# A novel therapy for pancreatic neuroendocrine tumors

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $353,627

## Abstract

The incidence of the pancreatic neuroendocrine tumor (PNETs) has increased over the past two
decades. The principal treatment for localized PNETs is surgical resection; however, there is no effective
therapy for patients with advanced unresectable or metastatic disease. The progression-free survival rate is at
the best 11 months with FDA approved agent Everolimus compared to 4.6 months with the placebo. However,
the majority of the patients develop drug resistance and there is a void in our understanding of the
mechanisms of resistance in PNETs. Frequent mutations in MEN1 (44%), DAXX/ATRX (43%), mTOR (15%)
pathway genes and Von Hippel Lindau disease (VHL) alongside several other hereditary disorders are
observed in PNETs. Loss of VHL has been linked to enhanced tumor aerobic glycolysis (Warburg effect). In
this scenario, cancer cells rely more heavily on Nicotinamide Adenine Dinucleotide (NAD) pool that is a crucial
co-factor in the redox reactions of metabolic pathways of cancer cells with high aerobic glycolysis. This over-
dependence on NAD may provide actionable therapeutic avenues within the NAD salvage pathway. Our
preliminary studies in PNET cell lines and patient derived tissue demonstrate activation of VHL regulated NAD
biosynthesis rate-limiting enzyme Nicotinamide Phosphoribosyltransferase (NAMPT) alongside the over-
expression of the mTOR promoter p21 activated kinase 4 (PAK4). PAK4 protein by virtue of its ability to
engage multiple ligands has been shown to regulate a repertoire of signaling pathways including PNET
resistance molecules. Significantly, PAK4-NAMPT dual RNAi suppressed proliferation in PNET cell lines. The
CRISPR/Cas9 validated PAK4-NAMPT dual inhibitor KPT-9274 (a Phase I drug) shows antitumor activity in
vitro, in PNET xenograft and could synergistically enhance the cytotoxicity of Everolimus. Molecular analysis of
combination treatment showed down-regulation of known Everolimus resistance promoter suppression of ATP
and NAD. Normal cells can utilize Nicotinate phosphoribosyltransferase (NAPRT1, an enzyme often absent in
tumors due to promoter methylation) to generate NAD through nicotinic acid. Therefore, nicotinic acid co-
treatment can allow KPT-9274 dose escalation without undue toxicity to normal tissue. We hypothesize that
targeting of PAK4-NAMPT signaling could become a broad and clinically viable therapeutic strategy for PNET.
Aim1: Profile the PAK4 and NAMPT aberrations in PNET patient tissue. Aim 2: Demonstrate the role of PAK4-
NAMPT in PNET therapy resistance. Aim 3: Demonstrate the preclinical in vivo efficacy of PAK4-NAMPT dual
inhibitors in PNET xenograft and define a biomarker of therapeutic response in biopsies from an ongoing
Phase I trial. Clinical impact: Our studies will enhance the fundamental understanding of PAK signaling and
NAD metabolism in PNET subsistence. This work will also uncover the ideal patient population based on their
NAPRT status for best treatment response. Our preclinical stud...

## Key facts

- **NIH application ID:** 10129918
- **Project number:** 5R01CA240607-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Asfar S Azmi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,627
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129918

## Citation

> US National Institutes of Health, RePORTER application 10129918, A novel therapy for pancreatic neuroendocrine tumors (5R01CA240607-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129918. Licensed CC0.

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