# Proj 2 - Exploiting Therapeutic Vulnerabilities

> **NIH NIH P01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $355,201

## Abstract

Neuroblastoma (NB) represents a prototypical pediatric cancer genetically, in that point mutations are rare, but
amplifications and segmental chromosomal copy number alterations (CNAs) occur commonly. Notably,
amplification of the MYCN oncogene and loss of chromosome 1p are both prominently associated with highrisk
disease. While these events commonly co-occur, their interdependence is poorly understood. We
hypothesize that both loss of chromosome 1p and amplification of MYCN create unique vulnerabilities
to therapy, including immunotherapy. MYCN amplification can be accurately modeled in immune-intact
genetically engineered mouse models (GEMM), but chromosome deletions have been challenging to model.
Using normal human induced pluripotent stem cells (iPSC) and CRISPR/Cas9 technology, we generated
isogenic in-vivo NB models driven by MYCN, observing increased penetrance in tumors carrying both MYCN
and engineered deletions in chromosome 1p. We thus have modeled MYCN-driven NB in the presence or
absence of 1p deletions, enabling us to identify therapeutic vulnerabilities associated with 1p loss. MYCN
broadly impacts the tumor immune response through regulation of checkpoint proteins such as PD-L1. We
have tested an array of targeted and conventional therapies for the treatment of NB, many directed against
MYCN, but the effects of these on the immune system are poorly understood. With recent FDA approval of
dinutuximab monoclonal antibody directed against the surface marker GD2, targeted immunotherapy is now
standard-of-care for NB. Using a MYCN driven mouse model developed in the PI’s lab, we will characterize NB
tumors with CyTOF mass cytometric single cell proteomics to measure markers of immune cells, tumor cells,
and signaling in both tumor and host cells simultaneously to identify and characterize small molecule inhibitors
that cooperate with immunotherapy in the treatment of neuroblastoma.
A1: Utilize human stem-cell based in-vivo models of neuroblastoma to identify therapeutic
vulnerabilities associated with chromosome 1p deletion
A2: Leverage MYCN-driven immunocompetent models of NB to identify effective combination therapy,
focusing on immunotherapy.
Successful completion of Aim 1 identifies therapeutic vulnerabilities in high-risk NB driven by both MYCN
amplification and 1p deletion. Successful completion of Aim 2 identifies targeted therapies that cooperate with
immunotherapy in the treatment of MYCN-driven NB. Both aims propose characterizing existing mouse models
of NB to leverage opportunities in precision medicine (immunotherapy and 1p-directed therapies). This
characterization provides targets, biomarkers, and actionable therapies for clinical trials in children with NB.

## Key facts

- **NIH application ID:** 10265478
- **Project number:** 5P01CA217959-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** JOHN M MARIS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $355,201
- **Award type:** 5
- **Project period:** 2017-09-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265478

## Citation

> US National Institutes of Health, RePORTER application 10265478, Proj 2 - Exploiting Therapeutic Vulnerabilities (5P01CA217959-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10265478. Licensed CC0.

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