Division of Cancer Therapeutics

Division of Cancer Therapeutics
National Cancer Center Research Institute

Pioneering Next-Generation Synthetic Lethality

Turning Cancer’s Genetic Vulnerabilities into Novel Therapeutics

1. Our Mission

"Curing Cancer with Drugs based on Scientific Evidence"

In the Division of Cancer Therapeutics, we are dedicated to developing personalized therapies targeting the specific genetic abnormalities inherent to cancer cells. Moving beyond conventional chemotherapy, we aim to provide effective, low-burden treatments optimized for each patient.

Our research strategy follows three key steps:

• 1. Discovery: Identify promising therapeutic targets for cancers with specific genetic deficiencies (loss-of-function mutations).
• 2. Mechanism: Elucidate the molecular mechanisms underlying cancer suppression and drug efficacy.
• 3. Development: Collaborate with pharmaceutical partners to translate these discoveries into clinical applications.

We are particularly focused on delivering innovative solutions for pediatric, juvenile (AYA), and refractory cancers that currently lack effective cures.

2. Research Focus

The Concept: Synthetic Lethality

Turning "Undruggable" Defects into Targets

Conventional genomic medicine has successfully targeted activated oncogenes (e.g., EGFR mutations, ALK fusions). However, many intractable cancers are driven by loss-of-function mutations in tumor suppressor genes. Because the function is "missing," these genes cannot be directly inhibited.

We address this challenge using Synthetic Lethality. When a cancer cell loses a specific gene function (Gene A), it often becomes critically dependent on another gene (Gene B) to survive. By inhibiting Gene B, we can selectively kill the cancer cells while sparing normal cells. This approach transforms a genetic "weakness" into a therapeutic opportunity.

Example: Our work on ARID1A-deficient cancers identified a vulnerability in glutathione metabolism, leading to a novel metabolic targeting strategy (Ogiwara et al., Cancer Cell, 2019).

Our Innovation: "Paralog Co-inhibition"

Next-Generation Target Discovery (The "1-to-2" Strategy)

Current databases (e.g., DepMap) focus on "one-to-one" synthetic lethality. However, this approach has reached its technical limits. To expand the druggable genome, we pioneered a proprietary strategy: The Paralog Co-inhibition Method.

• The Problem: "One-to-one" screening misses targets where redundancy exists (e.g., paralogous genes compensating for each other).
• Our Solution: We target paralog pairs—two highly homologous proteins—simultaneously.
• The Breakthrough: In SMARCB1-deficient cancers (e.g., Rhabdoid tumors, Epithelioid Sarcoma), we discovered that inhibiting either CBP or p300 alone is insufficient. However, simultaneous inhibition of the CBP/p300 paralog pair induces synthetic lethality (Sasaki et al., Nature Communications, 2024).

This "1-to-2" strategy opens a new frontier in drug discovery, allowing us to target chromatin remodeling complexes and other essential machineries in refractory cancers.

Key Publications

Recent Highlights

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.
Nat Commun. 2024; 15(1):4770.

Sasaki M and Ogiwara H*.
Synthetic Lethal Therapy Based on Targeting the Vulnerability of SWI/SNF Chromatin Remodeling Complex-Deficient Cancers.
Cancer Sci. 2020; 111(3):774-782. 

Ogiwara H*, Takahashi K., Sasaki M., Kuroda T., Yoshida H., Watanabe R., Maruyama A., Makinoshima H., Chiwaki F., Sasaki H., Kato T., Okamoto A., Kohno T*.
Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers.
Cancer Cell. 2019; 35:177-190.e8. 

Ogiwara H, Sasaki M., Mitachi T., Oike T., Higuchi S., Tominaga Y., Kohno T*. 
Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality via apoptotic cell death due to abrogation of MYC expression.
Cancer Discov. 2016; 6(4):430-445. 

Latest News

• June 26, 2024: New Discovery: Identification of promising therapeutic targets and inhibitors for SMARCB1-deficient pediatric and AYA cancers.
• January 25, 2019: Research Update: Discovery of a new metabolism-targeting treatment for ARID1A-mutated ovarian clear cell carcinoma.

For Pharmaceutical Companies

Collaborate on Drug Discovery

We possess a proprietary screening system based on our "Paralog Co-inhibition Method" and a robust library of intractable cancer models. We are eager to partner with pharmaceutical companies to translate our promising drug discovery seeds into clinical candidates.

• Opportunities: Licensing of drug targets, collaborative research on novel inhibitors, and validation using our refractory cancer models.

Contact Information

Division of Cancer Therapeutics National Cancer Center Research Institute 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Hideaki Ogiwara, Ph.D. (Chief) [Contact]