# Targeting the Unfolded Protein Response in PanNETs

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $494,442

## Abstract

The unfolded protein response (UPR) is an intracellular signaling pathway largely controlled by two ER
transmembrane kinases—IRE1 and PERK—that communicate the protein folding status of the endoplasmic
reticulum (ER) to the nucleus in order to maintain homeostasis within this organelle. Hypoxia, nutrient
deprivation, proteasome dysfunction, or sustained demands on the secretory pathway--conditions often
encountered by solid tumor cells--lead to the accumulation of misfolded proteins in the ER and cause “ER stress.”
Under remediable levels of ER stress, the UPR activates transcriptional and translational changes that promote
adaptation (Homeostatic UPR). But when confronted with irremediable levels of ER stress, these adaptive
measures fail, and the UPR instead switches strategies to trigger cell death (Terminal UPR).
Neuroendocrine tumors (e.g. carcinoids) are one class of solid tumor that may be particularly sensitive to protein
folding stress due to their high protein secretory activity. Derived from professional secretory cells,
neuroendocrine tumors can arise in many sites (e.g. gastrointestinal tract, lung), but these tumors universally
hypersecrete one or more peptide hormone(s). For the nearly 12,000 Americans diagnosed with a
neuroendocrine tumor each year, surgery is the only potentially curative treatment. Unfortunately, the five year
survival is extremely low for the ~25% of patients who develop metastatic disease.
We have evidence that the UPR is upregulated and required for the growth of pancreatic neuroendocrine tumors
(PanNETs), a representative model for this class of secretory solid tumors. Based on our preliminary data, we
hypothesize that PanNETs are reliant on elevated levels of Homeostatic UPR signaling to avoid the toxic effects
of protein folding stress, and that targeted interventions to either reduce Homeostatic UPR outputs or
alternatively trigger the Terminal UPR will have potent antitumor effects. We will use a variety of genetic,
chemical-genetic, and pharmacological tools developed in our laboratory to selectively activate or disable the
UPR master regulators (IRE1 and PERK) in order to accomplish two specific aims. (1): Define the activation
status, signaling outputs, and cell growth effects of the UPR regulators IRE1 and PERK in primary human
samples and murine xenograft models of PanNETs. (2): Determine the effects of pharmacologic inhibition of
IRE1 and/or PERK on the growth of PanNETs in murine xenograft and genetic models of PanNETs.
Our research project will provide powerful mechanistic insights into the role of the UPR on PanNET growth and
the use of small molecules to manipulate this pathway to control cell fate. If successful, our work promises to
validate drug targets to modify progression of PanNET and other neuroendocrine tumors.

## Key facts

- **NIH application ID:** 9843854
- **Project number:** 5R01CA219815-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Scott A. Oakes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $494,442
- **Award type:** 5
- **Project period:** 2019-08-12 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843854

## Citation

> US National Institutes of Health, RePORTER application 9843854, Targeting the Unfolded Protein Response in PanNETs (5R01CA219815-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843854. Licensed CC0.

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