# Pathological epigenetic hyper-plasticity promotes acquisition of pro-tumor states in cancer

> **NIH NIH K22** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $200,409

## Abstract

PROJECT SUMMARY
The candidate for this K22 NCI Transition Career Development Award is Dr. William Flavahan, a postdoctoral
fellow at Massachusetts General Hospital and the Broad Institute. This award focuses on Dr. Flavahan’s long-
term goal of becoming an independent investigator studying cancer epigenetics. Epigenetics are the fundamental
mechanisms that control cell identity, enforcing the transcriptional programs and driving cellular phenotypes.
Epigenetic processes are frequently altered in cancer, and may serve as initiating events for tumor formation,
driving malignant transformation of the cellular identity. Epigenetic processes are tightly calibrated, allowing
transitions along set cellular identity programs for processes such as cellular differentiation or response to
external stimuli. Building on Dr. Flavahan’s previous work, the enclosed application seeks to test the hypothesis
that cancer-specific epigenetic hyperplasticity forms the basis of a tumor-specific mechanism of regulatory
evasion and transformation. The biological setting this application proposes to test is that of succinate
dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST). While the majority of GIST present with
a mutation in the oncogene KIT and are highly clinically responsive to KIT inhibition, SDH-deficient GIST are
resistant to most forms of therapy. This application presents preliminary data showing that the primary
mechanism of tumor transformation is identical to Dr. Flavahan’s previously described paradigm of loss of
epigenetic insulation protecting an oncogene from a potent housekeeping superenhancer. These data show
that in SDH-deficient GIST, loss of an insulator activates FGF ligand genes, and a patient-derived xenograft
model of this disease is highly responsive to FGFR-targeted therapy. This application seeks to first test the
hypothesis that epigenetic plasticity is responsible for the transformation and vulnerability of these tumors to
FGFR inhibition and that it may drive resistance to the same treatment. Second, this application seeks to delve
into the underpinnings of the epigenetic lesion to demonstrate, using models of epigenetic inheritance and allele-
specific interrogation of clinical patient resection, that the loss of insulation occurs at tumor initiation and may be
the driver lesion behind SDH-deficient GIST. The application will leverage cutting edge epigenetic assays as
well as advanced cell culture engineering and xenograft models of disease. The main focus of this application is
to understand the fundamental epigenetic processes that enable cancer cells to drive the disease and hopefully
create insight that will allow for therapeutic targeting and treatment. As the underlying epigenetic state that
creates this lesion (DNA hypermethylation) is commonplace in cancer, the results from these projects may have
great relevance beyond GIST.

## Key facts

- **NIH application ID:** 10246788
- **Project number:** 5K22CA237846-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** William Alexander Flavahan
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $200,409
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246788

## Citation

> US National Institutes of Health, RePORTER application 10246788, Pathological epigenetic hyper-plasticity promotes acquisition of pro-tumor states in cancer (5K22CA237846-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246788. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*