The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/ SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-smallcell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes. Cancer Res; 73(17); 5508-18. Ó2013 AACR.

Oncogenic RET fusion gene, occurring in 1–2% of LADCs, was recently identified by us and others as a new targetable driver gene in lung adenocarcinoma. Existing FDA-approved inhibitors of RET tyrosine kinase, such as vandetanib, show promising therapeutic effects both in vitro and in vivo, as well as in a few patients. A phase II clinical trial, investigating the therapeutic effects of vandetanib, has been started in Japan (UMIN00001009) in Q1 of 2013. The RET fusion screening is being conducted in > 120 hospitals throughout Japan by a consortium designated “LC-SCRUM (Lung Cancer Genomic Screening Project for Individualized Medicine in Japan)”. Approximately 4% of >300 EGFR-mutation negative NSCLC patients screened have been diagnosed as being positive for RET fusion, and the therapy of several patients has started. Positive responses to vandetanib have been observed as expected. In addition, the structure of breakpoints of RET fusion in lung adenocarcinoma indicates that the different molecular processes generate oncogenic RET fusions between lung adenocarcinoma and papillary thyroid carcinoma. Etiology and therapeutic significance of RET fusion in lung adenocarcinoma will be discussed. Citation Format: Takashi Kohno, Koji Tsuta, Katsuya Tsuchihara, Tatsuji Mizukami, Kiyotaka Yoh, Koichi Goto. RET fusion gene: Translation to personalized lung cancer therapy. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A32.

Oncogenic RET fusion in LADC occurs through multiple pathways and involves the illegitimate repair of DNA strand breaks through mechanisms different from those identified in papillary thyroid carcinoma, where RET fusion also functions as a driver mutation.

Background: Carbon ion Radiotherapy for prostate cancer is widely used, however reports are limited from single institute or short follow up. We performed a prospective observational study (GUNMA0702) to evaluate the feasibility and efficacy of carbon ion radiotherapy for localized and locally advanced prostate cancer. Methods: Between June 2010 and August 2013, 304 patients with localized prostate cancer were treated, with a median follow-up duration of 60 months. All patients received carbon ion radiotherapy with 57.6 Gy (RBE) in 16 fractions over 4 weeks. Hormonal therapy was given according to the risk group. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 by the National Cancer Institute. Results: The overall 5-year biochemical relapse-free rate was 92.7%, with rates of 91.7, 93.4, and 92.0% in low-risk, intermediate-risk, and high-risk patients, respectively. The 5-year local control and overall survival rates were 98.4 and 96.6%, respectively. Acute grade 3 or greater toxicity was not observed. Late grade 2 and grade 3 genitourinary and gastrointestinal toxicity rates were 9 and 0.3%, and 0.3, and 0%, respectively. Conclusions: The present protocol of carbon ion radiotherapy for prostate cancer provided low genitourinary and gastrointestinal toxicity with good biochemical control within 5 years.