Basic Research and Development of Personalized Diagnosis and Treatment for GC and ESCC

Gastric Cancer（GC）

The study for GC：GC is one of the leading causes of cancer-related death worldwide. Histopathologically, GCs can be divided into two major categories: intestinal-type and diffuse-type. Unlike the decreasing incidence of intestinal-type, the prevalence of the diffuse-type is reportedly increasing worldwide. Although therapeutic results for GC have recently improved, the prognosis of patients with advanced diffuse-type GC still remains poor. Peritoneal dissemination is a frequent form of metastasis of diffuse-type GC. The survival rates of patients with peritoneal metastasis（P1）at 3 and 5 years are only 9.8% and 0%, respectively. Peritoneal lavage cytology（CY）provides important prognostic information for GC after surgery. CY positive（CY1）is well known as a poor prognostic factor in advanced GC patients. However, the optical therapeutic strategy for patients with CY1 has not yet been established. The 2-, 3-, and 5-year survival rates of GC patients with no peritoneal metastasis（P0）but with CY1 are 25.3, 13.8, and 7.8%, respectively. Development of a new therapeutic modality for peritoneal metastasis of GC is very important for improving the outcome of patients with P1/CY1 or P0/CY1. In 2016, we identified DDR2 as a potential regulator of peritoneal dissemination by collaborative integrated molecular profiling. For personalized medicine, we have developed mini DNA chips containing six markers and three control genes for predicting GC recurrence from peritoneal washings. The CY offers important prognostic information for GC after surgery, but has only a limited sensitivity and the task requires great skill. Our collaborating company continues to prepare a lot of supporting data for developing an in vitro diagnostic（IVD）.

Esophageal squamous cell carcinoma（ESCC）

The study for ESCC：Definitive chemoradiotherapy（CRT）is a less invasive therapy for ESCC; however, the five-year survival rate of locally advanced ESCC patients was only 37%. Therefore, the prediction of the CRT-responder is awaited. We have successfully identified 5 intrinsic subtypes（1a/M1, 2a/I, 3b, 5/M2, and 7/E）of ESCCs by gene expression profile-based unsupervised clustering of 274 biopsy samples obtained before treatment. For cases treated with CRT, the 5-year survival rate was 24% in subtype M2, whereas it was 74% in subtype E. Furthermore, we found transcriptional pathways activated characteristically in each subtype; the subtype E showed a differentiation phenotype, while the non-E subtypes including M1 and M2 showed an epithelial-mesenchymal transition phenotype. In 2016, we reported that SIX1 maintains tumor basal cells via TGF-β pathway and associates with poor prognosis in the non-E subtypes, and are preparing the investigator-initiated clinical trial of the immune checkpoint inhibitor for subtype I that shows tumor-specific cytotoxic T-lymphocyte activation signatures by CRT. To develop an IVD for predicting subtype E, we are collaborating with a pharmaceutical company and ten institutes for clinical investigation of 225 ESCC patients with the support of the Japan Agency for Medical Research and Development.