# Preclinical Analyses of NAD Kinase as a Redox Vulnerability for the Treatment of Pancreatic Cancer

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $513,809

## Abstract

Project Summary
A major effort in cancer research is focused on identifying genes directly responsible for promoting cancer
progression (referred to here as “drivers”). Perhaps nowhere is this need more acute than for pancreatic ductal
adenocarcinoma (PDAC), a notoriously aggressive disease without durable treatment options. Identifying
PDAC drivers and understanding their mechanism-of-action is critically important, as this information could
inform new PDAC diagnostics and therapeutics. To identify such PDAC drivers, we developed novel genetic
screening technologies to identify genes found mutated in PDAC that functionally cooperate with KRAS, the
major driver gene found in pancreatic cancer, to promote PDAC tumor development in mice. Our approach
identified the NAD Kinase (NADK), which is known in other organisms to influence redox metabolic pathways
that regulate cell growth and resistance to growth-related oxidative stress. Our preliminary results indicate that
NADK activation robustly drives PDAC initiation and growth, and NADK depletion significantly decreases
PDAC growth concomitant with high oxidative stress owning to changes in redox state. Recent work by others
has demonstrated the importance of redox pathways such as the glutamine reprogramming pathway (GRP) in
promoting and maintaining PDAC growth. We hypothesize that interplay between the GRP and NADK activity
centrally influences redox state and PDAC growth. We further hypothesize that NADK represents a redox
vulnerability, as inhibiting NADK in patient tumors would serve as a means to selectively kill PDAC cells or
sensitize them to cancer chemotherapeutics. In Aim1 we will use a large panel of PDAC cell lines and tumors
genetically modified to inducibly express or deplete NADK and GRP expression to evaluate their relative roles
in influencing redox state, oxidative stress and PDAC growth in culture assays and mice. In addition, we will
examine the combined effect of NADK depletion and gemcitabine, a first-line PDAC chemotherapy agent and
inducer of oxidative stress, to determine whether adjuvant use of NADK inhibitors would synergize with
gemcitabine to kill PDAC cells. Finally, we will measure relative levels of NADK protein and oxidative stress on
clinically- and genomically-annotated PDAC patient tumors, work intended to correlate these markers with
gemcitabine response to provide insight on NADK inhibitor responder (patient) identification. In Aim 2 we will
evaluate the in vivo role of NADK and therapeutic potential of NADK inhibitors by employing a novel
electroporation model that allows rapid and cost-effective NADK expression and depletion in the context of
activated KRAS in the mouse pancreas. In addition, we will examine NADK’s role in PDAC development and
maintenance of tumor redox state using a genetically engineered mouse model of PDAC harboring a NADK
conditional knockout allele. In the future, these models will also serve as a platform for testing additional
chemothe...

## Key facts

- **NIH application ID:** 9825531
- **Project number:** 5R01CA211176-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Sarah H. ELSEA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $513,809
- **Award type:** 5
- **Project period:** 2016-12-05 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9825531

## Citation

> US National Institutes of Health, RePORTER application 9825531, Preclinical Analyses of NAD Kinase as a Redox Vulnerability for the Treatment of Pancreatic Cancer (5R01CA211176-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9825531. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*