# Examining the EYA2/MYC axis in Group 3 Medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $425,149

## Abstract

Project Summary:
Medulloblastoma (MB) is the most common malignant brain tumor in children. Treatment for MB includes
surgery, radiation and chemotherapy. Unfortunately, long-term morbidity, including lifelong cognitive
deficiencies, endocrine dysfunction, neurological defects, emotional and social problems, and secondary
tumors are associated with current treatments. Such treatment associated side effects are particularly evident
in children, as their brains are still growing, and they can survive many years after treatment. MB is a
heterogeneous disease with at least 12 different subgroups identified. Patients with high MYC expressing MB
(25-30% of cases; referred to as Group3) have the worst prognosis (survival at 5 years is 41.9% in the Group
3γ subtype), and MYC is known to be a major driver of this MB subtype. Thus, for Group 3 MB there is a
pressing need to develop novel targeted therapies that confer limited toxicities. However, MYC has remained
“undruggable”. To identify novel therapeutic targets in high MYC expressing MBs, we have begun to examine
the role of the EYA2 transcriptional co-factor and dual phosphatase (Tyr and Ser/Thr in separable domains) in
MB progression. Intriguingly, EYA2 has been shown to control MYC, both transcriptionally and post-
translationally, during embryonic development, but is normally downregulated after development is complete.
Our preliminary data show that EYA2 is overexpressed in Group3 MB compared to normal cerebellum and
other subtypes of MB, that it controls MYC levels in the context of Group3 MB, and that KO of EYA2
dramatically diminishes in vivo growth of Group3 MB. Our main objective in this proposal is to identify novel
druggable targets in Group 3 MB; targets that when inhibited will not lead to the significant side effects
associated with current MB therapies. To this end, we will test the hypothesis that the SIX1/EYA2
transcriptional complex and/or EYA2 phosphatase plays a critical role in Group 3 MB progression via
transcriptionally activating and/or stabilizing MYC, and that novel inhibitors targeting the activity of
EYA2 can diminish disease progression while conferring limited side effects. To address this
hypothesis, we will carry out three aims: 1) Determine which activity of EYA2 regulates MYC and contributes to
the aggressive nature of Group 3 MBs, 2) Determine if regulation of MYC by EYA2 is required for its effects on
MB growth and progression, 3) Determine whether EYA2 inhibition, genetically or pharmacologically (using
novel small molecule inhibitors targeting either its transcriptional activity with SIX1 or its Tyr phosphatase
activity), will provide a unique means to inhibit the critical oncogene, MYC, preventing MB progression in vivo.
If our hypothesis is correct, and EYA2 is a key, druggable regulator of MYC, we will have identified an achilles
heel not only for Group3 MB, but potentially for the many other MYC-dependent tumors. Targeting MYC
remains a “holy grail” in cancer ...

## Key facts

- **NIH application ID:** 9928134
- **Project number:** 5R01NS108396-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Heide L. Ford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,149
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928134

## Citation

> US National Institutes of Health, RePORTER application 9928134, Examining the EYA2/MYC axis in Group 3 Medulloblastoma (5R01NS108396-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928134. Licensed CC0.

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