# Neutralizing Stromal NetrinG1 to Intercept Pancreatic Cancer

> **NIH NIH U54** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $397,088

## Abstract

PROJECT SUMMARY - PROJECT 2
Most patients with pancreatic cancer (PC) do not survive one year and less than 10% survive five years. This is
unfortunate, given the slow rate of growth of PC over many years, and the large window of opportunity for
potential intervention prior to diagnosis. Patients with hereditary familial PC (~10% of PC cases), as well as those
exposed to mutagens and presenting with predisposing clinical conditions like pancreatitis and new onset of
diabetes, are at high risk for PC and would benefit greatly from improved early detection, cancer prevention,
and/or interception strategies. The proposed project addresses this unmet need by joining the FCCC Cancer
Prevention-Interception Targeted Agent Discovery Program (CAP-IT) at the “Agent Identification and Screening”
stage. The proposal is the first, to our knowledge, to employ a stroma-targeting strategy to intercept progression
of precancerous tissue to overt PC. This proposal exploits our work in studying desmoplasia – a unique
microenvironment enriched in stromal fibroblasts and dense extracellular matrix (ECM) that characterizes PC.
We have defined distinct subsets of tumor-promoting and tumor-suppressing fibroblasts (TPFs and TSFs), which
can reversibly interconvert in phenotype. We have shown that TPFs arise in early precancerous tissue, and are
characterized by expression of Netrin G1 (NetG1). NetG1-dependent signaling is essential for premalignant cells
to thrive as tumors. Mechanistically, we have shown that NetG1+ TPFs provide nutritional support to
premalignant initiated epithelial cells (IECs) and tumors, allowing them to survive in the nutrient-poor
desmoplastic environment and escape immunosurveillance by inducing an immunosuppressive
microenvironment. While some support is delivered via TPF secretion of nutrients and chemokines; additional
support is provided by the TPF-generated ECM. Critically, we have shown that a commercial monoclonal
antibody (mAb) that inhibits NetG1 reverts all of these tumor-promoting properties and intercepts the formation
of PC. Although the commercial mAb is sufficient for proof-of-concept experiments, it is not sufficiently potent as
a clinical candidate. A large panel of mAbs targeting diverse NetG1 epitopes, with higher binding affinities than
the one above-mentioned, has been generated. In Aim 1, we will determine which of the new mAbs functionally
reverts TPFs to TSFs, based on the expression of molecular markers that distinguish between the two classes.
In Aim 2, co-culture experiments will be used to identify mAbs that reduce the ability of TPFs to provide nutritional
support to IECs, and assess whether the same mAbs decrease the ability of the ECM, produced by TPFs, to
enhance IEC growth. New IEC models will be engineered that parallel the loss of function genetic variants seen
in populations at high risk for PC. In Aim 3, the lead candidate mAbs that can intercept the transition from
precancer to cancer in vitro will be evalu...

## Key facts

- **NIH application ID:** 10909965
- **Project number:** 5U54CA272686-03
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Edna Cukierman
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,088
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909965

## Citation

> US National Institutes of Health, RePORTER application 10909965, Neutralizing Stromal NetrinG1 to Intercept Pancreatic Cancer (5U54CA272686-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10909965. Licensed CC0.

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