# Optimization of Autophagy Inhibition as a Clinical Target for Brain Tumors

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $340,927

## Abstract

Project Summary
Central nervous system (CNS) tumors are the leading cause of death in pediatric oncology. While there have
been great advancements in survival for some tumors, the presence of BRAF-mutations is correlated with a poor
prognosis. Additionally, low-grade gliomas (LGG) that present in the midline result in increased neurologic
impairment. The significant morbidity and mortality of these tumors highlights that new treatment strategies are
urgently needed for this population. My research combines two potential strategies to improve survival in this
high-risk patient population by 1) using a precision medicine approach and small molecule inhibitors targeting a
pathway upregulated by specific mutation, and 2) a broader approach by inhibiting survival pathways such as
autophagy. My published and preliminary data suggest autophagy inhibition in mitogen-activated protein kinases
(MAPK) pathway driven CNS tumors is an effective therapeutic target across tumor types, is synergistic with
MAPK pathway targeted chemotherapeutics, and can be optimized for rapid translation to clinical trials. It is vital
to better understand how and why autophagy inhibition is effective in these tumors, how best to inhibit the
pathway, and what additional biomarkers might be available for autophagy dependence to plan effective future
autophagy inhibition trials and improve the survival of these patients. These studies will develop the pre-clinical
data needed to establish and optimize autophagy inhibition as a clinical target for autophagy addicted brain
tumors. Aim 1 will determine the optimal target for autophagy inhibition in BRAF mutated CNS tumors. The multi-
step nature of autophagy lends itself to the several opportunities to disrupt the process. This aim will identify the
most appropriate pharmacologic autophagy inhibitors to pursue for CNS tumors. Aim 2 will determine if the
BRAFV600E mutation is required for autophagy dependence in CNS tumor cells, or if any cause of a dysregulated
MAPK pathway is sufficient to identify autophagy dependence. This aim will provide biomarkers of autophagy
dependence beyond BRAFV600E, which we have shown as a sensitive predictor of autophagy addiction and
response to autophagy targeted inhibitors. It will expand the pool of patients that may benefit from clinical
autophagy inhibition. Aim 3 will determine the mechanism by which autophagy inhibition overcomes BRAF
inhibitor resistance mechanisms in CNS tumors. This effect is consistent across multiple tumor types and
molecularly-distinct resistance mechanisms and preliminary evidence suggests this is related to regulation of
key BH3 proteins and apoptosis. Elucidating the mechanism by which autophagy reverses resistance to RAF
pathway inhibition will provide a better understanding of how to ensure continued response to these therapies
and suggest additional combination therapies, such as BH3 mimetics, that can be successful in these patients.

## Key facts

- **NIH application ID:** 10411996
- **Project number:** 5R01NS107313-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jean Marie Mulcahy Levy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $340,927
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10411996

## Citation

> US National Institutes of Health, RePORTER application 10411996, Optimization of Autophagy Inhibition as a Clinical Target for Brain Tumors (5R01NS107313-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10411996. Licensed CC0.

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