Research Projects

【Introduction】

Our Approach: Expanding the Druggable Genome

Current precision medicine primarily targets activated oncogenes. However, the majority of intractable cancers are driven by "loss-of-function" mutations in tumor suppressor genes, which have historically been considered "undruggable."

Our goal is to overcome this barrier. We develop innovative therapeutic strategies using Synthetic Lethality to target cancers that cannot be treated with conventional molecularly targeted drugs.

【Project1: Concept】

Targeting "Loss-of-Function" via Synthetic Lethality

• The Limitation: Conventional targeted therapies (e.g., EGFR inhibitors) are effective only against activated oncogenes. They are ineffective against cancers driven by the loss of tumor suppressor genes (e.g., ARID1A, SMARCB1).
• Our Strategy: We exploit the specific vulnerabilities created by these gene losses. When a cancer cell loses Gene A (Tumor Suppressor), it often becomes critically dependent on Gene B for survival. By inhibiting Gene B, we can induce Synthetic Lethality, selectively killing cancer cells while sparing normal cells.
• Key Focus: Identifying synthetic lethal partners for major tumor suppressor genes.

【Project 2: Target Area】

Focusing on Chromatin Regulators

• Why Chromatin? Next-generation sequencing has revealed that mutations in chromatin regulatory genes (SWI/SNF complexes, histone modifiers) are highly frequent across various cancer types.
• The Opportunity: These mutations often cause loss of function, creating distinct epigenetic dependencies. We focus on:
• Chromatin Remodeling Complexes: (e.g., SMARCB1, ARID1A)
• Histone Modifiers: (e.g., CBP, p300)
• Goal: Establish precision medicine for cancers with chromatin defects, which are common in refractory and pediatric cancers.

【Project 3: Methodology / Innovation】

Next-Generation Strategy: "Paralog Co-inhibition"

• Beyond "One-to-One": Traditional synthetic lethality searches look for single-gene targets. However, functional redundancy often masks potential targets.
• Our Innovation (The 1-to-2 Strategy): We developed a proprietary screening method called "Paralog Co-inhibition." This approach targets paralog pairs—two highly homologous proteins—simultaneously.
• Breakthrough: By inhibiting two paralogs at once (e.g., CBP and p300), we can induce lethality in cancers with specific genetic defects where single inhibition fails. This expands the potential drug targets exponentially beyond the limits of conventional screening.

【Summary & Impact】

Targeting Unmet Medical Needs

We are applying these strategies to develop treatments for:

• Refractory Solid Tumors: Lung cancer, Diffuse gastric cancer, Pancreatic cancer, Esophageal cancer.
• Gynecologic Cancers: Ovarian clear cell carcinoma.
• Pediatric & Rare Cancers: Malignant rhabdoid tumors, Epithelioid sarcoma, Synovial sarcoma.