# Targeting cell cycle dysregulation in GIST

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $285,490

## Abstract

PROJECT SUMMARY
Research: Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal neoplasms.
Most GISTs are initiated by KIT or PDGFRA gain-of-function mutations which are therefore already found in
microscopic forms of GISTs. During progression to aggressive disease, early GISTs acquire a canonical
sequence of chromosomal deletions including 14q deletions that inactivate MAX, fostering cell cycle
dysregulation through p16 transcriptional repression. Genomic mutations that directly inactivate p16 and other
cell cycle regulators occur at subsequent stages in progression. While tyrosine kinase inhibitor (TKI) therapies
for advanced GISTs result in dramatic clinical responses, secondary TKI resistance often leads to fatal disease
progression, highlighting the need for novel targets defined by biologic vulnerabilities, particularly aberrations
present across the entire metastatic burden in a given patient. The objective of this mentored research career
development proposal is to characterize the events in GIST genomic progression that lead to incremental cell
cycle dysregulation, particularly aberrations impacting p16/CDK4/RB1, with the goal of developing novel
therapies for patients with advanced GIST. Leveraging GIST as a unique model amongst sarcomas to study
genomic progression, my Aim 1 studies address the hypothesis that cell cycle perturbations, including
targetable aberrations of the p16/CDK4/RB1 pathway, are virtually universal events in advanced GIST. The
Aim 2 studies are motivated by my hypothesis that GIST responses to CDK4/6-inhibition will be maximized by
combination approaches. These studies use genome-wide CRISPR screens to identify synthetic lethals with
CDK4/6-inhibition in GIST. The Aim 3 studies are preclinical in vitro and in vivo validations of combination
therapies that might increase GIST response to CDK4/6 inhibition. Candidate Career Goals: To expedite these
translational research studies, I will foster international collaborations with experts in sarcoma genomics,
biology, pathology, medical/surgical oncology, and scientific innovation. The studies encompassed by this
career development award will be critical to obtain the training, knowledge, and expertise needed to
successfully establish an independent translational sarcoma research program and apply for a tenure-track
physician-scientist position in academic pathology. The proposed research will be performed under the
mentorship of Dr. Jonathan A. Fletcher, leader of two international GIST research consortia, with guidance
from an interdisciplinary Scientific Advisory Committee composed of leading experts in the sarcoma field.
Environment: Brigham and Women’s Hospital (BWH) houses internationally recognized research programs in
scientific discovery training physician-scientists for leadership roles in translational research. The BWH
Department of Pathology is home to global leaders in sarcoma/GIST diagnostics, biology, and genetics, who
collaborate...

## Key facts

- **NIH application ID:** 9975728
- **Project number:** 5K08CA241085-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Inga-Marie Schaefer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $285,490
- **Award type:** 5
- **Project period:** 2019-07-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975728

## Citation

> US National Institutes of Health, RePORTER application 9975728, Targeting cell cycle dysregulation in GIST (5K08CA241085-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975728. Licensed CC0.

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