研究者詳細 - 豊岡　伸一

Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations 査読

Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

Cancer Science 109 ( 5 ) 1493 - 1502 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

DOI： 10.1111/cas.13571

Preoperative short hookwire placement for small pulmonary lesions: evaluation of technical success and risk factors for initial placement failure 査読

Toshihiro Iguchi, Takao Hiraki, Yusuke Matsui, Hiroyasu Fujiwara, Yoshihisa Masaoka, Takashi Tanaka, Takuya Sato, Hideo Gobara, Shinichi Toyooka, Susumu Kanazawa

European Radiology 28 ( 5 ) 2194 - 2202 2018年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Verlag

Objectives: To retrospectively evaluate the technical success of computed tomography fluoroscopy-guided short hookwire placement before video-assisted thoracoscopic surgery and to identify the risk factors for initial placement failure. Methods: In total, 401 short hookwire placements for 401 lesions (mean diameter 9.3 mm) were reviewed. Technical success was defined as correct positioning of the hookwire. Possible risk factors for initial placement failure (i.e., requirement for placement of an additional hookwire or to abort the attempt) were evaluated using logistic regression analysis for all procedures, and for procedures performed via the conventional route separately. Results: Of the 401 initial placements, 383 were successful and 18 failed. Short hookwires were finally placed for 399 of 401 lesions (99.5%). Univariate logistic regression analyses revealed that in all 401 procedures only the transfissural approach was a significant independent predictor of initial placement failure (odds ratio, OR, 15.326
95% confidence interval, CI, 5.429–43.267
p &lt
0.001) and for the 374 procedures performed via the conventional route only lesion size was a significant independent predictor of failure (OR 0.793, 95% CI 0.631–0.996
p = 0.046). Conclusions: The technical success of preoperative short hookwire placement was extremely high. The transfissural approach was a predictor initial placement failure for all procedures and small lesion size was a predictor of initial placement failure for procedures performed via the conventional route. Key points: • Technical success of preoperative short hookwire placement was extremely high. • The transfissural approach was a significant independent predictor of initial placement failure for all procedures. • Small lesion size was a significant independent predictor of initial placement failure for procedures performed via the conventional route.

DOI： 10.1007/s00330-017-5176-2

術後難治性有瘻性膿胸に対して気管支充填術により瘻孔閉鎖を行った一例

A Multicenter Randomized Controlled Study of Paclitaxel plus Carboplatin versus Oral Uracil-Tegafur as the Adjuvant Chemotherapy in Resected Non-Small Cell Lung Cancer. 査読国際誌

Toyooka S, Okumura N, Nakamura H, Nakata M, Yamashita M, Tada H, Kajiwara S, Watanabe N, Okada M, Sakamoto J, Aoe M, Soh J, Miyoshi S, Hotta K, Matsuo K, Date H

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 ( 5 ) 699 - 706 2018年5月

山本寛斉, 原尚史, 西井和也, 頼冠名, 木浦勝行, 豊岡伸一

気管支学 40 ( Suppl. ) S281 - S281 2018年5月

β-1,3-Galactosyl-O-Glycosyl-Glycoprotein β-1,6-N-Acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読国際誌

Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Sato H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

Oncology research 26 ( 3 ) 431 - 444 2018年4月

Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer 査読

Takahiro Yoshioka, Kazuhiko Shien, Kei Namba, Hidejiro Torigoe, Hiroki Sato, Shuta Tomida, Hiromasa Yamamoto, Hiroaki Asano, Junichi Soh, Kazunori Tsukuda, Takeshi Nagasaka, Toshiyoshi Fujiwara, Shinichi Toyooka

Cancer Science 109 ( 4 ) 1166 - 1176 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer.

DOI： 10.1111/cas.13546

Clinical implementation of precision medicine

Shuta Tomida, Shinichi Toyooka

Japanese Journal of Cancer and Chemotherapy 45 ( 4 ) 601 - 604 2018年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

In the end of last year, the US Food and Drug Administration has announced the authorization of MSK-IMPACT™, clinical test based on multiplex cancer panel profiling for genetic mutations and other alterations in patients' tumors, while in Japan, NCC Oncopanel, domestic multiplex cancer panel, is scheduled to be clinically implemented as advanced medical care B in this coming spring, chasing the state of the art technology for cancer treatment. In this article, we outline a recently published roadmap for precision medicine in Japan, together with our years of experience on cancer diagnosis and treatment based on multiplex cancer panel at Okayama University Hospital and Okadai Biobank.

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection? 査読

Masahiro Miyajima, Atsushi Watanabe, Toshihiko Sato, Satoshi Teramukai, Masahito Ebina, Kazuma Kishi, Yukihiko Sugiyama, Haruhiko Kondo, Satoru Kobayashi, Yutaka Takahashi, Hiroyuki Ito, Ryoji Yamamoto, Shigeki Sawada, Hideki Fujimori, Kazunori Okabe, Jun Arikura, Yasushi Shintani, Hiroshige Nakamura, Shinichi Toyooka, Tohru Hasumi, Takehiro Watanabe, Yoshinobu Hata, Hisashi Iwata, Minoru Aoki, Kazuhito Funai, Shuhei Inoue, Osamu Kawashima, Tomohiko Iida, Hiroshi Date

Surgery today 48 ( 4 ) 404 - 415 2018年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

DOI： 10.1007/s00595-017-1605-8

【肺癌の集学的治療の現況】局所進行肺癌における集学的治療局所進行非小細胞肺癌に対する術前導入化学放射線療法後手術

[Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer]. 査読

Miura A, Soh J, Shien K, Yamamoto H, Toyooka S

Kyobu geka. The Japanese journal of thoracic surgery 71 ( 4 ) 270 - 277 2018年4月

IV期肺癌における呼吸器外科の役割は拡大しているか? 手術を契機に診断した胸膜播種・悪性胸水を伴うIVA期肺癌は切除非適応か? 多施設共同後方視的解析

藤原俊哉, 松浦求樹, 宗淳一, 枝園和彦, 山本寛斉, 牧佑歩, 上野剛, 杉本龍士郎, 岡崎幹生, 田尾裕之, 葉山牧夫, 片岡正文, 佐野由文, 岡部和倫, 山下素弘, 川真田修, 片岡和彦, 森山重治, 豊岡伸一, 岡山大学呼吸器外科研究会

日本呼吸器外科学会雑誌 32 ( 3 ) PD3 - 1 2018年4月

三浦章博, 宗淳一, 枝園和彦, 山本寛斉, 豊岡伸一

胸部外科 71 ( 4 ) 270 - 277 2018年4月

肺腺がんにおけるSpred2の役割の解明

太田陽子, 藤澤真義, 吉村禎造, スマルディカ・イワヤン, 枝園和彦, 阪口政清, 豊岡伸一, 松川昭博

日本病理学会会誌 107 ( 1 ) 414 - 414 2018年4月

肺癌登録合同委員会報告第7次事業「2010年肺癌手術症例に対する登録研究」の結果報告

岡見次郎, 新谷康, 奥村明之進, 伊藤宏之, 大塚崇, 豊岡伸一, 森毅, 渡辺俊一, 伊達洋至, 横井香平, 淺村尚生, 永安武, 高橋和久, 木浦勝行, 秋田弘俊, 滝口裕一, 宮岡悦良, 吉野一郎

日本呼吸器外科学会雑誌 32 ( 3 ) np4 - np4 2018年4月

Second primary cancer in survivors of locally advanced non-small cell lung cancer treated with concurrent chemoradiation followed by surgery 査読

Go Makimoto, Toshio Kubo, Isao Oze, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Junichi Soh, Shinichi Toyooka, Kuniaki Katsui, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Japanese Journal of Clinical Oncology 48 ( 3 ) 287 - 290 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press

The standard treatment for patients with locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT), but surgical resection following induction CRT can extend overall survival in a select population. However, patients who survive longer are at risk of developing a second primary cancer (SPC). This is the first report to determine the incidence of SPC in survivors with LA-NSCLC after trimodal therapy. Between October 1997 and October 2013, 112 Stage III NSCLC patients underwent trimodal therapy in our hospital. The 5-year overall survival rate was 71.8%. SPC developed in 10 of the 112 patients 0.60-15.0 (median 5.49) years after initiating CRT. The observed incidence of SPC was 1.8 per 100 patient-years. Although trimodal therapy can prolong patient survival, the estimated incidence of SPC does not increase. A large prospective study with a longer follow-up time is required to determine the effects of trimodal therapy, including the development of SPC.

DOI： 10.1093/jjco/hyy003

Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E 査読

Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

Oncologist 23 ( 2 ) 150 - 154 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley-Blackwell

We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

DOI： 10.1634/theoncologist.2017-0345

A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non–Small Cell Lung Cancer 査読

Katsuyuki Hotta, Keisuke Aoe, Toshiyuki Kozuki, Kadoaki Ohashi, Kiichiro Ninomiya, Eiki Ichihara, Toshio Kubo, Takashi Ninomiya, Kenichi Chikamori, Daijiro Harada, Naoyuki Nogami, Taizo Hirata, Shiro Hinotsu, Shinichi Toyooka, Katsuyuki Kiura

Journal of Thoracic Oncology 13 ( 2 ) 273 - 279 2018年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier Inc

Trastuzumab emtansine (T-DM1), an anti–erb-b2 receptor tyrosine kinase 2 (HER2) antibody-drug conjugate, has been shown to significantly improve survival in HER2-positive breast cancer. We report a phase II trial of T-DM1 monotherapy in relapsed NSCLC with documented HER2 positivity (an immunohistochemistry [IHC] score of 3+, both an IHC score of 2+ and fluorescence in situ hybridization positivity, or exon 20 mutation). This study was terminated early because of limited efficacy. The demographic characteristics in the 15 assessable patients were as follows: median age, 67 years
male sex, 47%
performance status of 0 to 1, 80%
HER2 status IHC 3+, 33%
HER status IHC 2+/fluorescence in situ hybridization–positive, 20%
and exon 20 mutation, 47%. The median number of delivered cycles was 3 (range 1–11). One patient achieved a partial response with an objective response rate of 6.7% (90% confidence interval: 0.2–32.0). With a median follow-up time of 9.2 months, the median progression-free survival time and median survival time were 2.0 and 10.9 months, respectively. Grade 3 or 4 adverse events included thrombocytopenia (40%) and hepatotoxicity (20%) without any treatment-related deaths. T-DM1 had a limited efficacy for HER2-positive NSCLC in our cohort. Applying the concept of precision medicine to tumors appears challenging
thus, additional molecular approaches are warranted.

DOI： 10.1016/j.jtho.2017.10.032

Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma 査読

Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

Oncogenesis 7 ( 1 ) 11 2018年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Publishing Group

Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

DOI： 10.1038/s41389-017-0017-3