Annual Report 2019
Division of Cancer Therapeutics
Hideaki Ogiwara, Mariko Sasaki, Hinako Masuda, Ryosuke Saito
Introduction
The Division of Cancer Therapeutics was launched in September 2019. “Cancer Genomic Medicine” is 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. We aim to develop methods for cancer therapy based on gene aberrations in each cancer patient. Specifically, we focus on 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 identification of promising therapeutic targets for loss-of-function mutated cancers.
Research activities
Previously, we found that ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, increases the intracellular levels of glutathione (GSH) by upregulating solute carrier family 7 member 11 (SLC7A11). Diffuse-type gastric cancer is an aggressive tumor that is frequently associated with ARID1A deficiency. We investigated the efficacy of GSH inhibition for the treatment of diffuse-type gastric cancer with ARID1A deficiency using ARID1A-proficient or -deficient patient-derived cells (PDCs). ARID1A-deficient PDCs were selectively sensitive to the GSH inhibitor APR-246, the GCLC inhibitor buthionine sulfoximine, and the SLC7A11 inhibitor erastin. Expression of SLC7A11, which is required for incorporation of cystine, and the basal level of GSH were lower in ARID1A-deficient PDCs than in ARID1A-proficient PDCs. Treatment with APR-246 decreased intracellular GSH levels, leading to the excessive production of reactive oxygen species (ROS), and these phenotypes are suppressed by supply of cystine and GSH compensators. Taken together, vulnerability of ARID1A-deficient gastric cancer cells to GSH inhibition is caused by decreased GSH synthesis due to diminished SLC7A11 expression. This study suggests that GSH inhibition is a promising strategy for the treatment of diffuse-type gastric cancers with ARID1A deficiency.
Ovarian clear cell carcinoma (OCCC) is often resistant to conventional standard chemotherapy using cytotoxic drugs. 50% of OCCC harbors a unique genomic feature of frequent ARID1A deficiency. We investigated standard chemotherapeutic options suitable for ARID1A-deficient OCCC patients. ARID1A-knockout and ARID1A-deficient OCCC cells had selective sensitivity to gemcitabine. IC50 values for gemcitabine of ARID1A-deficient cells were significantly lower than those of ARID1A-proficient cells. Growth of OCCC xenografts with ARID1A deficiency was inhibited by administration of gemcitabine, and gemcitabine treatment effectively induced apoptosis in ARID1A-deficient OCCC cells. Three ARID1A-deficient OCCC patients had significantly longer progression-free survival after gemcitabine treatment than four ARID1A-proficient OCCC patients. An ARID1A-deficient case that was resistant to multiple cytotoxic drugs, including paclitaxel plus carboplatin in the adjuvant and etoposide plus irinotecan in the first-line treatment, exhibited a dramatic response to gemcitabine in the second-line treatment.
Education
We trained young researchers 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 to clinical applications.
List of papers published in 2019
Journal
1. Sasaki M, Ogiwara H. Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex-deficient cancers. Cancer Sci, 111:774-782, 2020
2. Sasaki M, Chiwaki F, Kuroda T, Komatsu M, Matsusaki K, Kohno T, Sasaki H, Ogiwara H. Efficacy of glutathione inhibitors for the treatment of ARID1A-deficient diffuse-type gastric cancers. Biochem Biophys Res Commun, 522:342-347, 2020
3. Kuroda T, Ogiwara H, Sasaki M, Takahashi K, Yoshida H, Kiyokawa T, Sudo K, Tamura K, Kato T, Okamoto A, Kohno T. Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma. Gynecol Oncol, 155:489-498, 2019