptor, anaplastic lymphoma kinase, or c-ros oncogene 1. Finally, the factors contributing to better prognosis were explored in both PS 0 - 2 and PS 3 - 4 patient groups. RESULTS: The PS 0 - 2 patients showed a longer median OS than the PS 3 - 4 patients (5.5 vs. 1.6 months). PS 0 - 2 patients with positive biomarkers who received chemotherapy showed a significantly longer median OS than those without (18.1 vs. 3.7 months). Among the biomarker-negative/unknown PS 0 - 2 patients, the median OS showed no significant difference between those who received chemotherapy and those who did not (4.5 vs. 3.1 months). The multivariate analysis showed that treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors was related to better prognoses in the PS 0 - 2 group. CONCLUSION: Biomarker-matched therapy is effective even in very elderly patients. Meanwhile, the effectiveness of chemotherapy for biomarker-negative/unknown PS 0 - 2 patients is questionable.

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A 70-Year-Old Woman With Long-Term Nonresolving Pneumonia.

Tomiyasu S, Kabata H, Emoto K, Azekawa S, Maeda C, Masai K, Yasuda H, Fukunaga K

Chest 161 ( 4 ) e219 - e223 2022.04

ISSN 0012-3692

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Long-Term Treatment-Free Survival After Multimodal Therapy in a Patient with Stage IV Lung Adenocarcinoma.

Hatsuyo Takaoka, Hideki Terai, Katsura Emoto, Lisa Shigematsu, Fumimaro Ito, Ayaka Saito, Masahiko Okada, Keiko Ohgino, Shinnosuke Ikemura, Hiroyuki Yasuda, Ichiro Nakachi, Ichiro Kawada, Koichi Fukunaga, Kenzo Soejima

OncoTargets and therapy 15 981 - 989 2022

ISSN 1178-6930

We report the first case of a patient with non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE) who achieved disease- and treatment-free survival for nearly 10 years. A 50-year-old man was diagnosed with NSCLC with MPE and underwent chemotherapy and salvage thoracic surgery. The patient received chemotherapy with cisplatin, pemetrexed, and bevacizumab, and a partial response was achieved. After informed consent was obtained from the patient, right middle lobectomy was performed to achieve local tumor control. Postoperative adjuvant chemotherapy with pemetrexed and bevacizumab was discontinued after almost 1 year of chemotherapy due to side effects such as diarrhea and muscle weakness. The patient has survived without recurrence of lung cancer for more than 11 years after being diagnosed and nearly 10 years after discontinuing chemotherapy.

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A phase I/II study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer

Yasuda H., Ichihara E., Sakakibara-Konishi J., Zenke Y., Takeuchi S., Morise M., Hotta K., Sato M., Matsumoto S., Tanimoto A., Matsuzawa R., Kiura K., Takashima Y., Yano S., Koyama J., Fukushima T., Hamamoto J., Terai H., Ikemura S., Takemura R., Goto K., Soejima K.

Lung Cancer (Lung Cancer) 162 140 - 146 2021.12

ISSN 01695002

Objectives: Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Materials and methods: From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy. Results: Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC. Conclusions: Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.

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Longitudinal Assessment of Prognostic Understanding in Patients with Advanced Lung Cancer and Its Association with Their Psychological Distress

Arai D., Sato T., Nakachi I., Fujisawa D., Takeuchi M., Sato Y., Kawada I., Yasuda H., Ikemura S., Terai H., Nukaga S., Inoue T., Nakamura M., Oyamada Y., Terashima T., Sayama K., Saito F., Sakamaki F., Naoki K., Fukunaga K., Soejima K.

Oncologist (Oncologist) 26 ( 12 ) e2265 - e2273 2021.12

ISSN 10837159

Background: Accurate prognostic understanding in patients with advanced cancer is essential for shared decision making; however, patients may experience psychological burden through knowing the incurable nature of advanced cancer. It has been unclear how their prognostic understanding fluctuates and whether accurate prognostic understanding is associated with psychological distress from the time of diagnosis over time. Materials and Methods: We longitudinally investigated prognostic understanding in 225 patients with newly diagnosed advanced lung cancer at 16 hospitals in Japan until 24 months after diagnosis. We examined associated factors with being consistently accurate in prognostic understanding, especially focusing on its association with psychological well-being. Results: The proportion of patients with an inaccurate prognostic understanding remained approximately 20% over time with the presence of patients with inconsistent understanding. Patients with consistently accurate prognostic understanding showed a significantly lower Emotional Well-Being subscale score at both 3 and 6 months after diagnosis (p =.010 and p =.014, respectively). In multivariate analyses, being consistently accurate in prognostic understanding was significantly associated with female gender and higher lung cancer–specific symptom burden at 3 months (p =.008 and p =.005, respectively) and lower emotional well-being at 6 months (p =.006). Conclusion: Although substantial proportions of patients with advanced lung cancer had inaccurate prognostic understanding from the time of diagnosis over time, patients with consistently accurate prognostic understanding experienced greater psychological burden. Our findings highlight the importance of continuous psychological care and support for patients who understand their severe prognosis accurately. Implications for Practice: This study demonstrated that approximately 20% of patients with advanced lung cancer had an inaccurate understanding about their prognosis, not only at the time of diagnosis but also at the later time points. Being consistently accurate in prognostic understanding was significantly associated with elevated levels of psychological distress. Although accurate prognostic understanding is essential for decision making for treatment and advance care planning, health care providers should be aware of psychological burdens in patients that accept their severe prognosis accurately. Appropriate care and support for such patients are warranted from diagnosis over time.

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: study protocol.

Nakagawara K, Namkoong H, Terai H, Masaki K, Tanosaki T, Shimamoto K, Lee H, Tanaka H, Okamori S, Kabata H, Chubachi S, Ikemura S, Kamata H, Yasuda H, Kawada I, Ishii M, Ishibashi Y, Harada S, Fujita T, Ito D, Bun S, Tabuchi H, Kanzaki S, Shimizu E, Fukuda K, Yamagami J, Kobayashi K, Hirano T, Inoue T, Kagyo J, Shiomi T, Ohgino K, Sayama K, Otsuka K, Miyao N, Odani T, Oyamada Y, Masuzawa K, Nakayama S, Suzuki Y, Baba R, Nakachi I, Kuwahara N, Ishiguro T, Mashimo S, Minematsu N, Ueda S, Manabe T, Funatsu Y, Koh H, Yoshiyama T, Saito F, Ishioka K, Takahashi S, Nakamura M, Goto A, Harada N, Kusaka Y, Nakano Y, Nishio K, Tateno H, Edahiro R, Takeda Y, Kumanogoh A, Kodama N, Okamoto M, Umeda A, Hagimura K, Sato T, Miyazaki N, Takemura R, Sato Y, Takebayashi T, Nakahara J, Mimura M, Ogawa K, Shimmura S, Negishi K, Tsubota K, Amagai M, Goto R, Ibuka Y, Hasegawa N, Kitagawa Y, Kanai T, Fukunaga K

BMJ open respiratory research 8 ( 1 ) 2021.11

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Nasal delivery of single-domain antibody improves symptoms of SARS-CoV-2 infection in an animal model

Haga K., Takai-Todaka R., Matsumura Y., Song C., Takano T., Tojo T., Nagami A., Ishida Y., Masaki H., Tsuchiya M., Ebisudani T., Sugimoto S., Sato T., Yasuda H., Fukunaga K., Sawada A., Nemoto N., Murata K., Morimoto T., Katayama K.

PLoS Pathogens (PLoS Pathogens) 17 ( 10 ) e1009542 2021.10

ISSN 15537366

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.

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Upregulation of FGF9 in lung adenocarcinoma transdifferentiation to small cell lung cancer

Ishioka K., Yasuda H., Hamamoto J., Terai H., Emoto K., Kim T.J., Hirose S., Kamatani T., Mimaki S., Arai D., Ohgino K., Tani T., Masuzawa K., Manabe T., Shinozaki T., Mitsuishi A., Ebisudani T., Fukushima T., Ozaki M., Ikemura S., Kawada I., Naoki K., Nakamura M., Ohtsuka T., Asamura H., Tsuchihara K., Hayashi Y., Hegab A.E., Kobayashi S.S., Kohno T., Watanabe H., Ornitz D.M., Betsuyaku T., Soejima K., Fukunaga K.

Cancer Research (Cancer Research) 81 ( 14 ) 3916 - 3929 2021.07

ISSN 00085472

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9–FGFR axis as a therapeutic target for transdifferentiated SCLC.

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Direct derivation of human alveolospheres for SARS-CoV-2 infection modeling and drug screening

Ebisudani T., Sugimoto S., Haga K., Mitsuishi A., Takai-Todaka R., Fujii M., Toshimitsu K., Hamamoto J., Sugihara K., Hishida T., Asamura H., Fukunaga K., Yasuda H., Katayama K., Sato T.

Cell Reports (Cell Reports) 35 ( 10 ) 109218 2021.06

Although the main cellular target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is thought to be alveolar cells, the absence of their tractable culture system precludes the development of a clinically relevant SARS-CoV-2 infection model. Here, we establish an efficient human alveolosphere culture method and sphere-based drug testing platform for SARS-CoV-2. Alveolospheres exhibit indolent growth in a Wnt- and R-spondin-dependent manner. Gene expression, immunofluorescence, and electron microscopy analyses reveal the presence of alveolar cells in alveolospheres. Alveolospheres express ACE2 and allow SARS-CoV-2 to propagate nearly 100,000-fold in 3 days of infection. Whereas lopinavir and nelfinavir, protease inhibitors used for the treatment of human immunodeficiency virus (HIV) infection, have a modest anti-viral effect on SARS-CoV-2, remdesivir, a nucleotide prodrug, shows an anti-viral effect at the concentration comparable with the circulating drug level. These results demonstrate the validity of the alveolosphere culture system for the development of therapeutic agents to combat SARS-CoV-2.

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Trends of concerns from diagnosis in patients with advanced lung cancer and their family caregivers: A 2-year longitudinal study

Sato T., Fujisawa D., Arai D., Nakachi I., Takeuchi M., Nukaga S., Kobayashi K., Ikemura S., Terai H., Yasuda H., Kawada I., Sato Y., Satomi R., Takahashi S., Hashiguchi M.H., Nakamura M., Oyamada Y., Terashima T., Sayama K., Saito F., Sakamaki F., Inoue T., Naoki K., Fukunaga K., Soejima K.

Palliative Medicine (Palliative Medicine) 35 ( 5 ) 943 - 951 2021.05

ISSN 02692163

Background: Both advanced cancer patients and their family caregivers experience distress and have a range of concerns after cancer diagnosis. However, longitudinal studies on this topic have been lacking. Aim: To investigate concerns in both patients with advanced lung cancer and their family caregivers longitudinally from diagnosis. Design: A multi-center prospective questionnaire-based study. Setting/participants: We recruited patients with newly diagnosed advanced lung cancer and their family caregivers at 16 hospitals in Japan. We prospectively assessed the prevalence of their concerns using the Concerns Checklist and investigated the associations between their concerns and mental status as well as quality of life until 24 months after diagnosis. Results: A total of 248 patients and their 232 family caregivers were enrolled. The prevalence of serious concerns was highest at diagnosis (patients: 68.3%, family caregivers: 65.3%). The most common serious concern was concern about the future in both groups at diagnosis (38.2% and 40.5%, respectively) and this remained high in prevalence over time, while the high prevalence of concern about lack of information improved 3 months after diagnosis in both groups. Approximately one-third of patient-family caregiver dyads had discrepant reports of serious concerns. The presence of serious concerns was significantly associated with anxiety and depression continuously in both groups. Conclusions: The majority of advanced lung cancer patients and their family caregivers have serious concerns from diagnosis, which is associated with their psychological distress. The spectrum of concerns alters over the disease trajectory, warranting efficient tailored care and support for both groups immediately after diagnosis.

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HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.

Watanabe S, Goto Y, Yasuda H, Kohno T, Motoi N, Ohe Y, Nishikawa H, Kobayashi SS, Kuwano K, Togashi Y

Thoracic cancer 2021.01

ISSN 1759-7706

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Functional dissection of the KRAS G12C mutation by comparison among multiple oncogenic driver mutations in a lung cancer cell line model

Kobayashi K., Terai H., Yasuda H., Hamamoto J., Hayashi Y., Takeuchi O., Mitsuishi Y., Masuzawa K., Manabe T., Ikemura S., Kawada I., Suzuki Y., Soejima K., Fukunaga K.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 534 1 - 7 2021.01

ISSN 0006291X

© 2020 The Authors The development of molecular targeted therapy has improved clinical outcomes in patients with life-threatening advanced lung cancers with driver oncogenes. However, selective treatment for KRAS-mutant lung cancer remains underdeveloped. We have successfully characterised specific molecular and pathological features of KRAS-mutant lung cancer utilising newly developed cell line models that can elucidate the differences in driver oncogenes among tissues with identical genetic backgrounds. Among these KRAS-mutation-associated specific features, we focused on the IGF2-IGF1R pathway, which has been implicated in the drug resistance mechanisms to AMG 510, a recently developed selective inhibitor of KRAS G12C lung cancer. Experimental data derived from our cell line model can be used as a tool for clinical treatment strategy development through understanding of the biology of lung cancer. The model developed in this paper may help understand the mechanism of anticancer drug resistance in KRAS-mutated lung cancer and help develop new targeted therapies to treat patients with this disease.

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Basic Understandings of EGFR-mutated Lung Cancer and Its Clinical Applications

Yasuda H.

Japanese Journal of Lung Cancer (Japanese Journal of Lung Cancer) 61 ( 7 ) 911 - 918 2021

ISSN 03869628

In 2004, several groups reported the correlation between EGFR mutations and sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since then, multiple EGFR-TKIs have been developed, improving the prognosis of advanced EGFR-mutated lung cancer patients. However, most patients with advanced EGFR mutation-positive lung cancer die of lung cancer in less than five years, highlighting the need for the further development of effective therapies. To develop effective inhibitors or treatment strategies, a basic understanding of EGFR-mutated lung cancer is essential. In particular, the knowledge of how EGFR mutations activate EGFR kinase and how sensitivity to EGFR-TKIs is determined is important. In this review, I will summarize the knowledge and propose clinical insight on how to translate this basic knowledge into a clinical setting.

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An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Kawasaki K, Toshimitsu K, Matano M, Fujita M, Fujii M, Togasaki K, Ebisudani T, Shimokawa M, Takano A, Takahashi S, Ohta Y, Nanki K, Igarashi R, Ishimaru K, Ishida H, Sukawa Y, Sugimoto S, Saito Y, Maejima K, Sasagawa S, Lee H, Kim HG, Ha K, Hamamoto J, Fukunaga K, Maekawa A, Tanabe M, Ishihara S, Hamamoto Y, Yasuda H, Sekine S, Kudo A, Kitagawa Y, Kanai T, Nakagawa H, Sato T

Cell 2020.10

ISSN 0092-8674

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SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells.

Terai H, Hamamoto J, Emoto K, Masuda T, Manabe T, Kuronuma S, Kobayashi K, Masuzawa K, Ikemura S, Nakayama S, Kawada I, Suzuki Y, Takeuchi O, Suzuki Y, Ohtsuki S, Yasuda H, Soejima K, Fukunaga K

Molecular cancer research : MCR 2020.10

ISSN 1541-7786

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Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study.

Ishii M, Terai H, Kabata H, Masaki K, Chubachi S, Tateno H, Nakamura M, Nishio K, Koh H, Watanabe R, Ueda S, Terashima T, Suzuki Y, Yagi K, Miyao N, Minematsu N, Inoue T, Nakachi I, Namkoong H, Okamori S, Ikemura S, Kamata H, Yasuda H, Kawada I, Hasegawa N, Fukunaga K, Keio COVID-19 Research Consortium (K-CORC) and the Keio Donner Project Team.

The Journal of infection 2020.09

ISSN 0163-4453

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Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study.

Kakimi K, Matsushita H, Masuzawa K, Karasaki T, Kobayashi Y, Nagaoka K, Hosoi A, Ikemura S, Kitano K, Kawada I, Manabe T, Takehara T, Ebisudani T, Nagayama K, Nakamura Y, Suzuki R, Yasuda H, Sato M, Soejima K, Nakajima J

Journal for immunotherapy of cancer 8 ( 2 ) 2020.09

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Abstract 365: The role of protein fucosylation in lung cancer progression

Keita Masuzawa, Hiroyuki Yasuda, Atsushi Matsuda, Hideki Terai, Yuki Sugiura, Junko Hamamoto, Daisuke Arai, Shizuko Kagawa, Katsura Emoto, Shinnosuke Ikemura, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga

Tumor Biology (American Association for Cancer Research) 80 ( 16_Supplement ) 365 - 365 2020.08

ISSN 0008-5472

Abstract

Lung cancer is the leading cause of cancer-associated deaths worldwide. Metabolic reprogramming facilitates the growth advantage of cancer cells and is a hallmark of cancer. Although multiple studies have investigated the cancer-specific metabolic status of lung cancer, it remains unclear. Aberrant fucosylation, which results from the deficiency or overexpression of fucosyltransferases, is also associated with a variety of cancers, including lung cancer. However, the role and regulatory mechanism(s) of fucosylation in lung cancer remain largely unknown. In order to elucidate the specific metabolic status of human lung cancer tissues, we performed metabolomics profiling of paired tumor and normal tissues from patients with non-small cell lung cancer (NSCLC) using both capillary electrophoresis mass-spectrometry (CE-MS) and imaging mass-spectrometry (I-MS). We used principle component analysis (PCA) to confirm that human lung cancer has distinctive metabolic patterns. We revealed upregulation of the GDP-L-fucose de novo pathway, which regulates the level of fucosylated glycoproteins, in lung cancer tissues compared to the adjacent non-malignant lung tissues. In order to elucidate the mechanisms by which fucosylation is increased in lung cancer tissues, gene expression of fucosyltransferases (FUT1-9) were evaluated. We confirmed that fucosyltransferase 3 (FUT3) expression was increased in a significant proportion of human primary lung adenocarcinoma samples and was correlated with sLeX expression. A fucosylation inhibitor, 6-alkynyl-fucose, inhibited the proliferation and invasion of lung cancer cell lines with high endogenous FUT3 expression in vitro. Exogenous FUT3-overexpressing lung cancer cells did not show increased proliferation, but showed significantly increased invasion and adhesion activities in vitro. In order to confirm whether FUT3 promoted metastasis of A549 cells in an experimental lung metastatic mouse model, A549 lung cancer cells expressing EGFP (A549-EGFP) and A549 lung cancer cells overexpressing FUT3 (A549-FUT3) were intravenously administered to BALB/C nude mice and the numbers of metastatic nodules in the lungs were counted after 8 weeks. In concordance with our observations in vitro, there was no significant difference in tumor growth between the A549-EGFP and A549-FUT3 treatments in vivo. Interestingly, injection of A549-FUT3 resulted in an increase in the number of lung metastases compared to the injection of A549-EGFP, suggesting that FUT3 is a positive regulator of cancer invasion and metastasis. Furthermore, high expression of FUT3 in lung cancer tissues predicted a poorer prognosis for patients with lung adenocarcinoma. These findings highlight the important roles of protein fucosylation in lung cancer progression and provide the preclinical rationale to target this pathway in lung cancer treatment.

Citation Format: Keita Masuzawa, Hiroyuki Yasuda, Atsushi Matsuda, Hideki Terai, Yuki Sugiura, Junko Hamamoto, Daisuke Arai, Shizuko Kagawa, Katsura Emoto, Shinnosuke Ikemura, Ichiro Kawada, Kenzo Soejima, Koichi Fukunaga. The role of protein fucosylation in lung cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 365.

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Correction: EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas.

Jorge SE, Lucena-Araujo AR, Yasuda H, Piotrowska Z, Oxnard GR, Rangachari D, Huberman MS, Sequist LV, Kobayashi SS, Costa DB

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 9 ) 2277 2020.05

ISSN 1078-0432

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IGF2 Autocrine-mediated IGF1R activation is a clinically relevant mechanism of osimertinib resistance in Lung Cancer

Manabe T., Yasuda H., Terai H., Kagiwa H.D.A., Hamamoto J., Ebisudani T., Kobayashi K., Masuzawa K., Ikemura S., Kawa I.D.A., Hayashi Y., Fukui K., Horimoto K., Fukunaga K., Soeji K.M.A.

Molecular Cancer Research (Molecular Cancer Research) 18 ( 4 ) 549 - 559 2020.04

ISSN 15417786

© 2020 American Association for Cancer Research. EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a thirdgeneration EGFR tyrosine kinase inhibitor, is extensively used as a first-line or second-line treatment. However, lung cancer cells acquire resistance to osimertinib in 1 to 2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, nongenetically defined mechanisms are not well evaluated. For a thorough clarification of osimertinib resistance, both genetic and nongenetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for a thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-Autonomous ligand expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a nongenetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level.

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Intracellular levels of reactive oxygen species correlate with ABT-263 sensitivity in non-small-cell lung cancer cells

Ohgino K., Terai H., Yasuda H., Nukaga S., Hamamoto J., Tani T., Kuroda A., Arai D., Ishioka K., Masuzawa K., Ikemura S., Kawada I., Naoki K., Fukunaga K., Soejima K.

Cancer Science (Cancer Science) 2020

ISSN 13479032

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. ABT-263 (Navitoclax) is a BH3-mimetic drugs targeting anti-apoptotic B-cell lymphoma-2 (BCL-2) family proteins, including BCL-2, BCL-xL, and BCL-w, thereby inducing apoptosis. In small-cell lung cancer (SCLC) cells, the response to ABT-263 is associated with the expression of myeloid cell leukemia-1 (MCL-1) protein, however the efficacy of ABT-263 in non-small-cell lung cancer (NSCLC) has not been thoroughly evaluated. There are currently no established biomarkers for predicting the efficacy of ABT-263 treatment in NSCLC. We screened a panel of different NSCLC cell lines and found that ABT-263 inhibited cell proliferation and induced apoptosis in Calu-1, Calu-3, and BID007 cells. Inconsistent with previous reports on SCLC, low levels of MCL-1 did not predict the response to ABT-263 in NSCLC cells, however we found that intracellular levels of reactive oxygen species (ROS) in cancer cells were associated with sensitivity to ABT-263 in NSCLC cells. We also showed that increasing the level of intracellular ROS could enhance the sensitivity to ABT-263 in NSCLC cells. In summary, we propose that the intracellular levels of ROS could be used as a potential novel biomarker for predicting a response to ABT-263 in NSCLC. Furthermore, we show some evidence supporting the further assessment of ABT-263 as a new therapeutic strategy in patients with NSCLC combined with agents regulating ROS levels. We believe that our findings and follow-up studies on this matter would lead to novel diagnostic and treatment strategies in patients with NSCLC.

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TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations.

Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS

Molecular cancer research : MCR (Molecular Cancer Research) 17 ( 11 ) 2233 - 2243 2019.08

ISSN 1541-7786

© 2019 American Association for Cancer Research. Despite the worldwide approval of three generations of EGFR tyrosine kinase inhibitors (TKI) for advanced non- small cell lung cancers with EGFR mutations, no TKI with a broad spectrum of activity against all clinically relevant mutations is currently available. In this study, we sought to evaluate a covalent mutation-specific EGFR TKI, TAS6417 (also named CLN-081), with the broadest level of activity against EGFR mutations with a prevalence of ≥1%. Lung cancer and genetically engineered cell lines, as well as murine xenograft models were used to evaluate the efficacy of TAS6417 and other approved/in-development EGFR TKIs (erlotinib, afatinib, osimertinib, and poziotinib). We demonstrate that TAS6417 is a robust inhibitor against the most common EGFR mutations (exon 19 deletions and L858R) and the most potent against cells harboring EGFR-T790M (first/second-generation TKI resistance mutation). In addition, TAS6417 has activity in cells driven by less common EGFR-G719X, L861Q, and S768I mutations. For recalcitrant EGFR exon 20 insertion mutations, selectivity indexes (wildtype EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window. Taken together, we demonstrate that TAS6417 is a potent EGFR TKI with a broad spectrum of activity and a wider therapeutic window than most approved/in-development generations of EGFR inhibitors.

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Preclinical evaluation of TAS6417 as a highly effective, pan-mutation-selective EGFR tyrosine kinase inhibitor

Hibiki Udagawa, Shinichi Hasako, Akihiro Ohashi, Naomi Abe, Tomonori Haruma, Toshiharu Komori, Miki Terasaka, Ryoto Fujita, Kaoru Funabashi, Hiroyuki Yasuda, Kazutaka Miyadera, Koichi Goto, Daniel B. Costa, Susumu S. Kobayashi

CANCER RESEARCH (AMER ASSOC CANCER RESEARCH) 79 ( 13 ) 2019.07

ISSN 0008-5472

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Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations

Ikemura S., Yasuda H., Matsumoto S., Kamada M., Hamamoto J., Masuzawa K., Kobayashi K., Manabe T., Arai D., Nakachi I., Kawada I., Ishioka K., Nakamura M., Namkoong H., Naoki K., Ono F., Araki M., Kanada R., Ma B., Hayashi Y., Mimaki S., Yoh K., Kobayashi S., Kohno T., Okuno Y., Goto K., Tsuchihara K., Soejima K.

Proceedings of the National Academy of Sciences of the United States of America (Proceedings of the National Academy of Sciences of the United States of America) 116 ( 20 ) 10025 - 10030 2019.05

ISSN 00278424

© 2019 National Academy of Sciences. All rights reserved. Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of EGFR mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot EGFR mutations (n = 3,779) revealed that the majority (>90%) of cases with rare EGFR mutations, accounting for 5.5% of the cohort subjects, did not receive EGFR-tyrosine kinase inhibitors (TKIs) as a first-line treatment. To tackle this problem, we applied a molecular dynamics simulation-based model to predict the sensitivity of rare EGFR mutants to EGFR-TKIs. The model successfully predicted the diverse in vitro and in vivo sensitivities of exon 20 insertion mutants, including a singleton, to osimertinib, a third-generation EGFR-TKI (R2 = 0.72, P = 0.0037). Additionally, our model showed a higher consistency with experimentally obtained sensitivity data than other prediction approaches, indicating its robustness in analyzing complex cancer mutations. Thus, the in silico prediction model will be a powerful tool in precision medicine for NSCLC patients carrying rare EGFR mutations in the clinical setting. Here, we propose an insight to overcome mutation diversity in lung cancer.

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Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations

Hasegawa H., Yasuda H., Hamamoto J., Masuzawa K., Tani T., Nukaga S., Hirano T., Kobayashi K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

Lung Cancer (Lung Cancer) 127 146 - 152 2019.01

ISSN 01695002

© 2018 Elsevier B.V. Objectives: Epidermal growth factor receptor (EGFR) mutation-positive lung cancer accounts for a significant subgroup of non-small cell lung cancers (NSCLC). Approximately 4–10% of EGFR mutations in NSCLC are EGFR exon 20 insertion mutations, which are reportedly associated with resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. NSCLC patients carrying these mutations are rarely treated with EGFR-TKIs. The purpose of this study was to evaluate the efficacy of afatinib or osimertinib plus cetuximab combination therapy in experimental NSCLC models with EGFR exon 20 insertion mutations. Materials and methods: The EGFR mutations examined in this study were A763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNPG. Ba/F3 cells constitutively expressing wild type or mutated EGFR were used to determine the efficacy of afatinib or osimertinib plus cetuximab combination therapy in vitro. To determine the efficacy of the combination therapy in vivo, female BALB/c-nu mice were injected subcutaneously with 1 million Ba/F3 cells carrying EGFR A767_V769dupASV or Y764_V765insHH. Results: We observed a mild but significant (P < 0.05) additive effect of the combination therapy against several EGFR exon 20 insertion mutations in vitro. Regarding EGFR A767_V769dupASV and EGFR Y764_V765insHH, cetuximab and afatinib single treatment did not induce significant inhibition of tumor formation; however, afatinib plus cetuximab combination treatment induced significant (P < 0.05) tumor growth inhibition without significant body weight loss or skin rash. Conclusion: The combination therapy induced a more potent inhibitory effect against several EGFR exon 20 insertion mutations than either therapy alone. Cetuximab can potentially increase the efficacy of afatinib or osimertinib in NSCLC with EGFR exon 20 insertion mutations.

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Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts

Hegab A., Ozaki M., Kameyama N., Gao J., Kagawa S., Yasuda H., Soejima K., Yin Y., Guzy R., Nakamura Y., Ornitz D., Betsuyaku T.

Journal of Pathology (Journal of Pathology) 249 ( 2 ) 193 - 205 2019

ISSN 00223417

Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Cancer-associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)-dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma-like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF-secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell-recruiting cytokines. CAFs also enhanced the conversion of tumour-associated macrophages (TAMs) to the tumour-supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr-independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9-induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Monomer preference of EGFR tyrosine kinase inhibitors influences the synergistic efficacy of combination therapy with cetuximab

Oashi A., Yasuda H., Kobayashi K., Tani T., Hamamoto J., Masuzawa K., Manabe T., Terai H., Ikemura S., Kawada I., Naoki K., Soejima K.

Molecular Cancer Therapeutics (Molecular Cancer Therapeutics) 18 ( 9 ) 1593 - 1601 2019

ISSN 15357163

© 2019 American Association for Cancer Research. EGFR-mutated lung cancer is a significant subgroup of non–small cell lung cancer. To inhibit EGFR-mediated signals, multiple EGFR tyrosine kinase inhibitors (EGFR-TKI) have been developed; however, approximately one third of patients with EGFR-mutated lung cancer do not respond to EGFR-TKIs. More effective inhibition of EGFR-mediated signals is therefore necessary. For cancers expressing mutated EGFR, including EGFR T790M, which confers resistance to first- (gefitinib and erlotinib) and second- (afatinib) generation EGFR-TKIs, the synergistic efficacy of afatinib and cetuximab combination therapy has been reported in preclinical and clinical studies; however, the mechanisms underlying this effect remain elusive. In this study, we evaluated the effects of multiple EGFR-TKIs on the EGFR monomer–dimer equilibrium by inducing dimerization-impairing mutations in cells expressing EGFR. Interestingly, we found that afatinib and dacomitinib exhibit a monomer preference: cells expressing dimerization-impaired EGFR mutants exhibited increased sensitivity to afatinib and dacomitinib relative to those with dimerization-competent EGFR mutants. Although EGFR-TKIs themselves induce dimerization of EGFR, the inhibition of dimerization by cetuximab overcame EGFR-TKI–induced dimerization. By shifting the monomer–dimer equilibrium toward monomer dominance using cetuximab, the effectiveness of afatinib and dacomitinib improved significantly. We report a novel and clinically relevant phenomenon, the monomer preference of EGFR-TKIs, which can explain the mechanism underlying the synergism observed in afatinib and cetuximab combination therapy. In addition, we propose the novel concept that monomer–dimer equilibrium is an important factor in determining EGFR-TKI efficacy. These findings provide novel insights into treatment strategies for EGFR-TKI–refractory non–small cell lung cancer.

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A phase II trial of induction of erlotinib followed by cytotoxic chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer patients

Tani T., Naoki K., Yasuda H., Arai D., Ishioka K., Ohgino K., Yoda S., Nakayama S., Satomi R., Terai H., Ikemura S., Sato T., Soejima K.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 84 ( 5 ) 1065 - 1071 2019

ISSN 03445704

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Background: No consensus has been reached regarding the treatment order and timing of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and cytotoxic chemotherapy administration for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. Methods: In this phase II trial, chemotherapy-naïve patients harboring activating EGFR mutations with stage IIIB/IV or post-surgical recurrent non-squamous NSCLC were enrolled. Patients were treated with erlotinib induction at 150 mg/day for 3 months. This was followed by cytotoxic chemotherapy with platinum plus pemetrexed, with or without bevacizumab, when the induction erlotinib achieved a CR or PR. The primary end point was the 1-year progression-free survival (PFS) rate, while the secondary end points were the response rate (RR), PFS, safety, and overall survival (OS). Results: Twenty patients were enrolled in this study. The median age was 63 years. Eighteen patients had stage IV disease, and 2 patients had recurrent disease. Eleven patients achieved a PR after induction of erlotinib and 9 out of 11 patients were switched to chemotherapy. The 1-year PFS rate was 45.0% (90% CI 26.8–63.2), the overall RR was 55.0%, and the median PFS was 10.7 months in the intention-to-treat (ITT) population. Grade 3–4 adverse events were reported for 40% of the patients, including patients with leukopenia (10%), neutropenia (20%), and interstitial pneumonitis, bacterial pneumonia, rash, and nausea (all 5%). Conclusions: The primary end point of this study was not achieved. However, the therapy was well tolerated and may be a treatment option for a future study with patients responsive to short-term erlotinib treatment. Clinical trials registration number: UMIN ID: 000013125.

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Long-lasting response to nivolumab for a patient with lynch syndrome-associated lung adenocarcinoma

Masuzawa K., Asakura T., Ikemura S., Yasuda H., Kawada I., Takaoka S., Hayashi Y., Nakajima T., Arai M., Fukunaga K., Soejima K.

JCO Precision Oncology (JCO Precision Oncology) 3 74 - 78 2019

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EGFR exon 20 insertion mutations display sensitivity to HSP90 inhibition in preclinical models and lung adenocarcinomas

Jorge S., Lucena-Araujo A., Yasuda H., Piotrowska Z., Oxnard G., Rangachari D., Huberman M., Sequist L., Kobayashi S., Costa D.

Clinical Cancer Research (Clinical Cancer Research) 24 ( 24 ) 6548 - 6555 2018.12

ISSN 10780432

© 2018 American Association for Cancer Research. Purpose: EGFR exon 20 insertions account for up to 10% of all EGFR mutations in lung adenocarcinomas, representing the third most common cluster of mutations. The management of advanced cancers with these mutations remains elusive, without an approved inhibitor. Experimental Design: Preclinical models of a representative set of EGFR exon 20 insertion mutations to evaluate the efficacy of different inhibitors and description of the clinical outcome of an advanced lung cancer. Results: We show that select first-, second-, and third-generation EGFR inhibitors are unable to deter common EGFR exon 20 insertion mutants in concentrations that spare the wild-type kinase. Nonetheless, EGFR exon 20 insertion mutants associate with the Hsp90 chaperone system. We exploit this vulnerability to show that the nongeldanamycin Hsp90 inhibitor luminespib (formerly AUY922) degrades EGFR exon 20 mutations, downstream targets, and induces apoptosis. In addition, a patient whose EGFR inhibitor–insensitive lung adenocarcinoma harbored an EGFR exon 20 insertion mutation had a confirmed radiographic response to luminespib. Conclusions: The report confirms that EGFR exon 20 mutations are dependent on Hsp90 and are readily inhibited by the Hsp90 inhibitor luminespib; a treatment strategy that has been pursued in a confirmatory clinical trial (NCT01854034) for this group of lung adenocarcinomas that currently represent an unmet clinical need in precision oncology.

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Prognostic Understanding at Diagnosis and Associated Factors in Patients with Advanced Lung Cancer and Their Caregivers.

Sato T, Soejima K, Fujisawa D, Takeuchi M, Arai D, Nakachi I, Naoki K, Kawada I, Yasuda H, Ishioka K, Nukaga S, Kobayashi K, Masaki K, Inoue T, Hikima K, Nakamura M, Ohgino K, Oyamada Y, Funatsu Y, Terashima T, Miyao N, Sayama K, Saito F, Sakamaki F, Betsuyaku T

The oncologist (Oncologist) 23 ( 10 ) 1218 - 1229 2018.10

ISSN 1083-7159

© AlphaMed Press 2018 Background: Prognostic understanding in advanced cancer patients and their caregivers may have an impact on the delivery of effective care. The aims of this study were to explore prognostic understanding at diagnosis in both patients with advanced lung cancer and their caregivers and to investigate correlates of their understanding. Subjects, Materials, and Methods: A total of 193 patients with newly diagnosed advanced lung cancer and their 167 caregivers were enrolled at 16 hospitals in Japan. We assessed their perceptions of prognosis and goals of therapy and examined their associations with their sociodemographic characteristics, clinical status, quality of life, mood symptoms, and the status of disclosure of information by their treating physicians. Results: One fifth of patients and caregivers (21.7% and 17.6%, respectively) mistakenly believed that the patients’ cancer was “completely curable.” Substantial proportions of them (16.9% and 10.3%, respectively) mistakenly believed that the primary goal of therapy was to remove all the cancer. Levels of anxiety and depression in both patients and caregivers were significantly higher among those who had accurate understanding of prognosis. In multivariate analyses, inaccurate perceptions of prognosis in patients were associated with sex, better emotional well-being, and lower lung cancer-specific symptom burden. Caregivers’ inaccurate perceptions of patients’ prognoses were associated with better performance status and better emotional well-being of patients. Conclusion: Substantial proportions of advanced lung cancer patients and their caregivers misunderstood their prognosis. Interventions to improve their accurate prognostic understanding should be developed with careful attention paid to its associated factors. Implications for Practice: This study demonstrated that substantial proportions of patients with newly diagnosed advanced lung cancer and their caregivers had misunderstandings about their prognosis. Accurate perceptions of prognosis, which are indispensable in the delivery of effective care, were associated with elevated levels of anxiety and depression in both patients and caregivers, warranting psychosocial care and support for them immediately after diagnosis. Inaccurate perceptions of prognosis in patients were associated with better emotional well-being and lower lung cancer-specific symptom burden. Illness understanding in caregivers was associated with patients’ physical and mental status. Those findings provide insight into how they obtain accurate illness understanding.

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The FGF2 aptamer inhibits the growth of FGF2-FGFR pathway driven lung cancer cells

Hamamoto J., Yasuda H., Nonaka Y., Fujiwara M., Nakamura Y., Soejima K., Betsuyaku T.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 503 ( 3 ) 1330 - 1334 2018.09

ISSN 0006291X

© 2018 Elsevier Inc. Cancers, including lung cancer, are a leading cause of death worldwide. To overcome this deadly disease, multiple modality inhibitors have been developed. These include cytotoxic agents, molecular targeted small molecules, such as tyrosine kinase inhibitors, and neutralizing antibodies. An aptamer is a short single-stranded nucleic acid molecule that is selected in vitro from a large random sequence library based on its high and specific affinity to a target molecule. Aptamers can be applied to therapeutics of various types of diseases, including cancer, due to their strong and specific neutralizing activities. However, the efficacy of aptamer-based therapy for cancer cells is not well characterized. In this study, we aimed to show that the FGF2 aptamer is effective for the treatment of FGF2 dependent lung cancer cells. We previously developed PC9GR lung cancer cells, whose proliferation is dependent on EGFR and FGF2-FGFR pathways in a cell autonomous manner. Using PC9GR cells, we demonstrate that the addition of the FGF2 aptamer induces more significant inhibition of PC9GR cell proliferation than does the addition of EGFR inhibitor alone. Furthermore, the addition of the FGF2 aptamer more significantly inhibits the downstream signals and induces apoptosis to a higher extent than does the addition of EGFR inhibitor alone. Our results show that the FGF2 aptamer inhibits the growth of FGF2-FGFR pathway-dependent lung cancer cells. The findings provide preclinical evidence that aptamers can be useful for cancer treatment.

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Intermittent exposure to cigarette smoke increases lung tumors and the severity of emphysema more than continuous exposure

Kameyama N., Chubachi S., Hegab A., Yasuda H., Kagawa S., Tsutsumi A., Fukunaga K., Shimoda M., Kanai Y., Soejima K., Betsuyaku T.

American Journal of Respiratory Cell and Molecular Biology (American Journal of Respiratory Cell and Molecular Biology) 59 ( 2 ) 179 - 188 2018.08

ISSN 10441549

Copyright © 2018 by the American Thoracic Society. Lung cancer and chronic obstructive pulmonary disease are leading causes of morbidity and mortality worldwide, and cigarette smoking is a main risk factor for both. The presence of emphysema, an irreversible lung disease, further raises the risk of lung cancer in patients with chronic obstructive pulmonary disease. The mechanisms involved in smoke-induced tumorigenesis and emphysema are not fully understood, attributable to a lack of appropriate animal models. Here, we optimized a model of cigarette smoke (CS)–induced lung cancer and emphysema in A/J mice treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a potent carcinogen. We investigated whether variations in CS exposure patterns with the same total amount and duration of exposure affect tumorigenesis and/or development of emphysema. Continuous CS exposure for 3 months significantly suppressed 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone–induced development of adenomas and adenocarcinomas; however, emphysema independently developed during this period. Surprisingly, intermittent CS exposure increased the severity of emphysema and resulted in a higher incidence of adenocarcinomas. Furthermore, intermittent CS exposure elicited a marked increase in M2-polarized macrophages within and near the developed tumors. By employing a CS exposure protocol with repeated cycles of cessation and relapse, we provide evidence that intermittent CS exposure enhances tumorigenesis and emphysema progression more than that of continuous CS exposure.

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Comparison of detection methods of EGFR T790M mutations using plasma, serum, and tumor tissue in EGFR-TKI-resistant non-small cell lung cancer

Kobayashi K., Naoki K., Manabe T., Masuzawa K., Hasegawa H., Yasuda H., Kawada I., Soejima K., Betsuyaku T.

OncoTargets and Therapy (OncoTargets and Therapy) 11 3335 - 3343 2018.06

© 2018 Kobayashi et al. Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor, exerts remarkable effects against EGFR T790M resistance mutation-positive non-small cell lung cancer. Identifying T790M mutation by re-biopsy is essential before prescribing osimertinib. Tissue biopsy is the golden standard for this purpose, but several factors limit its success rate. The liquid biopsy with blood, using circulating tumor DNA, has been an alternative method. However, the true biological meaning and equivalence of liquid biopsy and tumor biopsy are still under investigation. Especially, the usefulness of serum samples to detect T790M mutation is not yet been known. Patients and methods: We prospectively evaluated the sensitivity, specificity, and parallelism of the detection of EGFR mutations in tissue re-biopsy and liquid biopsy (plasma and serum), simultaneously, from June 2016 to May 2017. EGFR mutations in tumor re-biopsy were evaluated by COBAS ver2 and PNA-LNA PCR clamp method, and those in liquid biopsy were evaluated with COBAS ver2. Results: Fifteen patients were enrolled. In 10 patients whose EGFR mutation was detected in liquid biopsy, the original EGFR mutation (exon 19 del or L858R) was detected in all patients. Detection of EGFR mutation by COBAS ver2 and by PNA-LNA method was almost the same in tissue re-biopsy. The detection rate of T790M was lower than that of the original EGFR mutation in liquid biopsy compared to that in tissue re-biopsy. The detection of T790M in serum exhibited a higher specificity (67%) and positive predictive value (50%) than that in plasma (50% and 40%, respectively). The detection sensitivity was similar in plasma and serum. Conclusion: Plasma, serum, and tissue genotyping can have complementary roles for detecting EGFR-T790M using COBAS ver2. Repeated tests with different samples and different methods may improve accuracy of T790M detection and will lead to the maximum benefit for the patient.

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Real-world Efficacy and Safety of Nivolumab for Advanced Non–Small-cell Lung Cancer: A Retrospective Multicenter Analysis

Kobayashi K., Nakachi I., Naoki K., Satomi R., Nakamura M., Inoue T., Tateno H., Sakamaki F., Sayama K., Terashima T., Koh H., Abe T., Nishino M., Arai D., Yasuda H., Kawada I., Soejima K., Betsuyaku T.

Clinical Lung Cancer (Clinical Lung Cancer) 19 ( 3 ) e349 - e358 2018.05

ISSN 15257304

© 2018 Elsevier Inc. We evaluated the real-world efficacy and safety of nivolumab in 142 patients with advanced non–small-cell lung cancer in Japan and identified the clinical characteristics that influence the efficacy. Negative EGFR/ALK mutation status and previous radiotherapy were significantly associated statistically with the treatment response. These findings might aid in the efficient immunotherapeutic management of lung cancer. Background: Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non–small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy. Materials and Methods: A total of 142 patients with advanced non–small-cell lung cancer who were administered nivolumab at Keio University and affiliated hospitals in Japan from January to July 2016 were enrolled. The treatment efficacy and adverse events were retrospectively reviewed, and the clinical characteristics associated with the nivolumab response were evaluated using univariate and stratified analyses and the Cochran-Mantel-Haenszel test. Results: The objective response rate was 17.0% (95% confidence interval [CI], 12.0%-24.0%), the median progression-free survival (PFS) was 58 days (95% CI, 50-67 days), and the proportion of patients with adverse events of any grade was 45.0%. EGFR/ALK mutation status was inversely associated with the treatment response (P <.05), and the difference in PFS for the mutation-positive versus mutation-negative patients was statistically significant (49 vs. 63 days; hazard ratio, 1.9; 95% CI, 1.1-5.2; P =.029). Previous radiotherapy also had a positive association with the treatment response (P =.012). Conclusion: The objective response rate, PFS, and adverse event profiles were comparable to those observed in previous clinical trials. EGFR/ALK mutation-negative status and previous radiotherapy might be key clinical characteristics associated with a positive treatment response. Our findings could aid in the efficient immunotherapeutic management of lung cancer.

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Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms

Hegab A., Ozaki M., Kagawa S., Hamamoto J., Yasuda H., Naoki K., Soejima K., Yin Y., Kinoshita T., Yaguchi T., Kawakami Y., Ornitz D., Betsuyaku T.

Lung Cancer (Lung Cancer) 119 25 - 35 2018.05

ISSN 01695002

© 2018 Elsevier B.V. Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. Materials and methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.

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Pharmacological and structural characterizations of naquotinib, a novel third-generation EGFR tyrosine kinase inhibitor, in EGFR-mutated non–small cell lung cancer

Hirano T., Yasuda H., Hamamoto J., Nukaga S., Masuzawa K., Kawada I., Naoki K., Niimi T., Mimasu S., Sakagami H., Soejima K., Betsuyaku T.

Molecular Cancer Therapeutics (Molecular Cancer Therapeutics) 17 ( 4 ) 740 - 750 2018.04

ISSN 15357163

© 2018 American Association for Cancer Research. Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) have been developed to effectively inhibit EGFR-derived signals in non–small cell lung cancer (NSCLC). In this study, we assessed the efficacy of EGFR-TKIs, including a novel third-generation inhibitor naquotinib (ASP8273), in clinically relevant EGFR mutations, including L858R, exon 19 deletion, L858RþT790M, exon 19 deletionþT790M with or without a C797S mutation, and several exon 20 insertion mutations. Using structural analyses, we also elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. The efficacy of naquotinib in cells with L858R, exon 19 deletion and exon 19 deletionþT790M was comparable with that of osimertinib. Interestingly, naquotinib was more potent than osimertinib for L858RþT790M. Additionally, naquotinib and osimertinib had comparable efficacy and a wide therapeutic window for cells with EGFR exon 20 insertions. Structural modeling partly elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in two EGFR exon 20 insertion mutants, A767_V769dupASV and Y764_V765insHH. In summary, we have characterized the efficacy of EGFR-TKIs for NSCLC using in vitro and structural analyses and suggested the mechanism of activation and resistance to EGFR-TKIs of EGFR exon 20 insertion mutations. Our findings should guide the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations and help clarify the biology of EGFR exon 20 insertion mutations.

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Targeted Therapy-induced Facial Skin Toxicities: Impact on Quality of Life in Cancer Patients

Yagasaki K., Komatsu H., Soejima K., Naoki K., Kawada I., Yasuda H., Hamamoto Y.

Asia-Pacific Journal of Oncology Nursing (Asia-Pacific Journal of Oncology Nursing) 5 ( 2 ) 172 - 177 2018.04

ISSN 23475625

© 2018 Medknow. All rights reserved. Objective: Targeted therapy-induced facial skin toxicities may reduce overall quality of life (QoL) in cancer patients. We investigated whether facial skin toxicities affect QoL and attempted to identify factors related to QoL in patients with advanced/recurrent cancer. Methods: We performed a cross-sectional study in 34 outpatients with advanced/recurrent cancer showing targeted therapy-induced facial skin toxicities in Japan between November 2016 and February 2017. For measurement, we used the Kessler Psychological Distress Scale (K6), Mental Adjustment to Cancer (MAC) Scale, and Dermatology Life Quality Index (DLQI). Data were analyzed using Spearman's rank correlation coefficient. Results: Mean DLQI score in 34 patients was 4.59 (standard deviation ± 4.70), which was interpreted as a small effect on a patient's life. Acneiform rash was the most common skin condition noted, followed by xerosis, pruritus, and erythema. Analysis of DLQI scores revealed that symptoms and feelings was the domain most commonly affected among different domains constituting the DLQI. MAC analysis revealed that the fighting spirit score was the highest among MAC scales. We found that age, K6, and fatalism construct in MAC were significantly correlated with total DLQI scores (age: Spearman's ρ= -0.48, P = 0.004; K6: ρ= 0.58, P < 0.001; fatalism; ρ= -0.39, P = 0.025). Conclusions: This is the first study investigating targeted therapy-induced facial skin toxicities in cancer patients. Our results suggest potential negative effects of facial skin toxicities on overall QoL in patients with advanced/recurrent cancer in middle and early old age.

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Secondary brain neoplasm after stereotactic radiosurgery in patients with metastatic non-small cell lung cancer

Nukaga S., Naoki K., Yasuda H., Kawada I., Ohara K., Soejima K., Betsuyaku T.

Internal Medicine (Internal Medicine) 57 ( 16 ) 2383 - 2387 2018

ISSN 09182918

© 2018 The Japanese Society of Internal Medicine. Stereotactic radiosurgery (SRS) using the Gamma Knife (GK) is now being increasingly utilized for the treatment of brain metastases. However, there are a few reported cases of SRS-induced brain neoplasms. We herein report the case of a Japanese woman with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR)-mutations who was treated four times with a GK for brain metastases. She developed glioblastoma 5.7 years after the initial GK surgery. Radiation-induced secondary neoplasms generally appear after a latency period of several years. Advances in cancer therapy have improved the survival of patients with NSCLC, providing enough time for secondary neoplasms to appear after SRS.

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Egfr-mutant non-small cell lung cancer accompanied by transient asymptomatic pulmonary opacities successfully treated with “stop-and-go” osimertinib

Kobayashi K., Naoki K., Kuroda A., Yasuda H., Kawada I., Soejima K., Betsuyaku T.

Internal Medicine (Internal Medicine) 57 ( 7 ) 1007 - 1010 2018

ISSN 09182918

© 2018 The Japanese Society of Internal Medicine. A 69-year-old man with post-operative recurrence of lung adenocarcinoma was treated with multiple che-motherapies, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A second biopsy revealed an EGFR T790M mutation. As 10th-line chemotherapy, osimertinib was initiated. After 24 weeks, chest computed tomography (CT) revealed asymptomatic ground-glass opacities in both lobes. After four weeks of osimertinib discontinuation, imaging revealed rapid lung cancer progression. Osimertinib was resumed. After 11 weeks, CT revealed decreased lung nodules with no exacerbation of interstitial lung disease. We describe a patient who experienced transient asymptomatic pulmonary opacities during treatment with osimertinib, which was successfully managed by a “stop-and-go” approach.

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Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports.

Okamori S, Asakura T, Masuzawa K, Yasuda H, Kamata H, Ishii M, Betsuyaku T

Medicine 96 ( 49 ) e9081 2017.12

Accepted, ISSN 0025-7974

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Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports

Okamori, S., Asakura, T., Masuzawa, K., Yasuda, H., Kamata, H., Ishii, M., Betsuyaku, T.

Medicine (United States) 96 ( 49 ) e9081 2017.12

ISSN 1536-5964

RATIONAL: The efficacy of nintedanib, a multitarget receptor tyrosine kinase inhibitor, has been demonstrated in recent randomized controlled trials involving patients with idiopathic pulmonary fibrosis (IPF). However, accelerated disease progression after nintedanib discontinuation has never been reported. PATIENT CONCERNS: We report 2 cases involving patients with a history of IPF who presented with respiratory deterioration at 3 weeks after the discontinuation of nintedanib therapy for IPF. Neither patient fulfilled the definition of "acute exacerbation of IPF" on unilateral computed tomography. DIAGNOSES: Accelerated disease progression after the discontinuation of nintedanib therapy for IPF. INTERVENTIONS: One patient received steroid therapy. The other patient refused to undergo steroid therapy. OUTCOMES: The first patient showed that the affected lobe exhibited volume loss with traction bronchiectasis after receiving steroid therapy, and succumbed to pneumothorax after 3 months. The other patient was transferred to another hospital because of a decline in his general condition. LESSONS: To our knowledge, this report is the first to document accelerated disease progression af

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Characterization of the efficacies of osimertinib and nazartinib against cells expressing clinically relevant epidermal growth factor receptor mutations

Masuzawa, K., Yasuda, H., Hamamoto, J., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Soejima, K., Betsuyaku, T.

Oncotarget 8 ( 62 ) 105479 - 105491 2017.12

ISSN 1949-2553

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Non-small cell lung cancer PC-9 cells exhibit increased sensitivity to gemcitabine and vinorelbine upon acquiring resistance to EGFR-tyrosine kinase inhibitors

Hamamoto, J., Yasuda, H., Aizawa, K., Nishino, M., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Betsuyaku, T. and Soejima, K.

Oncol Lett 14 ( 3 ) 3559 - 3565 2017.09

ISSN 1792-1074

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) are widely used for the treatment of non-small cell lung cancers (NSCLCs) harboring EGFR-activating mutations. However, lung cancer cells inevitably acquire resistance to these EGFR-TKIs. The majority of patients whose lung cancer acquires resistance to EGFR-TKIs are subjected to treatment using cytotoxic agents. The present study aimed to determine if lung cancer cells acquiring resistance to EGFR-TKIs also develop altered sensitivity to cytotoxic agents. It was revealed that lung cancer cells that had developed resistance to EGFR-TKIs had increased sensitivity to gemcitabine and vinorelbine compared with EGFR-TKI naive cells. The expression levels of ATP-binding cassette (ABC) transporter genes, including ABCC3, ABCC5 and ABCG2, were observed to be commonly repressed in EGFR-TKI-resistant cells. In addition, two cases were identified in which gemcitabine and vinorelbine exerted marked responses to lung cancers that had acquired resistance to EGFR-TKIs, even with late-line treatment. Therefore, it was proposed that gemcitabine and vinorelbine may be effective agents for patients with lung cancer previously treated with EGFR-TKIs.

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Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

Yotsukura, M., Yasuda, H., Shigenobu, T., Kaseda, K., Masai, K., Hayashi, Y., Hishida, T., Ohtsuka, T., Naoki, K., Soejima, K., Betsuyaku, T. and Asamura, H.

Lung Cancer 109 45 - 51 2017.07

ISSN 1872-8332

OBJECTIVES: Over the past decade, the biological and clinical characteristics of lung cancer with epidermal growth factor receptor (EGFR) mutation have been well studied. However, most studies have focused on advanced inoperable cancer, and not on resected early-stage lung adenocarcinoma. We aimed to elucidate the differences in the clinicopathological characteristics and postoperative prognosis according to the EGFR mutation status in early-stage lung adenocarcinoma. MATERIALS AND METHODS: We retrospectively collected clinical and pathological data from 369 patients with pathological stage I or II lung adenocarcinoma who underwent complete resection. Clinicopathological characteristics and postoperative prognosis were compared depending on the EGFR mutation status, using the Chi-squared test and the log-rank test, respectively. RESULTS AND CONCLUSION: Of the 369 patients, 160 (43.3%) had EGFR mutation, of which 64 (40.0%) were exon 19 deletion (Del-19) and 90 (56.3%) were exon 21 point mutation L858R. Although there was no difference in overall survival (OS) between patients with and without EGFR mutation (p=0.086), tumors with EGFR mutation were associated with a lower consolidation to tumor ratio (CTR) (p <0.001) and a higher incidence of a lepidic growth pattern by pathological evaluation (p <0.001) compared to those without EGFR mutation. Among tumors with EGFR mutation, there was no difference in OS (p=0.140) between Del-19 and L858R. Tumors with L858R were associated with a lower CTR (p=0.046), and tended to have a higher incidence of a lepidic growth pattern by pathological evaluation (p=0.073) compared to those with Del-19. In conclusion, although EGFR mutation status was not a prognostic indicator after surgery in early-stage lung adenocarcinoma, L858R and Del-19 had different radiological and pathological features.

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Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung

Kuroda, A., Hegab, A. E., Jingtao, G., Yamashita, S., Hizawa, N., Sakamoto, T., Yamada, H., Suzuki, S., Ishii, M., Namkoong, H., Asakura, T., Ozaki, M., Yasuda, H., Hamamoto, J., Kagawa, S., Soejima, K. and Betsuyaku, T.

Respir Res 18 ( 1 ) 69 2017.04

ISSN 1465-993X

BACKGROUND: Aldehyde dehydrogenases (ALDHs) play a major role in detoxification of aldehydes. High expression of ALDHs is a marker for stem cells of many organs including the lungs. A common polymorphism in ALDH2 gene (ALDH2*2) results in inactivation of the enzyme and is associated with alcohol flushing syndrome and increased risk for cardiovascular and Alzheimer's diseases and some cancers. The effect of this ALDH2 polymorphism on the lung and its stem cells has not been thoroughly examined. METHODS: We examined the association between the ALDH2*2 allele and lung function parameters in a population of healthy individuals. We also examined its association with the incidence of asthma and COPD in patient cohorts. We used the in vitro colony forming assay to detect the effect of the polymorphism on lung epithelial stem cells from both primary human surgical samples and Aldh2*2 transgenic (Tg) and Aldh2 -/- mice. Response to acute and chronic lung injuries was compared between wild type (WT), Aldh2*2 Tg and Aldh2 -/- mice. RESULTS: In humans, the ALDH2*2 allele was associated with lower FEV1/FVC in the general population, but not with the development of asthma or COPD. Both the bronchial and lung epithelium carrying the ALDH2*2 allele showed a tendency for lower colony forming efficiency (CFE) compared to ALDH2 allele. In mice, the tracheal epithelial thickness, nuclear density, and number of basal stem cells were significantly lower in Aldh2 -/- and Aldh2*2 Tg adult mice than in WT. Electron microscopy showed significantly increased number of morphologically abnormal mitochondria in the trachea of Aldh2 -/- mice. Aldh2 -/- tracheal and lung cells showed higher ROS levels and fewer functional mitochondria than those from WT mice. No significant differences were detected when tracheal and lung epithelial stem cells were examined for their in vitro CFE. When exposed to chronic cigarette smoke, Aldh2*2 Tg mice were resistant to emphysema development, whereas influenza infection caused more epithelial damage in Aldh2 -/- mice than in WT mice. CONCLUSIONS: ALDH2 polymorphism has several subtle effects on the lungs, some of which are similar to changes observed during normal aging, suggesting a "premature lung aging" effect.

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Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors

Nukaga, S., Yasuda, H., Tsuchihara, K., Hamamoto, J., Masuzawa, K., Kawada, I., Naoki, K., Matsumoto, S., Mimaki, S., Ikemura, S., Goto, K., Betsuyaku, T. and Soejima, K.

Cancer Res 77 ( 8 ) 2078 - 2089 2017.04

ISSN 1538-7445

EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. Cancer Res; 77(8); 2078-89. (c)2017 AACR.

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Erlotinib as second- or third-line treatment in elderly patients with advanced non-small cell lung cancer: Keio Lung Oncology Group Study 001 (KLOG001)

Miyawaki, M., Naoki, K., Yoda, S., Nakayama, S., Satomi, R., Sato, T., Ikemura, S., Ohgino, K., Ishioka, K., Arai, D., Namkoong, H., Otsuka, K., Miyazaki, M., Tani, T., Kuroda, A., Nishino, M., Yasuda, H., Kawada, I., Koh, H., Nakamura, M., Terashima, T., Sakamaki, F., Sayama, K., Betsuyaku, T. and Soejima, K.

Mol Clin Oncol 6 ( 3 ) 409 - 414 2017.03

ISSN 2049-9450

The aim of this study was to assess the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), as second- or third-line treatment for elderly Japanese patients with non-small-cell lung cancer (NSCLC). The patients eligible for this phase II trial were aged >/=70 years, had stage III/IV or recurrent NSCLC, and had previously received 1 or 2 chemotherapy regimens that did not include EGFR-TKIs. The patients received erlotinib at a dose of 150 mg/day. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. A total of 38 patients with a median age of 76 years were enrolled. The majority of the patients were men (66%), had an Eastern Cooperative Oncology Group performance status of 1 (58%), stage IV disease (66%) and adenocarcinoma (74%). Of the 35 patients, 13 (34%) had tumors with EGFR mutations. The ORR was 26.3% (95% confidence interval: 12.1-40.5%) and the disease control rate was 47.4%. The median PFS was 3.7 months and the median OS was 17.3 months. The grade 3 adverse events observed included rash (13%), diarrhea (5%), interstitial pneumonitis (5%), anorexia (3%) and gastrointestinal bleeding (3%). Grade 4 or 5 adverse events were not observed. The median OS did not differ significantly between patients aged <75 years (14.9 months) and those aged >/=75 years (19.0 months; P=0.226). Therefore, erlotinib was found to be effective and well-tolerated in elderly patients with previously treated NSCLC.

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Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer

Soejima, K., Yasuda, H. and Hirano, T.

Expert Rev Clin Pharmacol 10 ( 1 ) 31 - 38 2017.01

ISSN 1751-2441

INTRODUCTION: Significant advances have been made since the development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations in non-small-cell lung cancer (NSCLC), however, lung cancer cells eventually acquire resistance to those agents. Osimertinib (AZD9291) has been developed as 3rd generation EGFR-TKI with activities against sensitizing mutations and T790 M resistance mutation, which account for about 50% of the mechanisms of acquired resistance to 1st or 2nd generation EGFR-TKIs. A recent phase I/II clinical trial with osimertinib for advanced NSCLC patients with known sensitizing EGFR mutations and documented disease progression on prior EGFR-TKIs revealed promising effect with acceptable toxicities. Areas covered: This article summarizes current understanding and available preclinical and clinical data on osimertinib and also discusses future directions. The literature search included PubMed and the latest articles from international conferences. Expert commentary: The development of osimertinib has provided new therapeutic options for NSCLC patients harboring T790 M. Compared with other EGFR-TKIs including rociletinib, osimertinib seems to possess an advantage with respect to the effect and safety profile among existing EGFR-TKIs. However, tumor progression still occurs even when treating with osimertinib. A further understanding of the mechanisms of resistance is eagerly anticipated in order to develop next generation EGFR-TKIs.

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Overcoming EGFR Bypass Signal-Induced Acquired Resistance to ALK Tyrosine Kinase Inhibitors in ALK-Translocated Lung Cancer

Miyawaki, M., Yasuda, H., Tani, T., Hamamoto, J., Arai, D., Ishioka, K., Ohgino, K., Nukaga, S., Hirano, T., Kawada, I., Naoki, K., Hayashi, Y., Betsuyaku, T. and Soejima, K.

Mol Cancer Res 15 ( 1 ) 106 - 114 2017.01

ISSN 1557-3125

Activation of the EGFR pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well-defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs. To this end, ceritinib-resistant cells (H3122-CER) were established from the H3122 NSCLC cell line harboring the ALK gene rearrangement via long-term exposure to ceritinib. H3122-CER cells acquired resistance to ceritinib through EGFR bypass pathway activation. Furthermore, H3122 cells that became resistant to ceritinib or alectinib through EGFR pathway activation showed cross-resistance to other ALK-TKIs. Ceritinib and afatinib combination treatment partially restored the sensitivity to ceritinib. IMPLICATIONS: This study proposes a preclinical rationale to use ALK-TKIs and afatinib combination therapy for ALK-translocated lung cancers that have acquired resistance to ALK-TKIs through EGFR pathway activation. Mol Cancer Res; 15(1); 106-14. (c)2016 AACR.

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Variant CD44 expression is enriching for a cell population with cancer stem cell-like characteristics in human lung adenocarcinoma

Nishino, M., Ozaki, M., Hegab, A. E., Hamamoto, J., Kagawa, S., Arai, D., Yasuda, H., Naoki, K., Soejima, K., Saya, H. and Betsuyaku, T.

J Cancer 8 ( 10 ) 1774 - 1785 2017

ISSN 1837-9664

Background: Preliminary studies have identified cancer stem cells (CSCs) in various cancers and there are several ongoing clinical studies targeting these cells. CD44 (standard or variant isoforms) and/or aldehyde dehydrogenase (ALDH) expression is the most commonly used markers for the identification of CSCs. The goal of the current study was to examine the ability of CD44v, either alone or in combination with ALDH, to identify CSCs within human lung cancer cells lines. Methods: We examined several lung adenocarcinoma cell lines for the ability of CD44v and/or ALDH expression to enrich for cells with CSC characteristics such as in vitro differential proliferation rate, chemotherapeutic-resistance, tumorsphere formation, and in vivo tumorigenicity. We also compared their in vivo secondary tumor formation, and histological characteristics of their xenograft tumors, and examined their expression of PD-L1, EGFR, xCT, and reactive oxygen species (ROS). Results: Both CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells were enriched in cells with CSC characteristics, with the CD44vhigh/ALDHlow cells being more proliferative and more resistant to chemotherapeutics, whereas CD44vhigh/ALDHhigh cells were more efficient in forming tumorspheres in vitro, in making primary xenograft tumors, and in propagating secondary tumors in vivo. Applying stricter sorting gates to select for cells with the highest CD44v/ALDH expression caused the CD44vhigh/ALDHlow cells to lose their high proliferation rates and chemotherapeutic resistance ability, but enriched for the tumorsphere-forming cells among the CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells. CD44vhigh expression was associated with PD-L1 and xCT expression in both H1650 and HCC827 cells. This association was not modified by ALDH expression in the H1650 cell line. However, in the HCC827 cell line, ALDH expression was negatively associated with PD-L1 and positively associated with xCT expression. Conclusion: Lung adenocarcinoma cells with high CD44v expression are enriched for CSCs. Addition of ALDH as an enrichment marker bestowed some CSCs characteristics to CD44vhigh/ALDHlow cells and others to CD44vhigh/ALDHhigh cells. We propose that lung adenocarcinoma contains different CSCs, each of them endowed with different CSC characteristics.

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Sternoclavicular joint osteomyelitis extending to lung abscess complicated by Staphylococcal infective endocarditis

Masuzawa, K., Asakura, T., Ishii, M., Yasuda, H., Sugiura, H., Betsuyaku, T.

IDCases 9 36 - 37 2017

Accepted

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Successful treatment of non-small-cell lung cancer with afatinib and a glucocorticoid following gefitinib- and erlotinib-induced interstitial lung disease: A case report.

Tani T, Naoki K, Asakura T, Hirano T, Suzuki S, Masuzawa K, Hasegawa H, Kuroda A, Yasuda H, Ishii M, Soejima K, Betsuyaku T, Molecular, clinical oncology

Molecular and clinical oncology (Spandidos Publications) 5 ( 4 ) 488 - 490 2016.10

Accepted, ISSN 2049-9450

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Alectinib as a treatment option following recovery from crizotinib-induced interstitial lung disease in patients with anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer.

Shigenari Nukaga, Katsuhiko Naoki, Tetsuro Kamo, Keita Masuzawa, Hiroyuki Yasuda, Kenzo Soejima, Tomoko Betsuyaku

Molecular and clinical oncology 4 ( 6 ) 1085 - 1087 2016.06

ISSN 2049-9450

Crizotinib is a tyrosine kinase inhibitor that displays antitumor activity against anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer. However, crizotinib-associated interstitial lung disease (ILD) has been reported as an infrequent, but potentially fatal complication. We herein describe the case of a 63-year-old male patient with ALK-rearranged advanced lung adenocarcinoma. Chest computed tomography (CT) revealed extensive bilateral ground-glass opacity and airspace consolidation with traction bronchiectasis on day 27 of crizotinib therapy. No signs of infection or left heart failure were identified and we considered the lesions to be consistent with crizotinib-induced ILD. Following corticosteroid treatment and discontinuation of crizotinib, CT revealed improvement of ILD, but also showed regrowth of the tumor. Alectinib, a novel alternative ALK inhibitor, was initiated, and has been successfully continued, with neither disease progression nor recurrence of ILD. The present case indicates that alectinib may be considered as an alternative agent in cases of crizotinib-induced ILD, irrespective of the pattern of ILD, i.e., a diffuse alveolar damage (DAD) or non-DAD pattern, with careful observation.

Activation of EGFR Bypass Signaling by TGFalpha Overexpression Induces Acquired Resistance to Alectinib in ALK-Translocated Lung Cancer Cells

Tani, T., Yasuda, H., Hamamoto, J., Kuroda, A., Arai, D., Ishioka, K., Ohgino, K., Miyawaki, M., Kawada, I., Naoki, K., Hayashi, Y., Betsuyaku, T. and Soejima, K.

Mol Cancer Ther 15 ( 1 ) 162 - 71 2016.01

ISSN 1538-8514

Alectinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLC) harboring the EML4-ALK gene rearrangement. The precise mechanism of acquired resistance to alectinib is not well defined. The purpose of this study was to clarify the mechanism of acquired resistance to alectinib in ALK-translocated lung cancer cells. We established alectinib-resistant cells (H3122-AR) from the H3122 NSCLC cell line, harboring the EML4-ALK gene rearrangement, by long-term exposure to alectinib. The mechanism of acquired resistance to alectinib in H3122-AR cells was evaluated by phospho-receptor tyrosine kinase (phospho-RTK) array screening and Western blotting. No mutation of the ALK-TK domain was found. Phospho-RTK array analysis revealed that the phosphorylation level of EGFR was increased in H3122-AR cells compared with H3122. Expression of TGFalpha, one of the EGFR ligands, was significantly increased and knockdown of TGFalpha restored the sensitivity to alectinib in H3122-AR cells. We found combination therapy targeting ALK and EGFR with alectinib and afatinib showed efficacy both in vitro and in a mouse xenograft model. We propose a preclinical rationale to use the combination therapy with alectinib and afatinib in NSCLC that acquired resistance to alectinib by the activation of EGFR bypass signaling.

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A Case of Non-Small Cell Lung Cancer with Possible "Disease Flare" on Nivolumab Treatment.

Shotaro Chubachi, Hiroyuki Yasuda, Hidehiro Irie, Koichi Fukunaga, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku

Case reports in oncological medicine 2016 1075641 - 1075641 2016

Background. Recent clinical trials proven the clinically significant efficacy and tolerability of nivolumab, a programmed death 1 (PD-1) inhibitor, in previously treated patients with non-small cell lung cancer (NSCLC). Case Presentation. Here, we describe the case of a patient who experienced possible "disease flare" immediately after initiation of nivolumab treatment. A 54-year-old man was diagnosed with Stage IIB (T2N1M0) lung adenocarcinoma. After 7 years from recurrence, 10th line chemotherapy, nivolumab, was initiated. Six weeks later, after 3 cycles of nivolumab treatment, rapid lung cancer progression was observed with an increase in the size of the primary lesion, multiple novel nodules on both lungs, and multiple novel brain metastases. Conclusion. We believe that physicians should be made aware that, in a subset of NSCLC patients, disease flare might occur on nivolumab treatment.

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In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer

Hirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., Naoki, K., Costa, D. B., Kobayashi, S. S., Betsuyaku, T. and Soejima, K.

Oncotarget 6 ( 36 ) 38789 - 803 2015.11

ISSN 1949-2553

EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.

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Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer

Sato, Taicashi, Soejima, Kenzo, Arai, Eri, Hamamoto, Junko, Yasuda, Hiroyuki, Arai, Daisuke, Ishioka, Kota, Ohgino, Keiko, Naoki, Katsuhiko, Kohno, Takashi, Tsuta, Koji, Watanabe, Shun-Ichi, Kanai, Yae, Betsuyaku, Tomoko

ONCOLOGY REPORTS 34 ( 3 ) 1137 - 1145 2015.09

Research paper (scientific journal), ISSN 1021-335X

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Mimicking the niche of lung epithelial stem cells and characterization of several effectors of their in vitro behavior

Hegab, A. E., Arai, D., Gao, J., Kuroda, A., Yasuda, H., Ishii, M., Naoki, K., Soejima, K. and Betsuyaku, T.

Stem Cell Res 15 ( 1 ) 109 - 21 2015.07

ISSN 1876-7753

The niche surrounding stem cells regulate their fate during homeostasis and after injury or infection. The 3D organoid assay has been widely used to study stem cells behavior based on its capacity to evaluate self-renewal, differentiation and the effect of various medium supplements, drugs and co-culture with supportive cells. We established an assay to study both lung and trachea stem cells in vitro. We characterized their proliferation and differentiation spectrum at baseline then evaluated the effect of co-culturing with fibroblasts and endothelial cells and/or treating with several biologically relevant substances as possible contributors to their niche. We found that lung epithelial (but not tracheal basal) stem cells require co-culture with stromal cells to undergo clonal proliferation and differentiation. Fibroblasts were more efficient than endothelial cells in offering this support and the pattern of support varied based on the tissue origin of the stromal cells. Treating distal lung epithelial or basal stem cells with FGF2, FGF9, FGF10, LIF as well as ALK5 and ROCK inhibitors increased their colony formation efficiency and resulted in variable effects on colonies number, size and differentiation spectrum. This model and findings pave the way for better understanding of lung stem cell niche components and factors that can manipulate lung stem cell behavior.

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Mimicking the niche of lung epithelial stem cells and characterization of several effectors of their in vitro behavior

Hegab, Ahmed E., Arai, Daisuke, Gao, Jingtao, Kuroda, Aoi, Yasuda, Hiroyuki, Ishii, Makoto, Naoki, Katsuhiko, Soejima, Kenzo, Betsuyaku, Tomoko

STEM CELL RESEARCH 15 ( 1 ) 109 - 121 2015.07

Research paper (scientific journal), ISSN 1873-5061

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A Phase II study of S-1 and irinotecan combination therapy in previously treated patients with advanced non-small cell lung cancer

Ikemura, Shinnosuke, Naoki, Katsuhiko, Yasuda, Hiroyuki, Kawada, Ichiro, Yoda, Satoshi, Terai, Hideki, Sato, Takashi, Ishioka, Kota, Arai, Daisuke, Ohgino, Keiko, Kamata, Hirofumi, Miyata, Jun, Kabata, Hiroki, Betsuyaku, Tomoko, Soejima, Kenzo

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 4 ) 356 - 361 2015.04

Research paper (scientific journal), ISSN 0368-2811

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Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma

Arai, Daisuke, Hegab, Ahmed E., Soejima, Kenzo, Kuroda, Aoi, Ishioka, Kota, Yasuda, Hiroyuki, Naoki, Katsuhiko, Kagawa, Shizuko, Hamamoto, Junko, Yin, Yongjun, Ornitz, David M., Betsuyaku, Tomoko

JOURNAL OF PATHOLOGY 235 ( 4 ) 593 - 605 2015.03

Research paper (scientific journal), ISSN 0022-3417

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Multiple roles of extracellular fibroblast growth factors in lung cancer cells

Suzuki Takahiro, Yasuda Hiroyuki, Funaishi Koji, Arai Daisuke, Ishioka Kota, Ohgino Keiko, Tani Tetsuo, Hamamoto Junko, Ohashi Ayano, Naoki Katsuhiko, Betsuyaku Tomoko, Soejima Kenzo

International Journal of Oncology 46 ( 1 ) 423 - 429 2015.01

ISSN 1019-6439

Cancer cells are surrounded by the extracellular fluid, matrix, and stroma cells. Little is known about how extracellular components such as growth factor ligands affect the biology of lung cancer cells. The objective of this study was to determine whether extracellular fibroblast growth factors (FGFs) can affect the biology of lung cancer cells and to understand how extracellular FGFs affect the biology of lung cancer cells, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells. Out of the 23 reported FGFs, we focused on FGF2, FGF9 and FGF10. We examined the effect of FGFs on proliferation, treatment sensitivity, and apoptosis of NSCLC (PC9) and SCLC (H69, H82 and H146) cells in vitro. To determine which FGF was the most clinically relevant, we also examined FGF2 and FGF9 concentrations in the serum of patients with lung cancer. We found that extracellular FGFs can affect proliferation, treatment sensitivity, and apoptosis of lung cancer cells in a cell-specific manner. Our results indicate that extracellular FGFs affect the biology of lung cancer cells through multiple functions.

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Long-term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR-mutant PC9 lung cancer cell line

Terai Hideki, Soejima Kenzo, Yasuda Hiroyuki, Sato Takashi, Naoki Katsuhiko, Ikemura Shinnosuke, Arai Daisuke, Ohgino Keiko, Ishioka Kota, Hamamoto Junko, Kanai Yae, Betsuyaku Tomoko

International Journal of Oncology 46 ( 1 ) 430 - 436 2015.01

ISSN 1019-6439

This study was designed to identify epigenetically regulated genes and to clarify the contribution of epigenetic alteration to acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-T KIs). We established a gefitinib-resistant lung cancer cell line, PC9, which was originally gefitinib-sensitive, by serial long-term exposure to gefitinib. RNA and DNA were collected from both gefitinib-sensitive and -resistant PC9 cells, and comprehensive DNA methylation and mRNA expression analyses were performed using Infinium HumanMethylation27 Bead Arrays and Agilent SurePrint G3 Human Gene Expression 8x60K Array, respectively. DNA methylation was increased in 640 genes in gefitinib-resistant cells compared to parental cells. Among them, we selected 29 candidate genes that presented a decrease in mRNA expression in resistant PC9. We further studied four of the selected genes (C10orf116, IGFBP3, KL, and S100P) and found that KL or S100P silencing by siRNA induced a decrease in gefitinib sensitivity compared to that in the negative control in PC9. In conclusion, KL and S100P could be potential targets to overcome resistance to EGFR-TKIs.

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Methylation-induced downregulation of TFPI-2 causes TMPRSS4 overexpression and contributes to oncogenesis in a subset of non-small-cell lung carcinoma

Hamamoto, Junko, Soejima, Kenzo, Naoki, Katsuhiko, Yasuda, Hiroyuki, Hayashi, Yuichiro, Yoda, Satoshi, Nakayama, Sohei, Satomi, Ryosuke, Terai, Hideki, Ikemura, Shinnosuke, Sato, Takashi, Arai, Daisuke, Ishioka, Kota, Ohgino, Keiko, Betsuyaku, Tomoko

CANCER SCIENCE 106 ( 1 ) 34 - 42 2015.01

Research paper (scientific journal), ISSN 1347-9032

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FOXD1 Expression Is Associated with Poor Prognosis in Non-small Cell Lung Cancer

Nakayama, Sohei, Soejima, Kenzo, Yasuda, Hiroyuki, Yoda, Satoshi, Satomi, Ryosuke, Ikemura, Shinnosuke, Terai, Hideki, Sato, Takashi, Yamaguchi, Norihiro, Hamamoto, Junko, Arai, Daisuke, Ishioka, Kota, Ohgino, Keiko, Naoki, Katsuhiko, Betsuyaku, Tomoko

ANTICANCER RESEARCH 35 ( 1 ) 261 - 268 2015.01

Research paper (scientific journal), ISSN 0250-7005

A phase II study of biweekly paclitaxel and carboplatin in elderly patients with advanced non-small cell lung cancer

Soejima Kenzo, Naoki Katsuhiko, Ishioka Kota, Nakamura Morio, Nakatani Michie, Kawada Ichiro, Watanabe Hideo, Nakachi Ichiro, Yasuda Hiroyuki, Satomi Ryosuke, Nakayama Sohei, Yoda Satoshi, Ikemura Sinnosuke, Terai Hideki, Sato Takashi, Ohgino Keiko, Arai Daisuke, Tani Tetsuo, Kuroda Aoi, Nishino Makoto, Betsuyaku Tomoko

Cancer Chemotherapy and Pharmacology (Springer Science and Business Media LLC) 75 ( 3 ) 513 - 519 2015

ISSN 0344-5704

Purpose: The number of elderly patients with advanced non-small cell lung cancer (NSCLC) is increasing. Although several studies have suggested the benefit of chemotherapy with a platinum doublet for elderly patients with advanced NSCLC, this treatment is still controversial in this age group. To evaluate the efficacy and tolerability of combination chemotherapy with biweekly paclitaxel and carboplatin for elderly patients with advanced NSCLC, we conducted a multicenter, non-randomized, open label, phase II trial. Methods: We recruited patients aged ≥70 years with clinical stage IIIB and IV NSCLC and ECOG performance status (PS) of 0-2. Patients received paclitaxel (90 mg/m2) and carboplatin (AUC = 2.5) on day 1 and 15, every 4 weeks. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Sixty-five patients (median age 79 years; range 70-87 years) were enrolled. Forty-nine patients were men, and 48 were stage IV. The PS was 0, 1, and 2 in 28, 33, and 4 patients, respectively. The histological type of NSCLC was non-squamous in 69.3 % and squamous cell carcino

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β-catenin contributes to lung tumor development induced by EGFR mutations

Nakayama Sohei, Sng Natasha, Carretero Julian, Welner Robert, Hayashi Yuichiro, Yamamoto Mihoko, Tan Alistair J., Yamaguchi Norihiro, Yasuda Hiroyuki, Li Danan, Soejima Kenzo, Soo Ross A., Costa Daniel B., Wong Kwok Kin, Kobayashi Susumu S.

Cancer Research 74 ( 20 ) 5891 - 5902 2014.10

ISSN 0008-5472

The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that b-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.

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Identification and Characterization of ALK Kinase Splicing Isoforms in Non-Small-Cell Lung Cancer

de Figueiredo-Pontes, Lorena Lobo, Wong, Daisy Wing-Sze, Tin, Vicky Pui-Chi, Chung, Lap-Ping, Yasuda, Hiroyuki, Yamaguchi, Norihiro, Nakayama, Sohei, Jaenne, Pasi Antero, Wong, Maria Pik, Kobayashi, Susumu Soeda, Costa, Daniel Botelho

JOURNAL OF THORACIC ONCOLOGY 9 ( 2 ) 248 - 253 2014.02

Research paper (scientific journal), ISSN 1556-0864

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Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer

Yamaguchi Norihiro, Lucena-Araujo Antonio R., Nakayama Sohei, de Figueiredo-Pontes Lorena L., Gonzalez David A., Yasuda Hiroyuki, Kobayashi Susumu, Costa Daniel B.

Lung Cancer 83 ( 1 ) 37 - 43 2014.01

ISSN 0169-5002

Introduction: The multitargeted tyrosine kinase inhibitor (TKI) crizotinib is active against ALK translocated non-small-cell lung cancer (NSCLC); however acquired resistance invariably develops over time. ALK mutations have previously been implicated in only a third of resistant tumors. We sought to evaluate alternative mechanisms of resistance and preclinical strategies to overcome these in a cell line driven by EML4-ALK. Methods: We selected the NSCLC cell line NCI-H3122 (H3122: EML4- ALK E13;A20) and derived resistant variants that were able to grow in the presence of 1. μM crizotinib. These were analyzed for ALK mutations, sensitivity to crizotinib in combination with other TKIs, and for activation of alternative tyrosine kinases. Results: All H3122 crizotinib resistant (CR) clones lacked amplification or mutations in the kinase domain of ALK. To evaluate if possible alternative kinases functioned as "bypass" tracks for downstream signaling activation in these resistance cells, we performed of phosho-receptor tyrosine kinase array that demonstrated that CR clones had higher phospho-EGFR signals than H3122 cells before and after exposure to crizotinib. A functional approach of dual ALK TKI (with crizotinib) with combinatory TKI inhibition was used as a secondary screen for possible targets. Crizotinib. +. erlotinib (reversible EGFR TKI) and crizotinib. +. afatinib (irreversible EGFR/ERBB2 TKI) were able to inhibit the growth of H3122 CR clones, confirming EGFR activation as a mechanism of resistance. The removal of crizotinib from the culture media re-sensitized CR cells to crizotinib. Conclusions: We identified activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC. If EGFR activation is confirmed as a predominant mechanism of ALK TKI-induced resistance in patient-derived tumors, the use of ALK plus EGFR TKIs could be explored for this important cohort of NSCLCs. © 2013 Elsevier Ireland Ltd.

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Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer

Ohgino, Keiko, Soejima, Kenzo, Yasuda, Hiroyuki, Hayashi, Yuichiro, Hamamoto, Junko, Naoki, Katsuhiko, Arai, Daisuke, Ishioka, Kota, Sato, Takashi, Terai, Hideki, Ikemura, Shinnosuke, Yoda, Satoshi, Tani, Tetsuo, Kuroda, Aoi, Betsuyaku, Tomoko

LUNG CANCER 83 ( 1 ) 90 - 96 2014.01

Research paper (scientific journal), ISSN 0169-5002

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The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly

Namkoong Ho, Kameyama Youjyu, Yasuda Hiroyuki, Nakayama Sohei, Kaneko Hiroshi, Kawashima Chieko, Terajima Tomoko, Maezawa Kayoko, Hayashi Takeshi, Sandoh Mitsuru, Ishii Makoto, Tasaka Sadatomo, Kanayama Akiko, Kobayashi Intetsu, Betsuyaku Tomoko, Kizu Junko, Iwata Satoshi, Sato Yoshitake, Hasegawa Naoki

Journal of Infection and Chemotherapy 20 ( 6 ) 356 - 360 2014

ISSN 1341-321X

Biapenem has been widely used to treat bacterial pneumonia; however, there is little information concerning its efficacy and safety in elderly patients. Based on pharmacokinetic-pharmacodynamic theory, administration of biapenem thrice rather than twice daily would be expected to be more effective because of longer time above the minimum inhibitory concentration. In this study, we aimed to evaluate the efficacy, safety, and pharmacokinetics of biapenem (300 mg) administered thrice daily in pneumonic patients aged 65 years or older. Biapenem was effective in 22 of 25 patients, as assessed by the improvement in clinical symptoms and/or the eradication of the causative organisms, and caused no serious adverse events. The pharmacokinetic profile was established based on simulations using a modeling program. Among 17 patients whose causative organisms were detected, time above the minimum inhibitory concentration was estimated to be 100% in 16 patients, all of whom showed clinical improvement. The results of this study confirmed the efficacy and safety of 300 mg of biapenem administered thrice daily for the treatment of pneumonia in elderly patients. © 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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Claudin-1 is a novel target of miR-375 in non-small-cell lung cancer

Yoda Satoshi, Soejima Kenzo, Hamamoto Junko, Yasuda Hiroyuki, Nakayama Sohei, Satomi Ryosuke, Terai Hideki, Ikemura Shinnosuke, Sato Takashi, Naoki Katsuhiko, Betsuyaku Tomoko

Lung Cancer 85 ( 3 ) 366 - 372 2014

ISSN 0169-5002

Objectives: We previously reported low expression of miR-375 in squamous-cell carcinoma (SCC) and high expression in adenocarcinoma (AC) of the lung. miR-. 375's target genes and its function in non-small-cell lung cancer (NSCLC) have not been elucidated. Therefore, the present study was designed to identify the targets of miR-375 and to characterize its function in NSCLC. Materials and methods: Candidate targets of miR-375 were determined using a prediction database and previous data on differential gene expression between SCC and AC. We evaluated miR-375 and target-gene expression levels in 12 NSCLC cell lines. The effect of miR-375 overexpression and knockdown was evaluated in NSCLC cell lines by transfecting them with an miR-375 precursor or inhibitor. A luciferase-reporter assay was performed to confirm a direct interaction between miR-375 and its target gene. Further, a wound-healing assay was performed to evaluate the effect of miR-375 overexpression on the migration of SK-MES-1 cells. Finally, to assess the clinical relevance, 63 clinical NSCLC samples were analyzed. Results: Claudin-1 (CLDN1) has 4 putative miR-375 target sites in its 3'-untranslated region, and this gene was determined to be a target of miR-375. CLDN1 messenger RNA and protein expression were attenuated by overexpression of miR-375 and increased by knockdown of miR-375 in NSCLC cell lines. In a luciferase-reporter assay, miR-375 overexpression resulted in a 3-fold repression of luciferase activity (P<. 0.001). Cell migration was promoted by miR-375 overexpression, suggesting a high potential for invasion and metastasis in NSCLC expressing high levels of miR-375. In clinical NSCLC samples, there was a negative correlation between miR-375 and CLDN1 expression (r = -0.35, P = 0.005). In addition, high miR-375 expression was correlated with a shorter survival time among the clinical samples (P = 0.043). Conclusion: CLDN1 is a novel target of miR-375, and high miR-375 expression shortens survival in NSCLC.

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Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer

Yasuda Hiroyuki, Park Eunyoung, Yun Cai Hong, Sng Natasha J., Lucena-Araujo Antonio R., Yeo Wee Lee, Huberman Mark S., Cohen David W., Nakayama Sohei, Ishioka Kota, Yamaguchi Norihiro, Hanna Megan, Oxnard Geoffrey R., Lathan Christopher S., Moran Teresa, Sequist Lecia V., Chaft Jamie E., Riely Gregory J., Arcila Maria E., Soo Ross A., Meyerson Matthew, Eck Michael J., Kobayashi Susumu S., Costa Daniel B.

Science Translational Medicine 5 ( 216 ) 2013.12

ISSN 1946-6234

Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (∼10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770-N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770-N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763-Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763-Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.

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Identification of microRNAs differentially expressed between lung squamous cell carcinoma and lung adenocarcinoma

Hamamoto, Junko, Soejima, Kenzo, Yoda, Satoshi, Naoki, Katsuhiko, Nakayama, Sohei, Satomi, Ryosuke, Terai, Hideki, Ikemura, Shinnosuke, Sato, Takashi, Yasuda, Hiroyuki, Hayashi, Yuichiro, Sakamoto, Michiie, Takebayashi, Toru, Betsuyaku, Tomoko

MOLECULAR MEDICINE REPORTS 8 ( 2 ) 456 - 462 2013.08

Research paper (scientific journal), ISSN 1791-2997

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Activation of the FGF2-FGFR1 autocrine pathway

Terai Hideki, Soejima Kenzo, Yasuda Hiroyuki, Nakayama Sohei, Hamamoto Junko, Arai Daisuke, Ishioka Kota, Ohgino Keiko, Ikemura Shinnosuke, Sato Takashi, Yoda Satoshi, Satomi Ryosuke, Naoki Katsuhiko, Betsuyaku Tomoko

Molecular Cancer Research 11 ( 7 ) 759 - 767 2013.07

ISSN 1541-7786

Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2-FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2-FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs. © 2013 American Association for Cancer Research.

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Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

Basseres Daniela S., D'Alò Francesco, Yeap Beow Y., Löwenberg Ester C., Gonzalez David A., Yasuda Hiroyuki, Dayaram Tajhal, Kocher Olivier N., Godleski John J., Richards William G., Meyerson Matthew, Kobayashi Susumu, Tenen Daniel G., Halmos Balázs, Costa Daniel B.

Lung Cancer 77 ( 1 ) 31 - 37 2012.07

ISSN 0169-5002

Purpose: We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC). Methods: A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay. Results: Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p= 0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p< 0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9-3.1; p= 0.122). Conclusions: Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets. © 2012 Elsevier Ireland Ltd.

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Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer

Yasuda Hiroyuki, De Figueiredo-Pontes Lorena L., Kobayashi Susumu, Costa Daniel B.

Journal of Thoracic Oncology 7 ( 7 ) 1086 - 1090 2012.07

ISSN 1556-0864

INTRODUCTION: Most clinically available small-molecule kinase inhibitors are multi-targeted and can inhibit multiple kinases. Our driving hypothesis was that one of these multi-targeted tyrosine kinase inhibitors (TKIs) would have antiproliferative activity against ROS1 translocated non-small-cell lung cancer (NSCLC). METHODS: We selected NSCLC cell lines-A549 (KRAS G12S), NCI-H3255 (EGFR L858R), NCI-H3122 (EML4-ALK E13;A20), and HCC78 (SLC34A2-ROS1)-to evaluate the antiproliferative effects of submicromolar concentrations of the multitargeted TKIs imatinib, sorafenib, erlotinib, and crizotinib. RESULTS: Imatinib and sorafenib were unable to significantly inhibit proliferation of the aforementioned cell lines. Erlotinib only inhibited EGFR mutated NCI-H3255, as expected. Crizotinib displayed dose-dependent inhibition of anaplastic lymphoma kinase translocated NCI-H3122 and also ROS1-translocated HCC78. The SLC34A2-ROS1 translocated HCC78 cell line had phosphorylated levels of ROS1, AKT, and ERK inhibited by submicromolar doses of crizotinib, and subsequently underwent apoptosis. CONCLUSIONS: The ROS1-translocated HCC78 cell line was sensitive to inhibition by the multitargeted ALK/MET/RON/ROS1 inhibitor crizotinib. Preclinical data supports the clinical development of crizotinib for ROS1-translocated NSCLC. Copyright © 2012 by the International Association for the Study of Lung Cancer.

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EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications

Yasuda, Hiroyuki, Kobayashi, Susumu, Costa, Daniel B.

LANCET ONCOLOGY 13 ( 1 ) E23 - E31 2012.01

Research paper (scientific journal), ISSN 1470-2045

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The PCR-invader method (structure-specific 5 nuclease-based method), a sensitive method for detecting EGFR gene mutations in lung cancer specimens; Comparison with direct sequencing

Naoki Katsuhiko, Soejima Kenzo, Okamoto Hiroaki, Hamamoto Junko, Hida Naoya, Nakachi Ichiro, Yasuda Hiroyuki, Nakayama Sohei, Yoda Satoshi, Satomi Ryosuke, Ikemura Shinnosuke, Terai Hideki, Sato Takashi, Watanabe Koshiro

International Journal of Clinical Oncology 16 ( 4 ) 335 - 344 2011.08

ISSN 1341-9625

Background: Several sensitive assays, including the PCR-invader method (structure-specific 5 nuclease-based method), have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC). However, validation has not been reported. We assessed the detection rate of EGFR mutation by the PCR-invader method and direct sequencing using same clinical specimens. Patients and methods: EGFR mutations were analyzed with the PCR-invader method and compared with direct sequencing using paraffin tissues and pleural and pericardial effusions from NSCLC patients. The relationships between the treatment responses and mutations were evaluated retrospectively. Results: Fifty-four samples from 42 NSCLC patients were studied. EGFR mutations were identified in 52% of the patients and 52% of the samples with the PCR-invader method, but only in 43% of the patients and in 35% of the samples by direct sequencing. In the samples obtained from the same patients at different sites and different times, EGFR mutations were coincident in nine out of ten patients by the PCR-invader method but in six out of ten patients by direct sequencing. Seventeen patients with EGFR mutations were treated with gefitinib; the response rate (RR) and disease control rate (DCR) were 41 and 94%, and median treatment duration was more than 6 months. Seven EGFR mutation-negative patients were treated with gefitinib; the RR and DCR were 0 and 14%, and median treatment duration was 1 month. Conclusion: The PCR-invader method was useful for detecting EGFR mutations in clinical lung cancer specimens and is more sensitive than direct sequencing. © 2011 Japan Society of Clinical Oncology.

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Bronchoscopic Microsampling is a Useful Complementary Diagnostic Tool for Detecting Lung Cancer

Yasuda Hiroyuki, Soejima Kenzo, Nakayama Sohei, Kawada Ichiro, Nakachi Ichiro, Yoda Satoshi, Satomi Ryosuke, Ikemura Shinnosuke, Terai Hideki, Sato Takashi, Watanabe Hideo, Naoki Katsuhiko, Hayashi Yuichiro, Ishizaka Akitoshi

Lung Cancer 72 ( 1 ) 32 - 38 2011.04

ISSN 0169-5002

Purpose: Bronchoscopic microsampling (BMS) is a novel and direct method with which to obtain epithelial lining fluid (ELF) from the lungs. Analysis of DNA hypermethylation of tumor suppressor genes (TSGs) is expected to be a sensitive tool for the early detection of lung cancer. It has been reported that the existence of EGFR mutations and EML4-ALK gene rearrangements are related to the sensitivity of corresponding kinase inhibitors. We aimed to evaluate the suitability of ELF as a sample for analyzing molecular changes specific for lung cancer. Patients and methods: We collected ELF from 61 lung cancer patients by BMS from the airway close to the peripheral lung nodule and purified the nucleic acids. We performed methylation specific PCR in each ELF as well as matched serum and tumor tissue for TSGs for DNA methylation analysis. We also examined EGFR mutations and EML4-ALK rearrangement. Results: The sensitivity for detecting DNA hypermethylation in ELF vs serum was 74.1% vs 18.5%. We found 60.1% of patients had at least one hypermethylation in ELF, while only 27.9% had it in serum. Of note, DNA hypermethylation was detected even in stage I patients (60.0%) and the detection rate was almost the same level in each stage. We also found the sensitivity for detecting EGFR mutation in ELF vs serum was 58.3% vs 8.3%. We detected an EML4-ALK fusion gene using ELF in one patient. Conclusions: BMS is an alternative method to detect cancer specific genetic and epigenetic alterations and will be a useful complementary diagnostic tool for lung cancer. Summary: Investigation of genetic and epigenetic changes associated with lung cancer has clinical importance for its diagnosis and management. The clinical usefulness of bronchoscopic microsampling (BMS) in lung cancer has not yet been evaluated. This study demonstrates that BMS could be useful for detecting lung cancer specific molecular changes and valuable for early diagnosis and determination of treatment options for lung cancer. © 2010 Elsevier Ireland Ltd.

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A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Yoda, Satoshi, Soejima, Kenzo, Yasuda, Hiroyuki, Naoki, Katsuhiko, Kawada, Ichiro, Watanabe, Hideo, Nakachi, Ichiro, Satomi, Ryosuke, Nakayama, Sohei, Ikemura, Sinnosuke, Terai, Hideki, Sato, Takashi, Morosawa, Maiko, Asano, Koichiro

CANCER CHEMOTHERAPY AND PHARMACOLOGY 67 ( 3 ) 717 - 722 2011.03

Research paper (scientific journal), ISSN 0344-5704

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Distinct epigenetic regulation of tumor suppressor genes in putative cancer stem cells of solid tumors

Yasuda, Hiroyuki, Soejima, Kenzo, Watanabe, Hideo, Kawada, Ichiro, Nakachi, Ichiro, Yoda, Satoshi, Nakayama, Sohei, Satomi, Ryosuke, Ikemura, Shinnosuke, Terai, Hideki, Sato, Takashi, Suzuki, Sadafumi, Matsuzaki, Yumi, Naoki, Katsuhiko, Ishizaka, Akitoshi

INTERNATIONAL JOURNAL OF ONCOLOGY 37 ( 6 ) 1537 - 1546 2010.12

Research paper (scientific journal), ISSN 1019-6439

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Distinct epigenetic regulation of tumor suppressor genes in putative cancer stem cells of solid tumors

Yasuda Hiroyuki, Soejima Kenzo, Watanabe Hideo, Kawada Ichiro, Nakachi Ichiro, Yoda Satoshi, Nakayama Sohei, Satomi Ryosuke, Ikemura Shinnosuke, Terai Hideki, Sato Takashi, Suzuki Sadafumi, Matsuzaki Yumi, Naoki Katsuhiko, Ishizaka Akitoshi

International Journal of Oncology 37 ( 6 ) 1537 - 1546 2010.12

ISSN 1019-6439

Epigenetic gene regulation plays essential roles in differentiation of embryonic and tissue stem cells. In these benign undifferentiated cells, some polycomb targeted genes are kept in a state of DNA hypomethylation and they have a distinct chromatin signature termed bivalent chromatin structure to maintain their plasticity. We hypothesized that cancer stem cells (CSC), the malignant counterpart of these cells, are also under the control of epigenetics like benign stem cells. We compared the DNA methylation and chromatin structure in 10 tumor suppressor genes between CSC and differentiated cancer cells of MCF7 and Huh7 cells. We found that the level of DNA methylation was indeed significantly lower in CSC, while surprisingly, the bivalent chromatin structure was more ubiquitously seen in differentiated cancer cells compared to CSC. However, repressive marks of chromatin structure, namely H3K27me3 and EZH2, were significantly lower in CSC. As a consequence, CSC remained in a higher transcriptionally active chromatin state compared to differentiated cancer cells. We found that the differentiation of CSCs is also epigenetically regulated. These findings could help towards a comprehensive understanding of CSC, and also improve the development of eradicative therapies against human malignancies.

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The Combination of Multiple Receptor Tyrosine Kinase Inhibitor and Mammalian Target of Rapamycin Inhibitor Overcomes Erlotinib Resistance in Lung Cancer Cell Lines through c-Met Inhibition

Nakachi, Ichiro, Naoki, Katsuhiko, Soejima, Kenzo, Kawada, Ichiro, Watanabe, Hideo, Yasuda, Hiroyuki, Nakayama, Sohei, Yoda, Satoshi, Satomi, Ryosuke, Ikemura, Shinnosuke, Terai, Hideki, Sato, Takashi, Ishizaka, Akitoshi

MOLECULAR CANCER RESEARCH 8 ( 8 ) 1142 - 1151 2010.08

Research paper (scientific journal), ISSN 1541-7786

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S-1/Radiation併用療法によってCRが得られたGefitinib抵抗性の非小細胞肺癌術後再発の1例

藤本博行, 小山孝彦, 水渡哲史, 橋本浩平, 亀山洋樹, 安田浩之, 石塚広司

癌と化学療法 ((株)癌と化学療法社) 37 ( 2 ) 295 - 298 2010.02

ISSN 0385-0684

症例は35歳、女性。肺腺癌c-T2N2M0に対して術前CDDP+DOCを3コース施行。NCの効果判定で左肺下葉切除術およびND2a系統的縦隔リンパ節郭清術を施行した。p-T2N2M0であった。術後療法としてgefitinibを投与。2ヵ月間の内服後の評価で気管分岐下リンパ節の腫脹とSLXの上昇を認めたため、gefitinibの投与を中止した。術後4ヵ月より縦隔へ放射線を総量50Gy照射した。術後5ヵ月よりS-1化学療法を施行した。S-1は100mg/dayで1日二分割投与、4週投与2週休薬とした。S-1の増量は行わず、6コースの化学療法を施行した。縦隔リンパ節腫脹は消失、SLXも正常化し、complete response(CR)となった。その後UFT内服にて外来経過観察中であり術後36ヵ月以上経過するが、現在のところ再発の徴候はない。(著者抄録)

FDG-PET imaging of benign pulmonary diseases

Terai Hideki, Soejima K., Naoki K., Kawada I., Nakachi I., Satomi R., Nakayama S., Yoda S., Ikemura S., Sato T., Ishizaka A., Yasuda H.

Japanese Journal of Clinical Radiology 55 ( 1 ) 163 - 172 2010

ISSN 0009-9252

The usefulness of fluorodeoxyglucose (FDG) -positron emission tomography (PET) has been established for the diagnosis of cancer. However, we often experience false positive as well as false negative cases in clinical practice. Examining those will be useful to understand more adequate use of FDG-PET. So we evaluated all the PET/CT results (n=467) conducted from April 2003 to March 2008 and selected 54 cases diagnosed eventually as benign pulmonary diseases. As a whole, the PET positive rate in the benign disease was 48.1% (26/54). In contrast, 149 cases with primary lung cancer examined in the same period yielded the positive rate of 86.6% (129/146). We analyzed the changes of PET positive rate by the shape or the size of the shadow, and by the disease. And we summarized false positive results from FDG-PET study and classified them into seven categories (inflammation, interstitial lung disease, pneumoconiosis, radiation pneumonia, granulomatous disease, large vessel vasculitis, mediastinal disease).

A case of complete response treated by S-1 with concurrent radiotherapy for a gefitinib-resistant non-small cell lung cancer patient

Fujimoto, H., Oyama, T., Suito, T., Hashimoto, K., Kameyama, Y., Yasuda, H., Ishizuka, H.

Japanese Journal of Cancer and Chemotherapy 37 ( 2 ) 2010

Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells.

Hideo Watanabe, Kenzo Soejima, Hiroyuki Yasuda, Ichiro Kawada, Ichiro Nakachi, Satoshi Yoda, Katsuhiko Naoki, Akitoshi Ishizaka

Cancer cell international 8 15 - 15 2008.11

BACKGROUND: Alterations in the processing of the genetic information in carcinogenesis result from stable genetic mutations or epigenetic modifications. It is becoming clear that nucleosomal histones are central to proper gene expression and that aberrant DNA methylation of genes and histone methylation plays important roles in tumor progression. To date, several histone lysine methyltransferases (HKMTs) have been identified and histone lysine methylation is now considered to be a critical regulator of transcription. However, still relatively little is known about the role of HKMTs in tumorigenesis. RESULTS: We observed differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. Modifications in the H3 tails affect the binding of proteins to the histone tails and regulate protein function and the position of lysine methylation marks a gene to be either activated or repressed. In the present study, suppression by siRNA of HKMTs (EZH2, G9A, SETDB1 and SUV39H1) that are over-expressed in immortalized and transformed cells lead to reduced cell proliferation and much less anchorage-independent colony growth. We also found that the suppression of H3-K9, G9A and SUV39H1 induced apoptosis and the suppression of H3-K27, EZH2 caused G1 arrest. CONCLUSION: Our results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.

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Clinical evaluation of the deep venous thrombosis and pulmonary embolism after total joint arthroplasty

Sui, O., Kubo, A., Yasuda, H., Hirohashi, N., Yoshikawa, Y., Kato, Y., Inoue, T., Tonai, T.

Japanese Journal of Clinical Radiology 52 ( 1 ) 2007

20.無気肺を契機に発見され高周波スネアにて切除した気管支内過誤腫の1例(第116回日本呼吸器内視鏡学会関東支部会)

堀口速史, 安田浩之, 石井誠, 鈴木雄介, 赤塚誠哉, 小林紘一

気管支学 (特定非営利活動法人日本呼吸器内視鏡学会) 28 ( 4 ) 327 - 327 2006

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