Annual Report 2024
Division of Cancer Therapeutics
Hideaki Ogiwara, Mariko Sasaki, Shohei Takase, Harumi Hirano, Makoto Fukushima, Yoshie Okimoto, Hinako Masuda
Introduction
Our laboratory focuses on genetic mutations, a hallmark of cancer, with the goal of developing optimal therapies tailored to the specific genetic profile of each patient. In particular, we concentrate on chromatin-regulating genes, which frequently undergo loss-of-function mutations in many types of cancer, including those that are difficult to treat. We are dedicated to discovering specific and promising therapeutic targets in cancers that harbor these genetic deficiencies. By identifying therapeutic targets based on these genetic abnormalities and elucidating their underlying mechanisms, we aim to establish new, evidence-based cancer therapies. Furthermore, we work to translate our findings into clinical applications by pursuing an integrated approach, from target discovery to novel drug development, in collaboration with pharmaceutical companies.
The Team and What We Do
We work on identifying promising therapeutic targets based on a loss-of-function mutation in refractory cancers.
Research Activities
Genetic mutations in the SWI/SNF chromatin remodeling complex are found in approximately 20% of all cancers. In our research, we have identified multiple novel therapeutic targets for cancers harboring these mutations.
First, we discovered that CBP/p300 inhibitors exhibit synthetic lethality in cancers deficient in the cBAF subcomplex of the SWI/SNF complex, which includes subunits such as SMARCB1 and SMARCA4. We elucidated the mechanism, showing that these drugs induce apoptosis (cell death) in cancer cells by suppressing the transcription of KREMEN2. A press release for this finding was issued on June 26, 2024, and we are currently advancing drug development in collaboration with a pharmaceutical company.
Second, we revealed that cancers with deficiencies in a broad range of SWI/SNF factors, including ARID1A, SMARCB1, and PBRM1, are vulnerable to oxidative stress. Exploiting this characteristic, we found that the glutathione inhibitor eprenetapopt is an effective therapeutic option.
Furthermore, we identified the deubiquitinating enzyme USP8 as a novel therapeutic target, specifically in ARID1A-deficient ovarian clear cell carcinoma. We determined the mechanism whereby inhibiting USP8 suppresses the FGFR2-STAT3 pathway, leading to the induction of apoptosis in cancer cells.
These findings provide promising therapeutic strategies for SWI/SNF-mutated cancers, which have been notoriously difficult to treat, and we are exploring drug development for these targets in partnership with pharmaceutical companies.
Education
We provided research supervision and educational guidance to researchers, including coaching for presentations at academic conferences and other scientific meetings.
Future Prospects
We will collaborate with pharmaceutical companies and other partners to engage in drug discovery and development for novel inhibitors. These inhibitors will target the new therapeutic targets that have emerged from our research, which are expected to be effective against cancers with specific genetic abnormalities. The ultimate goal is to advance these drugs through clinical trials to realize their application as a new cancer therapy.
List of papers published in 2024
Journal
1. Sasaki M, Kato D, Yoshida H, Shimizu T, Ogiwara H. Efficacy of CBP/p300 Dual Inhibitors against Derepression of KREMEN2 in cBAF-Deficient Cancers. Cancer research communications, 5:24-38, 2025
2. Saito R, Fukushima M, Sasaki M, Okamoto A, Ogiwara H. Targeting USP8 causes synthetic lethality through degradation of FGFR2 in ARID1A-deficient ovarian clear cell carcinoma. NPJ precision oncology, 9:69, 2025
3. Sasaki M, Kato D, Murakami K, Yoshida H, Takase S, Otsubo T, Ogiwara H. Targeting dependency on a paralog pair of CBP/p300 against de-repression of KREMEN2 in SMARCB1-deficient cancers. Nature communications, 15:4770, 2024
4. Sasaki M, Ogiwara H. Efficacy of glutathione inhibitor eprenetapopt against the vulnerability of glutathione metabolism in SMARCA4-, SMARCB1- and PBRM1-deficient cancer cells. Scientific reports, 14:31321, 2024