Annual Report 2022

Division of Cancer Therapeutics

Hideaki Ogiwara, Mariko Sasaki, Rie Komatsuzaki, Hinako Masuda

Introduction

 “Cancer Genomic Medicine” is an optimized cancer therapy based on gene aberrations. 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 based on a loss-of-function mutation in refractory 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 and gastric cancer. To investigate the identification of novel therapeutic targets for ARID1A-deficient cancers, we have established cancer cell line panels and ARID1A-deficient cancer cell line models. By using these models, we identified promising therapeutic targets for ARID1A-deficient cancers. We translated our research into drug discovery and development of an inhibitor in collaboration with a pharmaceutical company to apply this inhibitor for ARID1A-deficient cancers to clinical use.

 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. We identified a synthetic lethal target for SMARCB1-deficient cancers. In addition, we investigated the mechanism of synthetic lethality between a target gene and SMARCB1. Furthermore, 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. We have just identified candidates of inhibitors for the target.

Education

 Young researchers were trained for 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 2022

Journal

1. Kanada R, Kagoshima Y, Suzuki T, Nakamura A, Funami H, Watanabe J, Asano M, Takahashi M, Ubukata O, Suzuki K, Aikawa T, Sato K, Goto M, Setsu G, Ito K, Kihara K, Kuroha M, Kohno T, Ogiwara H, Isoyama T, Tominaga Y, Higuchi S, Naito H. Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor. Journal of medicinal chemistry, 66:695-715, 2023