# Exploring the epigenetic control of pancreatic cancer subtypes

> **NIH NIH R37** · FRED HUTCHINSON CANCER CENTER · 2022 · $402,600

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related mortality in the United States.
Unfortunately, both genomic and transcriptomic analyses of PDA have failed to identify therapeutically relevant
targets. Combination chemotherapy remains the standard of care for the majority of patients who present with
locally advanced or metastatic disease, resulting in a median overall survival of less than one year. PDA has
been subclassified into 2-4 transcriptional subsets, which can be defined by their unique epigenetic states rather
than a specific genetic profile. Of these subsets, the quasi-mesenchymal (QM) subtype is characterized by the
worst prognosis, thus highlighting the importance of identifying new therapeutic avenues for QM PDA. The short-
term goals of this proposal are to elucidate the genetic or epigenetic mechanisms regulating QM PDA subtype
determination and to leverage that understanding toward the development of targeted therapies for QM disease.
Our preliminary data suggest PDA may downregulate a novel epigenetic regulator and tumor suppressor in PDA
in order to achieve this more aggressive QM PDA phenotype, while at the same time rendering tumor cells more
sensitive to specific targetable therapies. This epigenetic regulator, a histone deacetylase called sirtuin 6
(SIRT6), was recently shown to act as a potent tumor suppressor in genetically engineered mouse models
(GEMMs) of PDA, and inversely correlates with poor prognosis in patient samples. However, how SIRT6 is
downregulated in PDA and its role in regulating PDA subtypes remains unknown. Here we propose three
specific aims: (1) To identify novel mechanisms of SIRT6 downregulation in PDA; (2) To determine the
functional role of SIRT6 in regulating PDA subtypes; and (3) To develop novel therapeutic approaches for this
QM subset of PDA tumors. To accomplish these aims, we will apply a combination of cytogenetics, high-
throughput sequencing, genetic gain of function and loss of function approaches and pharmaceutical
interventions to a robust panel of molecularly characterized PDA GEMMs, human PDA cell lines and patient-
derived xenografts from the NCI Patient-Derived Models Repository. Our approach also takes advantage of an
innovative class of targeted therapeutics, which bind covalently to a specific residue on their target protein in
order to achieve greater inhibition and specificity. The long-term goal of our work is to transform the clinical
paradigm for this cancer from combination chemotherapy, toward a precision medicine-based approach utilizing
predictive biomarkers to tailor more effective and less toxic therapies for PDA patients.

## Key facts

- **NIH application ID:** 10418754
- **Project number:** 5R37CA241472-05
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Sita Kugel
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,600
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418754

## Citation

> US National Institutes of Health, RePORTER application 10418754, Exploring the epigenetic control of pancreatic cancer subtypes (5R37CA241472-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10418754. Licensed CC0.

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