# cGAS-STING and therapeutic immune responses in neuroblastoma

> **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $211,259

## Abstract

PROJECT SUMMARY AND ABSTRACT
 The goal of this proposed five-year training program is to foster the development of the applicant's
independent research career as a pediatric oncologist focused on exploiting inflammatory sensing pathways to
improve immunotherapy in pediatric solid tumors. The candidate has completed a rigorous clinical training course
and has a strong research foundation. In the short term, he will benefit from training to obtain research skills to
study transcriptional regulation, work with immunocompetent mouse models of neuroblastoma, and analyze the
tumor immune microenvironment. His mentors for this award are Dr. Chi Dang, an eminent cancer biologist with
expertise in studying transcriptional regulation, and Dr. Michael Hogarty, a world-wide leader in neuroblastoma
research. To add broad scientific expertise and provide additional career guidance, he has assembled a
Mentoring Committee composed of scientists from diverse and complementary fields. Dr. Wolpaw will benefit
from the rich resources and opportunities available at The Children's Hospital of Philadelphia, the University of
Pennsylvania, and the Wistar Institute.
 The proposed research focuses on investigating the regulation of the inflammatory sensing cGAS-STING
pathway in neuroblastoma to promote immune-targeting of mesenchymal state neuroblastoma (NBLMES).
Neuroblastomas are composed of cells in an adrenergic (NBLADR) state that predominate at diagnosis and a
NBLMES state that is initially a minor subpopulation but is a driver of relapse. Dr. Wolpaw's prior work shows that
NBLMES cells have higher levels of inflammatory signaling at baseline in vitro and in vivo and are more responsive
to some inflammatory stimuli, suggesting a unique immune vulnerability of this critical population. His current
proposal capitalizes on these findings by focusing on the clinically relevant inflammatory sensing cGAS-STING
pathway. This pathway responds to cytosolic DNA by broadly activating inflammatory signaling and is required
for an immunogenic response to radiation therapy, including synergistic and systemic effects when local radiation
is combined with immune checkpoint blockade. His preliminary data support the hypothesis that restoration of
cGAS-STING will render NBLMES cells vulnerable to immuno-radiation therapy. To test this hypothesis, Dr.
Wolpaw will purse two specific aims: 1) Elucidate the impact of NBLADR/NBLMES state on the transcriptional
regulation of cGAS-STING and 2) Define the effect of restored cGAS expression on the response to radiation.
Together, these aims will advance our understanding of how inflammatory sensors like cGAS-STING are
regulated in neuroblastoma and how their manipulation can promote tumor-immune interactions. This will lay the
foundation for improved immunotherapies in neuroblastoma and provide the training and experience needed to
transition Dr. Wolpaw into an independent physician scientist.

## Key facts

- **NIH application ID:** 10524601
- **Project number:** 1K08CA266914-01A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Adam J Wolpaw
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $211,259
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10524601

## Citation

> US National Institutes of Health, RePORTER application 10524601, cGAS-STING and therapeutic immune responses in neuroblastoma (1K08CA266914-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10524601. Licensed CC0.

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