Annual Report 2020
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 the loss-of-function (LOF) gene mutation. Strategy for LOF gene mutated cancers is targeting vulnerability, including addiction to complemental genes or functional pathways. We have been 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. Previously, we found that ARID1A regulate the increase of the intracellular levels of glutathione (GSH) by upregulating solute carrier family 7 member 11 (SLC7A11) in models of ovarian clear cell carcinoma (OCCC) and diffuse-type gastric cancer. These cancers are aggressive and are frequently associated with ARID1A deficiency. Many of genes other than the ARID1A coding subunit of the SWI/SNF chromatin remodeling complex are frequently deficient in various cancers. Therefore, the efficacy of GSH inhibition has been investigated for the treatment of cancers with SWI/SNF chromatin remodeling complex deficiency. SWI/SNF-deficient cells derived from various cancers were selectively sensitive to the GSH inhibitors. Taken together, SWI/SNF-deficient cancer cells are vulnerable to GSH inhibition. This study suggests that GSH inhibition is a promising strategy for the treatment of cancers with SWI/SNF deficiency.
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, these cancer patients are required for promising molecular target therapy, but it has not been developed. Therefore, we investigate development of synthetic lethal therapy for SMARCB1-deficient cancers. By performing multiplex screening, a synthetic lethal target for SMARCB1-deficient cancers has been identified. However, there is no potent and selective drug available for clinical use. Therefore, developing an inhibitor is needed for SMARCB1-deficient cancer. We are investigating elucidation of mechanism of synthetic lethality between target and SMARCB1. Based on proof of concept and mode of action obtained in this study, we aim to translate our research into drug discovery and development of an inhibitor in collaboration with a pharmaceutical company and apply this inhibitor for SMARCB1-deficient cancers for 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.