# Identifying targets for combination therapy with FOLFIRINOX and investigating cell polarity loss as a potential driver of invasion in basal-like PDAC

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $34,454

## Abstract

Abstract
 Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a dismal five-year survival rate of
9% even with current treatments. There are two molecular tumor subtypes of PDAC; basal-like PDAC is more
aggressive and associated with shorter survival times. Recent clinical trials have found that basal-like PDAC
patients fail to respond to first-line chemotherapies including FOLFIRINOX, so it is critical to find better
treatment options for this subtype. To study PDAC subtypes, organoids are utilized as they have been shown
to represent both molecular subtypes, unlike conventional 2D cell lines. First, this study aims to identify genes
whose depletion increases basal-like PDAC sensitivity to FOLFIRINOX using a CRISPR/Cas9 loss-of-function
screen targeting 395 basal-like marker genes in basal-like PDAC organoids. The synthetic lethality hits may be
studied in the future as drug targets for use in combination with FOLFIRINOX as a more efficacious therapeutic
strategy for basal-like PDAC. To study the biology of basal-like PDAC, I will investigate the role of
dysregulation of cell polarity in the PDAC subtypes using organoid models. Preliminary data suggest that
basal-like PDAC is characterized by a loss of cell polarity while classical PDAC maintains it. Basal-like
organoids do not organize to form hollow lumens like classical organoids and the most differentially
phosphorylated proteins and pathways between subtypes involve cell adhesion and cell polarity. Dysregulation
of cell polarity may increase cancer cell invasion, potentially contributing to poor outcomes in basal-like PDAC.
Using fluorescence microscopy, this study will determine whether the localization of cell polarity markers is
altered in basal-like PDAC compared to classical in a manner consistent with a loss of cell polarity. It will also
be tested whether genetic depletion of cell polarity genes results in a shift from classical to basal-like
phenotype, as measured by loss of organoid lumens and increased invasion. Understanding this facet of
subtype biology could lead to future therapeutic strategies leveraging cell polarity to convert basal-like PDAC to
a more classical phenotype, as classical PDAC is more responsive to current treatments. Overall, this project
will advance our understanding of the biology underlying PDAC subtypes and move toward the development of
therapeutic strategies for basal-like PDAC. This project will be supported by the extensive resources of the
UNC Chapel Hill and the Department of Pharmacology as well as by co-mentorship by Drs. Jen Jen Yeh and
Gaorav Gupta.

## Key facts

- **NIH application ID:** 10140662
- **Project number:** 1F31CA257224-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Sandra Zarmer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,454
- **Award type:** 1
- **Project period:** 2021-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140662

## Citation

> US National Institutes of Health, RePORTER application 10140662, Identifying targets for combination therapy with FOLFIRINOX and investigating cell polarity loss as a potential driver of invasion in basal-like PDAC (1F31CA257224-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10140662. Licensed CC0.

---

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