# Altered Histidine Metabolism in Pancreatic Cancer: A Novel Metabolic Target to Enhance Gemcitabine Efficacy

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $169,392

## Abstract

Project Summary
Pancreatic cancer (PC) is one of the most lethal malignancies in the United States with a rising
incidence and mortality. Gemcitabine (GEM) has been the cornerstone for PC treatment but GEM
resistance develops within weeks of chemotherapy initiation, resulting in only a modest impact on
survival. Combining GEM with other chemotherapeutic drugs often leads to severe toxicity,
without much improvement in survival. It is becoming clear that PC patients exhibit metabolic
impairments that can impact their prognosis and survival. In fact, reprogrammed metabolism is a
feature of cancer cells and there is an escalated interest in targeting metabolic pathways as a
way to improve therapy response. To this end, glutamine metabolism has been widely studied to
target cancer cell proliferation. However, the role of other amino acids in modulating PC
pathogenesis is still unclear. Our preliminary data provide compelling evidence that serum His
level is lower and tissue histidine ammonia lyase (HAL) expression is higher in mice exhibiting
PC and human PC patients, compared to controls. Our studies in PC cell-lines showed that His
induces cytotoxicity, with a concomitant increase in ammonia production. Moreover, His in
combination with GEM exerted a greater cytotoxicity accompanied by a greater reduction in IGF-
1R/mTOR/S6K signaling compared to individual treatments. Therefore, we hypothesize that His
and HAL are novel regulators of PC pathogenesis and that targeting His metabolism is a
promising approach to enhance the anti-cancer effects of GEM. We will employ nutritional,
pharmacological, and metabolic approaches to determine the role and mechanisms by which
altered His metabolism regulates the response of PC to GEM therapy. We propose two specific
aims: In Specific Aim 1, we will determine the mechanisms by which histidine in combination
with gemcitabine exerts enhanced cytotoxic effects against PC cell-lines and PC organoids in
vitro. In Specific Aim 2, we will evaluate the therapeutic efficacy of His in combination with GEM
in orthotopic and genetic mouse models of PC. Altogether, the studies will uncover the role of His
in modulating PC cell metabolism, identify potential mechanisms, and set the stage for future
therapeutic discoveries.

## Key facts

- **NIH application ID:** 9893865
- **Project number:** 5R21CA238953-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Satyanarayana Rachagani
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,392
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893865

## Citation

> US National Institutes of Health, RePORTER application 9893865, Altered Histidine Metabolism in Pancreatic Cancer: A Novel Metabolic Target to Enhance Gemcitabine Efficacy (5R21CA238953-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9893865. Licensed CC0.

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