# Project 3: The AMPK Autophagy Pathway as a Metabolic Liability in Pancratic Ductal Adenocarcinoma

> **NIH NIH P01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2024 · $443,412

## Abstract

PROJECT SUMMARY – Project 3: Autophagy
Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest forms of cancer with few effective therapies.
The poor performance of current treatments is partly due to metabolic adaptations in both the tumor and stromal
compartments, such as the recycling of proteins and organelles through increased autophagy. As a hallmark of
PDA, autophagy provides a key source of nutrients in the restrictive tumor microenvironment (TME).
Accumulating evidence also implicates the autophagy program as a critical mediator of resistance to numerous
therapeutics, including chemotherapy, MEK inhibitors, and immune checkpoint inhibition. Foundational research
from the Shaw group decoded key biochemical steps involved in the initiation of autophagy, including upstream
regulation of AMPK and its downstream activation of ULK1 and ULK2, the kinases that drive autophagosome
formation. More recent work from the Shaw group has also revealed that AMPK can block the translocation of
Class II HDACs to the nucleus. Despites these advances, the specific roles of AMPK in autophagy control and
epigenetic regulation have never been investigated in pancreatic cancer. Moreover, while autophagy has
emerged as an attractive therapeutic target in pancreatic cancer, efforts to translate this to the clinic have been
hindered by a lack of autophagy-specific inhibitors, with only broad lysosomotropic agents like chloroquine
available for study. To address this gap, the lab has developed novel, bioavailable inhibitors of ULK1 and ULK2,
two of only three druggable enzymes specific to the autophagy pathway. These inhibitors provide critical tools
with which to dissect the contributions of autophagy to PDA growth and form the basis for a new approach for
overcoming therapeutic resistance in this deadly disease. Here, experiments proposed in Aim 1 will define when
and where different facets of AMPK signaling and autophagy are activated during disease progression in the
autochthonous mouse KPC model of PDA. In collaboration with Project 1, conditional deletions of AMPK or its
downstream targets ULK1/2 and HDAC3 will be used to evaluate their contribution to metabolic adaptations
driving tumor growth and epigenetic changes mediating tumor cellular functions. In addition, the contribution of
AMPK pathway components in supporting PDA resistance to chemotherapeutics and targeted therapies will be
dissected. In Aim 2, the roles of canonical and noncanonical autophagy in non-cell autonomous support of
pancreatic tumor growth will be delineated by comparing stromal deletion of ULK1/2 and ATG7. In addition,
experiments will dissect cell-specific requirements for autophagy within the fibroblast and myeloid compartments
in supporting PDA therapeutic resistance. In Aim 3, the Shaw lab’s novel, bioavailable ULK inhibitor will be used
to determine how selective inhibition of autophagy impacts PDA growth through reprogrammed tumor and
stromal cell function. The potential...

## Key facts

- **NIH application ID:** 10883568
- **Project number:** 5P01CA265762-02
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Reuben Shaw
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $443,412
- **Award type:** 5
- **Project period:** 2023-07-06 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883568

## Citation

> US National Institutes of Health, RePORTER application 10883568, Project 3: The AMPK Autophagy Pathway as a Metabolic Liability in Pancratic Ductal Adenocarcinoma (5P01CA265762-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10883568. Licensed CC0.

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