Annual Report 2021

Division of Cancer Therapeutics

Hideaki Ogiwara, Mariko Sasaki, Rie Komatsuzaki, Hinako Masuda, Ryosuke Saito

Introduction

 “Cancer Genomic Medicine” is an optimized cancer therapy based on gene aberrations. An oncopanel system using “NCC OncoPanel” became covered by insurance in June 2019. Cancer Genomic Medicine has started in earnest in Japan. Synthetic Lethal Therapy is promising for cancer with loss-of-function (LOF) gene mutations. The strategy for LOF gene mutated cancers is targeting vulnerability, including addiction to complementary genes or functional pathways. We have proposed therapeutic strategies for cancer cells. We aim to develop methods for cancer therapy based on gene aberrations in each cancer patient. Specifically, we focus on the development of therapeutic methods for cancer patients with loss-of-function mutations of chromatin regulator genes.

The Team and What We Do

 We work on the identification of promising therapeutic targets for loss-of-function mutated cancers.

Research activities

 ARID1A is a subunit of the SWI/SNF chromatin remodeling complex. ARID1A is deficient in many cancers, such as ovarian clear cell carcinoma, gastric cancer and pancreatic cancer. To investigate the identification of novel therapeutic targets for ARID1A-deficient cancers, we assembled cancer cell line panels including cell lines derived from ovarian, gastric, and pancreatic cancers. In addition, we established ARID1A-deficient cancer cell line models. By using these models, we are now screening promising therapeutic targets for ARID1A-deficient cancers.

 SMARCB1 is another subunit of the SWI/SNF chromatin remodeling complex. SMARCB1 is deficient in high-grade pediatric and juvenile cancers, including malignant rhabdoid tumor and epithelioid sarcoma. These cancer patients are firstly given surgery but later suffer from metastasis and relapse. Therefore, they require promising molecular target therapy, but it has not been developed. Therefore, we investigate the development of synthetic lethal therapy for SMARCB1-deficient cancers. We performed several multiplex screenings, and identified a synthetic lethal target for SMARCB1-deficient cancers. In addition, we investigated the mechanism of synthetic lethality between a target gene and SMARCB1. Based on the proof of concept and mode of action obtained in this study, we translated our research into drug discovery and development of an inhibitor in collaboration with a pharmaceutical company to apply this inhibitor for SMARCB1-deficient cancers to clinical use.

Education

 Young researchers were trained for obtaining a degree and participating in academic conferences.

Future Prospects

 Based on our research, we investigate drug discovery and development of our identified therapeutic targets. We hope that our research translates into clinical applications.

List of papers published in 2021

Journal

1. Kobayashi Y, Takeda T, Kunitomi H, Chiwaki F, Komatsu M, Nagai S, Nogami Y, Tsuji K, Masuda K, Ogiwara H, Sasaki H, Banno K, Aoki D. Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer. Pharmaceuticals (Basel, Switzerland), 15:2022