# Mechanisms of resistance to WEE1 inhibition in Myc driven medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $419,996

## Abstract

PROJECT SUMMARY
Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and
demonstrates high level of heterogeneity. Treatment for MB includes chemotherapy and
radiation often resulting in long-term morbidity. MYC driven MB in particular are high risk
tumors with poor long-term survival. We previously identified WEE1 as a target in MYC driven
MB. WEE1 regulates MYC driven replication stress and high throughput chemical screening
identified high degree of synergy with gemcitabine. Further data suggest that MB tumors
become resistant to WEE 1 inhibition and that this mechanism is mediated by CDK7.. We
hypothesize CDK7 re-sensitizes MB cells to WEE1 inhibition by reprograming
the enhancer landscape to alter metabolic pathways and suppressing homologous
recombination DNA repair networks. To CDK7
that inhibition of
inhibition
MB
and
homologous
targeting
approaches
for
validate inhibition in combination with WEE1
as a therapeutic strategy we will pursue three key questions. 1. How dose CDK7 alter
enhancer landscape to modulate sensitivity to WEE1 inhibition? 2. Is combination of WEE1
CDK7 inhibition therapeutically effective in MB in vivo? 3. Can addition of agents that target
recombination mediated DNA repair potentiate CDK7/WEE1 mediated therapeutic
of MB? The results of this work are expected to yield important insights into
that could be used to inhibit MYC function in high-risk MB, and provide a rationale
the treatment of MYC driven MB, which represents the long-term goal of our research.

## Key facts

- **NIH application ID:** 10763383
- **Project number:** 5R01NS091219-08
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Rajeev Vibhakar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,996
- **Award type:** 5
- **Project period:** 2015-04-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763383

## Citation

> US National Institutes of Health, RePORTER application 10763383, Mechanisms of resistance to WEE1 inhibition in Myc driven medulloblastoma (5R01NS091219-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10763383. Licensed CC0.

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