# Credentialing Delta-like 3 (DLL3) as an oncoprotein and immunotherapeutic target in neuroblastoma

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $45,520

## Abstract

Project Summary
Neuroblastoma (NBL) is a pediatric solid tumor that arises from deregulated development of the sympathetic
nervous system. The five-year survival of patients with high-risk NBL is only 40% and relapse-free survival is
extremely rare. This underscores the need to identify biologically-relevant and clinically-actionable targets for
children with high-risk disease. One genomic aberration found in high-risk NBL is amplification of a lineage-
specific oncogene, MYCN. Once amplified, the MYCN transcription factor can invade enhancers of other lineage
oncogenes and establish a core regulatory circuit (CRC), whereby these transcription factors autoregulate
themselves and each other to maintain expression of the circuit. Due to the developmental nature of NBL, these
tumors display unique cell-surface molecules and may be susceptible to immunotherapy. An antibody-based
therapy (dinutuximab) targeting the glycosphingolipid molecule, GD2, extends the 5-year survival rates of
patients with aggressive, high-risk NBL. However, GD2 is also found on cells of the peripheral nervous system
and treatment with dinutuximab causes agonizing pain. To avoid these on-target / off-tumor side effects, we aim
to identify NBL tumor-specific surface molecules that are regulated by the CRC and associated with the
undifferentiated, malignant state of NBL. Our preliminary analysis of CRC-bound genes revealed both novel and
known immunotherapeutic targets, including ALK and L1CAM. Another CRC-regulated cell-surface protein
identified in our analysis is Delta-like canonical notch ligand 3 (DLL3). DLL3 has NBL-specific cell-surface
expression, and is known as an inhibitor of Notch signaling in other cell types. Clinical trials with DLL3-targeted
immunotherapies in adult cancers are currently ongoing, however, the oncogenic mechanism of DLL3 in these
tumor-types, and in NBL, is uncharacterized and poorly understood. In this proposal, we also aim to uncover the
relevant biology of DLL3 in NBL in order to credential DLL3 as a viable immunotherapeutic target for this pediatric
malignancy. Our preliminary data shows that shRNA-depletion of DLL3 reduces the cellular viability in NBL cell
line models with high expression of DLL3. Furthermore, CRISPR-Cas9 genomic depletion of DLL3 results in
increased expression of a canonical Notch target gene, HES1. Therefore, we postulate that DLL3 inhibits Notch
signaling to promote persistent NBL cell survival, and that the CRC transcriptionally regulates DLL3 to cause
overexpression. This project will combine integrative approaches in bioinformatics and molecular biology to 1)
describe differentially expressed, cell-surface targets driven by the CRC and 2) determine the role of DLL3 in
the malignant state of NBL. We also anticipate that we can apply our CRC computational workflow to other
cancers with established transcriptional circuits. This NRSA F31 will provide insight into NBL biology and the
regulation of candidate immunotherapeu...

## Key facts

- **NIH application ID:** 9907428
- **Project number:** 1F31CA239424-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathan Michael Kendsersky
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907428

## Citation

> US National Institutes of Health, RePORTER application 9907428, Credentialing Delta-like 3 (DLL3) as an oncoprotein and immunotherapeutic target in neuroblastoma (1F31CA239424-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9907428. Licensed CC0.

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