# Project 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors

> **NIH NIH P50** · UNIVERSITY OF IOWA · 2021 · $99,779

## Abstract

Neuroendocrine tumors (NETs) are indolent malignancies that are increasing in incidence, display profound 
resistance to conventional therapies, and are a growing clinical challenge. Mechanisms underlying NET 
development are only partly understood, and diagnostic / prognostic biomarkers of the disease are lacking. 
While progress in managing pancreatic NETs (PNETs) over the past several decades has been slow, new 
targeted therapies such as mTOR inhibitors have emerged as we've learned more about molecular 
mechanisms of PNET pathogenesis. Mounting evidence suggests that greater benefits (improved efficacy and 
reduced resistance) will be obtained by targeting multiple steps of the PI3K/Akt/mTOR pathway. Better 
understanding of PI3K/Akt/mTOR regulation and identification of PNET biomarkers that risk stratify patients 
into subgroups of those who will (or will not) respond to particular therapies will improve patient treatment. This 
project was developed with those goals in mind. Aim 1 builds upon our discovery that RABL6A (a novel 
oncoprotein) is essential for PNET cell survival and proliferation, Akt/mTOR activity, and control of other 
clinically relevant PNET pathways, such as Rb1. Aim 2, which is based on pilot studies that identified several 
chromosomal alterations capable of discriminating pancreatic from ileal NETs (including RABL6A amplification 
on chr 9q), seeks to define new DNA and protein biomarkers that distinguish four different types of NETs 
(pancreatic, ileal, bronchial and cervical). The integration of findings from Aims 1 and 2 will establish novel 
relationships between the status of drug-targetable PNET pathways (RABL6A-Akt/mTOR, RABL6A-Rb1) with 
genetic alterations that discriminate NET type and prognosis, thus advancing clinical management of this 
disease. 
Aim 1. Define clinically relevant therapeutic targets that control PNET proliferation and survival. 
Aim 2. Identify genetic and proteomic biomarkers that discriminate NET type and prognosis. 
This research will identify molecular alterations that are common or unique to various types of NETs, as well as 
primary versus metastatic tumors. Pilot studies have already identified RABL6A and other specific genetic 
alterations as strong candidate PNET biomarkers, and proposed pre-clinical studies will determine the efficacy 
of unique drug combinations that target RABL6A effector pathways for reducing PNET burden. The most 
immediate clinical outcome of this translational project will be the development of fast and inexpensive genetic 
(FISH-based) and proteomic (IHC-based) tests for differentiating various types of NETs in patients. This should 
markedly improve NET diagnosis, classification, prognosis and treatment.

## Key facts

- **NIH application ID:** 10487603
- **Project number:** 3P50CA174521-05S3
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** DAWN E QUELLE
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $99,779
- **Award type:** 3
- **Project period:** 2015-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487603

## Citation

> US National Institutes of Health, RePORTER application 10487603, Project 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors (3P50CA174521-05S3). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10487603. Licensed CC0.

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