# Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer

> **NIH NIH U54** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $234,172

## Abstract

Project Summary: Early systemic dissemination, extraordinary local invasion, late diagnosis, and inadequate
response to the existing chemotherapy contribute to poor prognosis for pancreatic ductal adenocarcinoma
(PDAC) patients. While pancreatic tumors generally show a low intrinsic response to chemotherapies, most
acquire resistance over the course of the treatment. Hence, there is an urgent need to understand the
mechanisms contributing to acquired resistance to therapies and to identify novel therapies/therapeutic
combinations that would significantly improve survival in patients. We have demonstrated that metabolic
reprogramming presents a targetable vulnerability for abrogating acquired resistance and improving the therapy
response in PDAC. The therapy resistance depends on both tumor cell-intrinsic mechanisms and a metabolic
and signaling crosstalk between tumor cells and tumor microenvironment. Our unbiased preliminary data with
multiple human PDAC patient-derived xenograft models identified peptidyl arginine deiminase 1 (PADI1) as the
top upregulated gene that correlated significantly with poor patient prognosis. Citrullination or deimination of
arginine residues produces a loss of a positive charge, increasing the mass and the acidity of the amino acid
side chain, and the post-translational modification results in altered protein-protein interactions, signaling, and
transcriptional responses. We noted robust expression of PADI1 in human PDAC tumors and cell lines and a
correlation with patient survival. Inhibiting PADI activity or PADI1 knockdown significantly improved the
responsiveness of PDAC cell lines and organoids to components of FOLFIRINOX therapy. PADI1 expressing
PDAC tumors also demonstrated a significant correlation with the glycolytic phenotype and hypoxia gene
signature, showing a reciprocal relationship with oxidative phosphorylation. We also performed an unbiased
CRISPR screen and identified novel metabolic vulnerabilities that may be efficacious for co-targeting with agents
inhibiting PADI1 downstream metabolic pathways. PADI expression also correlated with the reprogramming of
immune and non-immune stroma in the microenvironment. Hence, the proposed project 1 will test the hypothesis
if targeting PADI1 or downstream metabolic reprogramming will abrogate the development of resistance
to FOLFIRINOX in PDAC. We will also investigate the mechanistic basis of stromal remodeling in PDAC
tumors and the stromal reprogramming that contributes to acquired FOLFIRINOX resistance. We propose
three specific aims to test the hypothesis. Aim 1 will investigate the efficacy of targeting PADI1 downstream
pathways and associated mechanisms of stromal remodeling for abrogating resistance to FOLFIRINOX therapy.
Aim 2 will determine the mechanism of tumor-cell intrinsic metabolic reprogramming that also feeds into stromal
reprogramming by PADI1. Aim 3 will investigate the efficacy of targeting the pathways identified in Aims 1 and 2
in PDX m...

## Key facts

- **NIH application ID:** 10926946
- **Project number:** 5U54CA274329-03
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Pankaj Kumar Singh
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,172
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926946

## Citation

> US National Institutes of Health, RePORTER application 10926946, Metabolic regulation of FOLFIRINOX acquired resistance in pancreatic cancer (5U54CA274329-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10926946. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*