# Inhibitors of Oxidative Protein Folding For The Treatment of Cancer

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $490,849

## Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the
deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed
and a lack of effective therapies. The long-term goal of this research program is to discover new therapeutic
approaches and drug combinations for the treatment of PDAC and other incurable cancers. Previous studies
by our group identified a new class of protein disulfide isomerase (PDI) inhibitor with activity in a variety of solid
and hematological cancer types including PDAC. PDIs are emerging oncology targets that play a critical role in
the proper folding of newly synthesized proteins. PDIs are overexpressed in a variety of tumor types and are
attractive oncology targets. In an unbiased screen of FDA-approved oncology drugs, we found this new class
of drug could dramatically enhance the activity of histone deacetylase (HDAC) inhibitors with the strongest
synergy being observed in PDAC models. The specific objectives of this study are: (1) to uncover the
molecular mechanism responsible for the remarkable synergy between PDI and HDAC inhibitors in PDAC, (2)
to resolve binding of novel PDI inhibitors to their target using X-ray crystallography, and (3) to demonstrate the
preclinical anti-cancer activity of lead PDI inhibitors as single agents and in combination with HDAC inhibitors
in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the
existing literature and strong preliminary data. This work is innovative because we investigate the activity and
mechanism of a new drug candidate and new treatment combination for the treatment of PDAC, a cancer in
desperate need of new therapies. It is our expectation that this work will deliver a new drug candidate and
combination treatment regimen for the treatment of PDAC, provide insight into the druggability of an emerging
cancer drug target in PDI, and uncover molecular mechanisms that enhance the activity of HDAC inhibitors.

## Key facts

- **NIH application ID:** 10437641
- **Project number:** 5R01CA245081-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Nathan G. Dolloff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $490,849
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437641

## Citation

> US National Institutes of Health, RePORTER application 10437641, Inhibitors of Oxidative Protein Folding For The Treatment of Cancer (5R01CA245081-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437641. Licensed CC0.

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