# Characterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma

> **NIH NIH R00** · DANA-FARBER CANCER INST · 2020 · $249,000

## Abstract

Project Description/Abstract
 The targeting of chromatin modifiers is an increasingly attractive novel strategy to therapeutically inhibit
transcription factors. MYC, one of the most frequently amplified oncogenes in cancer, is one such transcription
factor that has proved difficult to target directly. Pediatric MYC-amplified medulloblastoma is a devastating
disease. 25% of all medulloblastoma harbor amplification of MYC-isoforms that result in activation of MYC
pathways. These tumors exhibit resistance to standard therapies used to treat medulloblastoma and are
characterized by rapid and rampant tumor progression. Strategies to inhibit MYC activation pathways are
desperately needed in the clinic for children diagnosed with this disease.
 Recently, inhibition of the epigenetic readers, BET-bromodomain proteins, has been found to be effective in
suppressing the growth of preclinical models of MYC driven tumors, including medulloblastoma. Indeed, early
phase clinical trials involving BET-bromodomain inhibitors are planned for children with recurrent MYC-driven
tumors including medulloblastoma. However, the precise mechanism of action of these inhibitors remains
unclear. In addition, clinical experience with other novel small molecule inhibitors has revealed that cancers
evolve to acquire resistance to targeted therapeutics. Characterizing resistance mechanisms allows for novel
therapeutic strategies to be designed to overcome these mechanisms and increase clinical efficacy of targeted
therapeutics. The goal of this proposal is to systematically characterize cancer cell evolution in
response to BET-bromodomain inhibition. This project will shed insight on the mechanism of action of
BET-bromodomain inhibitors and guide the development of combination therapies to optimize efficacy.
 Cancers have been shown to acquire genetic alterations to develop resistance to targeted therapeutics.
However, the mechanisms by which cancers evolve to acquire resistance to inhibition of chromatin modifiers
have not been determined. BET-bromodomain proteins regulate the transcription of genes key to determination
of cell-identity and cell-state. BET-bromodomain inhibitors have been shown to alter cell-state and cell-identity.
It is thus possible that changes in cell-state can influence sensitivity to BET-bromodomain inhibition and
contribute to the development of resistance. This proposal will systematically characterize the resistance
mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma. To achieve this, a number of
novel methodologies will be applied to characterize the genomic and epigenomic alterations that contribute to
the acquisition of resistance to BET-bromodomain inhibition. This proposal will determine whether the
acquisition of resistance is predetermined, will identify specific alterations in genes that contribute to resistance
and will explore how resistance to BET-bromodomain inhibition is influenced by
 This work will guide the devel...

## Key facts

- **NIH application ID:** 9902350
- **Project number:** 5R00CA201592-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pratiti Bandopadhayay
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-05-03 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902350

## Citation

> US National Institutes of Health, RePORTER application 9902350, Characterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastoma (5R00CA201592-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9902350. Licensed CC0.

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