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.