# ABT-199 based therapies to treat  neuroblastoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $359,846

## Abstract

High-risk neuroblastoma accounts for the second most pediatric cancer deaths.
Amplification of MYCN accounts for many of these cases, while other less-understood mechanisms account for
non-MYCN amplified high-risk neuroblastoma. We have recently demonstrated that amplified MYCN is
synthetic lethal to the FDA-approved BCL-2 inhibitor, venetoclax (ABT-199). Herein, we uncover several
rational implementations of venetoclax in MYCN-amplified neuroblastoma therapy and aim to preclinically test
them. In addition, we provide rational and evidence that venetoclax can be effective in combination in high-risk
MYCN-wild-type neuroblastoma, based on a newly discovered apoptotic block in these cancers. Lastly,
through high-throughput drug screening, we uncover a novel class of drug that has potent, specific and broad
activity across neuroblastoma, and combines with venetoclax to eliminate virtually all neuroblastoma cells.
Objectives: High-risk neuroblastoma is refractory to current treatment regimens. By studying the molecular
vulnerabilities of these cancers, we propose several new promising treatments to specifically combat subsets
of high-risk neuroblastoma, with the overall goal to ready these for clinical testing.
Specific Aim #1. Determine anti-cancer activity of standard-of-care chemotherapy and venetoclax
against molecularly heterogeneous neuroblastoma cell lines and animal models.
Here, we will evaluate the efficacy of venetoclax with the standard-of-care chemotherapy in multiple mouse
models of neuroblastoma.
Specific Aim 2: Characterize the efficacy and safety of venetoclax/ MDM2 inhibitor combination therapy
in p53 wild-type neuroblastoma in cell lines and animal models.
Here, we will determine the mechanisms of in vitro efficacy of MDM2 inhibitors in combination with venetoclax
in p53 wild-type neuroblastoma, and define vivo efficacy and safety.
Specific Aim 3: Characterize the efficacy and safety of H3K27me3 inhibition alone and in combination
with venetoclax.
We have identified a novel class of drug with potent and specific activity in neuroblastoma. We will further
define the mechanism(s) of this sensitivity in vitro and in vivo.
Study Design/Methods: Utilizing an innovative pharmacogenomics approach that has uncovered several
novel targeted therapies that have reached or are headed to clinical trials, we will evaluate other novel drugs
for efficacy in neuroblastoma in combination with venetoclax. Using multiple in vitro models of neuroblastoma,
we will study the relationship between particular drug vulnerabilities and the molecular underpinnings of that
sensitivity. Lastly, we will rigorously evaluate preclinical efficacy and safety of our novel targeted therapy
combinations in multiple and diverse animal models of neuroblastoma.

## Key facts

- **NIH application ID:** 9899951
- **Project number:** 5R01CA215610-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Anthony Charles Faber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $359,846
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899951

## Citation

> US National Institutes of Health, RePORTER application 9899951, ABT-199 based therapies to treat  neuroblastoma (5R01CA215610-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899951. Licensed CC0.

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