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Division of Cancer Therapeutics

Original Thinking. Original Drugs.

Division of Cancer Therapeutics, National Cancer Center Research Institute

Unraveling synthetic lethality at its deepest level — from this lab, to the world.

We integrate proprietary paralog co-inhibition screens with rare-cancer cell line panels to advance from mechanistic discovery to drug-discovery seeds — building a global hub for synthetic lethality research that links textbook-rewriting biology to therapeutics for tomorrow's patients.

Our Research Identity

Originality × Depth × Global Hub

Our research is built on three intersecting axes that run through every project in the laboratory.

Originality

We pursue cancer vulnerabilities through screens of our own design. Our flagship paralog co-inhibition strategy — together with custom CRISPR/Cas9 screens against rare-cancer cell line panels — surfaces targets that conventional one-to-one synthetic lethality screens have systematically missed.

Depth

We do not stop at "what works." We pursue mechanism to its biochemical and structural endpoint. Resolving exactly why a vulnerability exists, and how it can be drugged selectively, is our prerequisite for translational reproducibility.

Global Hub

Centered on SWI/SNF-deficient cancers and their metabolic vulnerabilities, we are building the international center of gravity for synthetic lethality research — anchored in Tokyo, with collaborations spanning academia and the pharmaceutical industry worldwide.

Disease Focus

We target cancers driven by chromatin-remodeling defects and other genetic alterations for which no effective targeted therapies are currently available — clear unmet medical needs at the intersection of rare, refractory, and pediatric oncology.

Category	Representative Cancers	Driver Alterations
Rare, pediatric, and AYA cancers	Malignant rhabdoid tumor / epithelioid sarcoma / synovial sarcoma	SMARCB1 deficiency / SS18-SSX fusion
Refractory gynecologic and gastrointestinal cancers	Ovarian clear cell carcinoma / diffuse-type and scirrhous gastric cancer	ARID1A deficiency / SMAD4 deficiency
Refractory solid tumors	Non-small cell lung cancer / pancreatic cancer / esophageal cancer / renal cell carcinoma	SMARCA4 / KDM6A / PBRM1 deficiency / KRAS mutations

What unites these cancers is a shared paradox: each carries a clear genetic vulnerability, yet none has a targeted therapy that exploits it directly. Our mission is to identify those vulnerabilities and convert them into selective therapies.

→ See Research Projects for project-level details on each disease focus.

Recent Highlights

The three studies below illustrate the laboratory's signature pattern: mechanistic dissection paired directly with drug-discovery seed generation.

1. GCLC Inhibitors Trigger Ferroptosis in SMARCB1-Deficient Rare Cancers

Takeuchi et al., Cancer Res. 2026

We discovered that SMARCB1-deficient rare cancers — including malignant rhabdoid tumor — are critically dependent on glutathione metabolism for redox homeostasis. Our newly developed GCLC inhibitors (GCLCi1 / GCLCi0) deplete intracellular glutathione and induce ferroptosis (iron-dependent cell death), producing strong antitumor activity in preclinical models. This work was conducted in collaboration with Ono Pharmaceutical Co., Ltd.

→ Research Highlight: Glutathione Metabolic Vulnerability

2. Pyrimidine Metabolic Vulnerability and the Repositioning of Gemcitabine in ARID1A-Deficient Diffuse Gastric Cancer

Hirano et al., Mol Cancer Res. 2026

ARID1A loss in diffuse-type gastric cancer (including scirrhous gastric cancer) suppresses the pyrimidine transporter SLC28A3 and creates a metabolic bottleneck in the dCTP pool. Treating these cells with the existing chemotherapeutic gemcitabine exploits this dual-hit vulnerability and induces selective cell death — a paradigmatic example of drug repositioning grounded in a defined molecular mechanism.

→ Research Highlight: Drug Repositioning

3. USP8 Synthetic Lethality in ARID1A-Deficient Ovarian Clear Cell Carcinoma

Saito et al., NPJ Precis Oncol. 2025

By integrating CRISPR/Cas9 screens with DepMap dependency analysis, we identified the deubiquitinating enzyme USP8 as a synthetic-lethal target in ARID1A-deficient ovarian clear cell carcinoma. USP8 inhibition triggers FGFR2 degradation and selectively eliminates ARID1A-deficient cells — a flagship case of our data-driven target discovery approach.

→ Research Highlight: Data-Driven Target Discovery

From target to lead — our discoveries are advancing toward therapeutics.

Research Strategy

Our work is organized around three complementary strategies.

1. Paralog Co-Inhibition Strategy

A next-generation framework for synthetic lethality, pioneered in our laboratory.

Approximately one-third of human genes have functional paralogs whose redundancy buffers single-gene loss-of-function. Conventional one-to-one synthetic lethality screens systematically miss these paralog-redundant targets. We have developed a screening platform that simultaneously inhibits paralog pairs, uncovering targets such as the CBP/p300 axis in SMARCB1-deficient cancers — a class of vulnerabilities invisible to conventional approaches.

Key publications: Nat Commun 2024 (Sasaki et al.); Cancer Res Commun 2025 (Sasaki et al.).

2. Targeting Metabolic Vulnerabilities Driven by Epigenetic Dysregulation

Loss of SWI/SNF chromatin remodeling complex subunits (ARID1A, SMARCB1, SMARCA4, PBRM1) creates collateral fragility in defined metabolic pathways — most notably glutathione and pyrimidine metabolism. We dissect these vulnerabilities through integrated metabolomics and multi-omics profiling (RNA-seq, ATAC-seq, CUT&RUN), and convert the resulting mechanistic insight into therapeutic strategies.

Key publications: Cancer Cell 2019 (Ogiwara et al.); Cancer Res 2026 (Takeuchi et al.); Mol Cancer Res 2026 (Hirano et al.).

3. Clinical-Grade Screening Platforms

Leveraging the National Cancer Center's clinical specimen network, we have built proprietary cell line panels, PDX models, and organoids representing rare and Japan-specific cancer subtypes — many absent from public dependency databases such as DepMap. This enables translational evaluation in models with direct clinical relevance, end-to-end from target identification to chemical lead validation.

→ See Research Projects for the full strategy and Research Highlights for thematic deep dives.

Selected Publications and News

Selected Publications

The three papers below define the laboratory's intellectual trajectory. The complete publication list is on the Publications page.

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. Flagship paper for the paralog co-inhibition strategy. Established CBP/p300 dual inhibition as a synthetic-lethal therapy in SMARCB1-deficient cancers. → PubMed

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(2):177-190.e8. Demonstrated that ARID1A-deficient cancers are dependent on glutathione metabolism — a foundational paper for the metabolic-vulnerability program. → PubMed

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. Origin paper for the laboratory's synthetic-lethality program — established p300 dependency in CBP-deficient cancers and laid the conceptual groundwork for paralog-based synthetic lethality. → PubMed

Drug-Discovery Seeds (Published Research Compounds)

Our peer-reviewed publications include the following research-stage compounds:

CP-C27 — dual CBP/p300 inhibitor (Sasaki et al., Nat Commun 2024)
GCLCi1 / GCLCi0 — novel GCLC inhibitors (Takeuchi et al., Cancer Res 2026)

These are research-use compounds disclosed in the corresponding publications.

Engage with Us

We welcome three modes of engagement.

For Industry and Academic Partners — Collaboration

Bringing an academic drug-discovery engine to your pipeline.

Our partnership offering is anchored by:

A proprietary paralog co-inhibition library — not available in public dependency databases.
Clinical-grade rare-cancer cell line panels, PDX models, and organoids — including Japan-specific cancer subtypes underrepresented in international resources.
End-to-end translational evaluation — from target identification, through chemical-lead validation, to indication-expansion analysis.

→ Contact for collaboration inquiries

For Postdocs and Graduate Students — Recruitment

A laboratory where clinical questions become molecular answers.

International applicants are welcome.
Affiliated graduate programs include Tokyo University of Science, Institute of Science Tokyo, and Nagasaki University.
We accept candidates from medical, pharmaceutical, and basic-science backgrounds, with structured mentoring and publication support.
Direct inquiries (CV and research statement) to the PI: hogiwara●ncc.go.jp.

→ Lab Members and Recruitment

For Media — Press Inquiries

For interviews and commentary on our research, please contact us via the address below.

→ Contact and Access

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Last Updated: 2026-05-06 Editor: Hideaki Ogiwara (PI)