# Proj 3 - Targeting the Pro-tumorigenic Microenvironment

> **NIH NIH P01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $555,724

## Abstract

SUMMARY/ABSTRACT 
The overall objective of Project 4 is to discover and exploit extrinsic mechanisms of therapy resistance by 
focusing on the contribution of tumor-associated macrophages (TAMs) and tumor-associated fibroblasts 
(TAFs) in the tumor microenvironment (TME). Our overarching hypothesis is that TAMs and TAFs cooperate 
in creating a favorable tumorigenic environment that ultimately leads to the emergence of therapeutic 
resistance and immune escape in NB. We also postulate that as tumors are treated, the TME is altered in its 
composition and function to become increasingly favorable to therapeutic resistance. This hypothesis is based 
on published and preliminary data from our group demonstrating that TAMs and TAFs are abundantly present 
in an inflammatory subtype of NB at diagnosis associated with a high risk of recurrence and extremely poor 
prognosis. We also have evidence that TAMs and TAFs when exposed to tumor cells stimulate their 
proliferation, survival and drug-resistance via the paracrine production of pro-tumorigenic cytokines and 
chemokines that activate in tumor cells signaling pathways such as STAT3 and ERK. Our project has 3 aims. 
Aim 1, will examine mechanisms of cooperation between TAMs and TAFs, testing the hypothesis that in 
MYCN amplified tumors that do not produce the TAM chemoattractant CCL-2/MCP-1, TAFs are a source of 
this chemokine. We will also examine the contribution of cytokines and chemokines generated in co-culture of 
TAMs, TAFs and NB cells and the signaling pathways they activate in NB cells leading to increased 
proliferation and survival. Aim 2, will examine changes in the TME landscape secondary to chemotherapy in 
syngeneic murine NB models (with Project 2) and validate the data in patient tumor samples obtained via Core 
B. By examining changes in the transcriptome that occur in NB cells chronically exposed to TAM/TAF and 
their potential epigenetic origin (with Project 3), aim 2 will also identify vulnerabilities to prevent resistance to 
chemotherapy or targeted therapy (with Project 1). Aim 3, will then translate these discoveries in pre-clinical 
tumor models. We will test the therapeutic efficacy of the most promising agents targeting TAFs, TAMs, or 
pathways they activate in tumor cells in combination with chemotherapy or immunotherapy (with Project 5), 
using human NB lines and patient-derived xenotransplants in immunodeficient mice as well as murine cell lines 
in immunocompetent mice (with Project 2), The most effective agent(s) will then be proposed for early phase 
clinical trials to the NANT (Core B). Thus Project 4 brings a unique contribution to the overall objective of this 
PPG through its focus on the TME and on non-autonomous mechanisms leading towards therapeutic 
resistance and immune escape.

## Key facts

- **NIH application ID:** 10265474
- **Project number:** 5P01CA217959-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Yves A DeClerck
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $555,724
- **Award type:** 5
- **Project period:** 2017-09-18 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265474

## Citation

> US National Institutes of Health, RePORTER application 10265474, Proj 3 - Targeting the Pro-tumorigenic Microenvironment (5P01CA217959-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10265474. Licensed CC0.

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