# Proj 1 - Targeting Evolving Therapy Resistance

> **NIH NIH P01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $320,207

## Abstract

SUMMARY/ABSTRACT 
Neuroblastoma (NB) remains a leading cause of childhood cancer deaths, and the children who do survive are 
left with long-term side effects, many of which can be life threatening. In this era of more precise therapies, 
considerable efforts are being made to identify optimal targets. While the paradigm of molecularly targeted 
therapies holds great promise, genomic studies have revealed that NBs are characterized by extensive 
intratumor genetic heterogeneity, with subclonal oncogenic drivers often selected for during standard 
chemoradiotherapy. Our group discovered gain-of-function mutations in the ALK receptor tyrosine kinase as 
the etiology for familial NB, and at the same time co-discovered with several other groups identical mutations 
as the most frequent somatic single nucleotide variants leading to a potent oncogenic driver in up to 15% of 
newly diagnosed high-risk cases. Our more recent work has shown that activating mutations in the ALK-RAS- 
MAPK pathway are highly enriched in the relapse NB genome, providing the impetus for deep and 
comprehensive characterization of the subclonal landscape of genes within these pathways across the 
continuum of therapy. This serves at the motivation for this Project and provides the opportunity to both adapt 
therapeutic approaches as tumors evolve, and also target subclonal mutations earlier to prevent the acquisition 
of chemotherapy resistant dominant clones. The central hypothesis to be explored here is that high-risk NBs 
are characterized by extensive intratumoral and stroma-derived heterogeneity and harbor pre-existing and 
acquired subclonal populations that confer therapy resistance that can exploited with rationally selected 
targeted agents. We will test our central hypothesis in three Specific Aims: 1) Define the frequency and clinical 
significance of subclonal driver mutations; 2) Identify therapeutic vulnerabilities imparted by inhibition of 
oncogenic ALK and/or RAS-MAPK signaling; 3) Target tumor cell intrinsic and extrinsic oncogenic 
vulnerabilities for development of rational novel therapeutics. The first Aim will employ a custom ultra-deep 
sequencing platform to define the clonal and subclonal architecture and mutational landscape in diagnostic and 
relapse NBs, including PDX models. Aim 2 is devoted to defining therapeutically exploitable oncogenic 
vulnerabilities with a focus on demonstrating that inhibition of FAK leads to robust anti-tumor activity in ALK- 
and RAS-driven NBs treated with inhibitors of these pathways. The final Aim will garner the preclinical 
justification required to move combination therapies to the clinic, building on our extensive preliminary data of 
synergistic drug interactions in our oncogene-driven models. We consider this project significant because it will 
result in new mechanism-based biomarker-defined therapeutic strategies that ultimately should significantly 
improve high-risk NB patient outcomes. This will address the...

## Key facts

- **NIH application ID:** 10265472
- **Project number:** 5P01CA217959-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Yael P Mosse
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $320,207
- **Award type:** 5
- **Project period:** 2017-09-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265472

## Citation

> US National Institutes of Health, RePORTER application 10265472, Proj 1 - Targeting Evolving Therapy Resistance (5P01CA217959-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10265472. Licensed CC0.

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