Project 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors

神经内分泌肿瘤（NET）是一种发病率不断增加的惰性恶性肿瘤，表现出深刻的 对常规疗法的抗性，并且是日益增长的临床挑战。NET底层机制 发展仅被部分理解，并且缺乏疾病的诊断/预后生物标志物。 虽然过去几十年来管理胰腺NETs（PNETs）的进展缓慢，但新的 随着我们对mTOR抑制剂等分子靶向治疗的了解越来越多， PNET发病机制。越来越多的证据表明，更大的好处（提高疗效和 降低的抗性）将通过靶向PI 3 K/Akt/mTOR途径的多个步骤来获得。更好 了解PI 3 K/Akt/mTOR调节和鉴定可对患者进行风险分层的PNET生物标志物 将对特定疗法有反应（或无反应）的患者分组将改善患者治疗。这 该项目是在考虑这些目标的情况下开发的。目的1建立在我们发现RABL 6A（一种新的 癌蛋白）对于PNET细胞存活和增殖、Akt/mTOR活性和其他细胞因子的控制是必需的。 临床相关的PNET途径，如Rb 1。目标2是基于试点研究， 能够区分胰腺和回肠NET的染色体改变（包括RABL 6A扩增 在chr 9 q上），试图定义新的DNA和蛋白质生物标志物，以区分四种不同类型的NET （胰腺、回肠、支气管和颈部）。整合目标1和2的结果将建立新的 药物靶向PNET通路（RABL 6A-Akt/mTOR，RABL 6A-Rb 1）的状态与 基因改变，区分NET类型和预后，从而推进临床管理，这 疾病 目标1.定义控制PNET增殖和存活的临床相关治疗靶点。 目标二。识别区分NET类型和预后的遗传和蛋白质组学生物标志物。 这项研究将确定分子改变是共同的或独特的各种类型的NET，以及 原发性与转移性肿瘤。初步研究已经确定了RABL 6A和其他特定的遗传 作为强有力的候选PNET生物标志物，拟议的临床前研究将确定疗效 靶向RABL 6A效应子途径以降低PNET负荷的独特药物组合。最 这个转化项目的直接临床结果将是快速和廉价的遗传学的发展。 （基于FISH）和蛋白质组学（基于IHC）测试用于区分患者中的各种类型的NET。这应该 显著改善NET的诊断、分型、预后和治疗。

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.