Faculty Profiles - TOYOOKA Shinichi

Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma Reviewed

Junichi Soh, Shinichi Toyooka, Keitaro Matsuo, Hiromasa Yamamoto, Ignacio I. Wistuba, Stephen Lam, Kwun M. Fong, Adi F. Gazdar, Shinichiro Miyoshi

ONCOLOGY LETTERS 10 ( 3 ) 1775 - 1782 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Mutations or copy number gains (CNGs) of the EGFR and KRAS genes are representative alterations in lung adenocarcinomas that are individually associated with patient characteristics such as ethnicity, smoking status and gender. However, the effects of combinations of these genetic alterations have not been statistically examined. The present study analyzed previously examined lung adenocarcinoma cases in Asian (n=166) and non-Asian (n=136) individuals in whom all four EGFR and KRAS alterations had been studied. The polynomial logistic regression models were used following adjustment for gender and smoking status, and using patients without any type of EGFR/KRAS alterations as a reference. Between the two ethnic groups, EGFR CNGs (gEGFR) occurred more frequently than EGFR mutations (mEGFR) (46 vs. 38% in Asians; 21 vs. 10% in non-Asians), whereas KRAS mutations (mKRAS) were more frequent than KRAS CNGs (gKRAS) (13 vs. 7% and 35 vs. 4%, respectively). Additionally, gEGFR and gKRAS occurred significantly more frequently in respective mutant cases, and all EGFR alterations were almost exclusive of all KRAS alterations. The polynomial logistic regression models confirmed that all types of EGFR alterations were significantly more frequent among Asian individuals than among non-Asian individuals, independent of gender and smoking status (odds ratios, 2.36-6.67). KRAS alterations occurred less frequently among Asian individuals than among non-Asian individuals, although a significant difference was not detected. The present study results indicated that the EGFR and KRAS profiles, including mutations and CNGs, differ between Asian and non-Asian individuals with lung adenocarcinoma, suggesting that ethnicity strongly affects the molecular characteristics of lung adenocarcinoma.

DOI： 10.3892/ol.2015.3414

Primary pulmonary melanoma: a report of two cases Reviewed

Mototsugu Watanabe, Hiromasa Yamamoto, Shinsuke Hashida, Junichi Soh, Seiichiro Sugimoto, Shinichi Toyooka, Shinichiro Miyoshi

WORLD JOURNAL OF SURGICAL ONCOLOGY 13 274 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Malignant melanoma is a refractory malignancy with a dismal prognosis. It generally arises from the skin in most cases, and cases of primary pulmonary malignant melanoma are rare and often behave aggressively. We have treated two cases of localized primary pulmonary malignant melanoma using surgical resection. Pulmonary malignant melanomas often metastasize to the brain and liver; one of our cases exhibited metastasis to the cecum at about 8 months after surgery. Because cutaneous melanomas often carry activating mutations in the BRAF gene (V600E), we performed a BRAF mutational analysis using direct sequencing for both of these tumors arising from the lung. However, no BRAF mutations were detected. We detected a p53 mutation, which was thought to be a potential somatic mutation, in one of the two cases using a sequencing panel targeting 20 lung cancer-related genes. Although we also checked the expression of programmed death ligand 1 (PD-L1) on the surface of the tumor cells by immunohistochemical testing, neither of our two cases expressed PD-L1. Further molecular analyses may uncover the characteristics of primary pulmonary malignant melanomas.

DOI： 10.1186/s12957-015-0695-2

TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant Reviewed

Hiromasa Yamamoto, Hiroki Otani, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S311 - S312 2015.9

Distant Bystander Effect of REIC/Dkk-3 Gene Therapy through Immune System Stimulation in a Murine Model of Thoracic Malignancies Reviewed

Suzawa Ken, Shien Kazuhiko, Huang Peng, Sakaguchi Masakiyo, Watanabe Masami, Hashida Shinsuke, Soh Junichi, Yamamoto Hiromasa, Maki Yuho, Asano Hiroaki, Tsukuda Kazunori, Nasu Yasutomo, Kumon Hiromi, Miyoshi Shinichiro, Toyooka Shinichi

JOURNAL OF THORACIC ONCOLOGY 10 ( 9 ) S599 2015.9

Anti-tumor effect of afatinib, an irreversible EGFR/HER2 dual inhibitor, in lung cancers harboring HER2 oncogene Reviewed

Suzawa Ken, Toyooka Shinichi, Sakaguchi Masakiyo, Ohtsuka Tomoaki, Watanabe Mototsugu, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro

CANCER RESEARCH 75 2015.8

Identification of a novel binding protein playing a critical role in HER2 activation in lung cancer cells Reviewed

Ohtsuka Tomoaki, Sakaguchi Masakiyo, Takata Katsuyoshi, Hashida Shinsuke, Watanabe Mototsugu, Suzawa Ken, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Toyooka Shinichi

CANCER RESEARCH 75 2015.8

Anti-tumor effect of Dasatinib in HER2 positive breast cancer with Trastuzumab resistance Reviewed

Takeda Tatsuaki, Kanzaki Hirotaka, Toyooka Shinichi, Watanabe Mototsugu, Ohtsuka Tomoaki, Suzawa Ken, Hashida Shinsuke, Maki Yuho, Yamamoto Hiromasa, Soh Junichi, Asano Hiroaki, Tsukuda Kazunori, Miyoshi Shinichiro, Kitamura Yoshihisa, Sendo Toshiaki

CANCER RESEARCH 75 2015.8

Simultaneous Multiple Preoperative Localizations of Small Pulmonary Lesions Using a Short Hook Wire and Suture System Reviewed

Toshihiro Iguchi, Takao Hiraki, Hideo Gobara, Hiroyasu Fujiwara, Yusuke Matsui, Seiichiro Sugimoto, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi, Susumu Kanazawa

CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY 38 ( 4 ) 971 - 976 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The aim of the study was to retrospectively evaluate simultaneous multiple hook wire placement outcomes before video-assisted thoracoscopic surgery (VATS).
Thirty-eight procedures were performed on 35 patients (13 men and 22 women; mean age, 59.9 years) with 80 lung lesions (mean diameter 7.9 mm) who underwent simultaneous multiple hook wire placements for preoperative localizations. The primary endpoints were technical success, complications, procedure duration, and VATS outcome; secondary endpoints included comparisons between technical success rates, complication rates, and procedure durations of the 238 single-placement procedures performed. Complications were also evaluated.
In 35 procedures including 74 lesions, multiple hook wire placements were technically successful; in the remaining three procedures, the second target placement was aborted because of massive pneumothorax after the first placement. Although complications occurred in 34 procedures, no grade 3 or above adverse event was observed. The mean procedure duration was 36.4 +/- A 11.8 min. Three hook wires dislodged during patient transport to the surgical suite. Seventy-four successfully marked lesions were resected. Six lesions without hook wires were successfully resected after detection by palpation with an additional mini-thoracotomy or using subtle pleural changes as a guide. The complication rates and procedure durations of multiple-placement procedures were significantly higher (P = 0.04) and longer (P < 0.001) than those in the single-placement group, respectively, while the technical success rate was not significantly different (P = 0.051).
Simultaneous multiple hook wire placements before VATS were clinically feasible, but increased the complication rate and lengthened the procedure time.

DOI： 10.1007/s00270-014-1028-5

山本寛斉, 牧佑歩, 宗淳一, 三好新一郎, 豊岡伸一

日本臨床 73 ( 増刊6 家族性腫瘍学 ) 433 - 436 2015.8

TAE226, a Bis-Anilino Pyrimidine Compound, Inhibits the EGFR-Mutant Kinase Including T790M Mutant to Show Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells Reviewed

Hiroki Otani, Hiromasa Yamamoto, Munenori Takaoka, Masakiyo Sakaguchi, Junichi Soh, Masaru Jida, Tsuyoshi Ueno, Takafumi Kubo, Hiroaki Asano, Kazunori Tsukuda, Katsuyuki Kiura, Shinji Hatakeyama, Eiji Kawahara, Yoshio Naomoto, Shinichiro Miyoshi, Shinichi Toyooka

PLOS ONE 10 ( 6 ) e0129838 2015.6

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). In this study, we investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The antitumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity. In summary, we showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation.

DOI： 10.1371/journal.pone.0129838