# Repurposing Bruton's tyrosine kinase (BTK) inhibitors to reverse immunosuppression in high-grade serous ovarian cancer (HGSC)

> **NIH NIH R03** · DANA-FARBER CANCER INST · 2022 · $89,000

## Abstract

Project Summary
Background: Patients with high grade ovarian serous carcinoma (HGSC) have limited therapeutic options
beyond surgery and chemotherapy. Metastatic HGSC has remained largely incurable and almost always
unresponsive to immunotherapies due to its extremely “cold” tumor microenvironment (TME). Success in curing
this devastating cancer will likely rely upon new therapies targeting the crucial drivers of immunosuppression in
the TME, yet to be determined.
Innovation: The all too common failure of drugs that are efficacious in pre-clinical models to translate to efficacy
in human malignancies requires the development of assays that mimic the tumor in its native setting of the TME.
This proposal helps bridge that gap by taking advantage of an all-human, high-throughput drug screen that
leverages for the first time the immunosuppressive features of HGSC malignant ascites. To repurpose small-
molecule drugs for novel therapy of HGSC, we designed a custom compound library containing 4, 292 small
molecules either FDA-approved or druggable with a known mechanism of action (MOA), screening of which has
identified 9 top targets including BTK inhibition. To date, BTK inhibitors have been approved as a treatment for
hematologic malignancies but have not been studied in many solid tumors including ovarian cancer (OvCa). The
proposal utilizes both novel syngeneic mouse models carrying the most frequent mutations in human OvCa and
a patient-derived organoid model as a faithful representation of the TME to determine the efficacy and MOA of
BTK inhibitors for HGSC therapy.
Hypothesis: BTK inhibitors can improve HGSC outcomes by simultaneous activation of anti-tumor immunity
and direct inhibition of tumor growth.
Specific Aims:
Aim 1: What is the role of BTK in HGSC tumor cells?
Aim 2: How does BTK inhibition activate HGSC intratumoral immune cells?
Aim 3: Do BTK inhibitors reduce tumor growth in vivo?
Impact: Success in this patient-focused, hypothesis-driven proposal will not only advance the current
understanding of key immunosuppressive mechanisms in HGSC, but also lead to discovery of novel therapeutic
small molecule targets and unique biomarkers. Additionally, our project may suggest new combinational
therapies of these novel targets with already marketed or in clinical trial drugs in the setting of HGSC. If
successful, our study will provide a novel treatment paradigm for HGSC immunotherapy.

## Key facts

- **NIH application ID:** 10512441
- **Project number:** 1R03CA262839-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** LAURIE Hollis GLIMCHER
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $89,000
- **Award type:** 1
- **Project period:** 2022-07-07 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512441

## Citation

> US National Institutes of Health, RePORTER application 10512441, Repurposing Bruton's tyrosine kinase (BTK) inhibitors to reverse immunosuppression in high-grade serous ovarian cancer (HGSC) (1R03CA262839-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10512441. Licensed CC0.

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