# Project 1: Inhibition of Metastasis Utilizing Pharmacological Ascorbate in Pancreas Cancer

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2021 · $509,053

## Abstract

Project Summary/Abstract - Project 1:
Adenocarcinoma of the pancreas is the 4th leading cause of cancer death in the U.S. Metastasis is a major
cause of cancer mortality, accounting for as many as 90% of cancer-related deaths. Although a goal of
cytotoxic therapies is to minimize metastatic tumor growth, therapies specifically designed to inhibit the
mechanisms of invasion that drive metastasis are not currently utilized as a part of pancreatic cancer
treatment. We believe that targeting invasion and metastasis of pancreatic tumors should be considered as an
important goal when treating pancreatic cancer, even in the absence of detectable metastatic disease. This
proposed research program will investigate the use of pharmacologic ascorbate (P-AscH-, high-dose, IV
delivery of vitamin C) in the treatment of pancreatic cancer. Intravenous ascorbate, but not oral ascorbate,
produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our
group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells;
this cytotoxicity appears to be greater in tumor vs. normal cells. We have firmly established that P-AscH- is a
pro-drug for delivery of hydrogen peroxide (H2O2) in tumor cells. Recent clinical studies have demonstrated
that P-AscH- is safe and well tolerated. In addition, patients with stage IV pancreatic cancer did not develop
metastatic disease, had reductions in metastases during treatment, and increased median survival from 6
months to 16 months. Epithelial-to-mesenchymal transition (EMT) induced by hypoxia is one of the critical
events in pancreatic cancer metastases. HIF-1α mediates hypoxia responses and is overexpressed in
pancreatic cancer. Stabilization and activation of HIF-1α triggers its target genes related to metastasis, which
correlate with many difference cellular processes, such as proliferation, angiogenesis and EMT. The current
proposal will test the hypothesis that production of H2O2 mediates P-AscH--induced inhibition of metastatic
disease in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims: 1)
Determine if P-AscH- reduces metastatic disease by inhibiting the EMT process and tumor cell invasion via a
H2O2-mediated mechanism; 2) Determine if decreased expression of H2O2-metabolizing enzymes (i.e.,
catalase) in metastatic PDAC cells mediates the increased sensitivity to P-AscH−. 3) In a phase II trial,
determine efficacy of P-AscH− combined with gemcitabine/nab-Paclitaxel as defined by an increase in
progression free survival and/or overall survival. Our proposal combines complimentary approaches to
demonstrate that P-AscH- can be used successfully as an adjuvant to improve responses in the treatment of
pancreatic cancer. Furthermore, we will investigate the mechanism by which P-AscH- inhibits metastatic
disease. If we can rigorously demonstrate that P-AscH- induces preferential oxidative stress and su...

## Key facts

- **NIH application ID:** 10240530
- **Project number:** 5P01CA217797-04
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Joseph J Cullen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $509,053
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240530

## Citation

> US National Institutes of Health, RePORTER application 10240530, Project 1: Inhibition of Metastasis Utilizing Pharmacological Ascorbate in Pancreas Cancer (5P01CA217797-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240530. Licensed CC0.

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