Project 2: Molecular Mechanisms and Biomarkers of Neuroendocrine Tumors

神经内分泌肿瘤 (NET) 是一种惰性恶性肿瘤，其发病率不断增加，显示出深刻的影响 对传统疗法的耐药性，是一个日益严峻的临床挑战。 NET 的底层机制 人们对这种疾病的发展仅部分了解，并且缺乏该疾病的诊断/预后生物标志物。 虽然过去几十年来管理胰腺 NET (PNET) 的进展缓慢，但新的 随着我们对分子生物学的了解越来越多，mTOR 抑制剂等靶向疗法也应运而生。 PNET 发病机制。越来越多的证据表明，更大的好处（提高疗效和 通过靶向 PI3K/Akt/mTOR 通路的多个步骤来获得耐药性降低）。更好 了解 PI3K/Akt/mTOR 调节并识别对患者进行风险分层的 PNET 生物标志物 将那些会对（或不会）对特定疗法产生反应的人分成亚组将改善患者的治疗。这个 项目的开发就是考虑到这些目标。目标 1 建立在我们发现 RABL6A（一部小说 癌蛋白）对于 PNET 细胞的存活和增殖、Akt/mTOR 活性以及其他细胞因子的控制至关重要 临床相关的 PNET 通路，例如 Rb1。目标 2，基于试点研究，确定了几个 能够区分胰腺和回肠 NET 的染色体改变（包括 RABL6A 扩增） 在 chr 9q 上），试图定义新的 DNA 和蛋白质生物标志物来区分四种不同类型的 NET （胰腺、回肠、支气管和宫颈）。目标 1 和目标 2 的研究结果的整合将建立新颖的 药物靶向 PNET 通路（RABL6A-Akt/mTOR、RABL6A-Rb1）的状态与 区分 NET 类型和预后的基因改变，从而推进该疾病的临床管理 疾病。 目标 1. 确定控制 PNET 增殖和存活的临床相关治疗靶点。 目标 2. 识别区分 NET 类型和预后的遗传和蛋白质组生物标志物。 这项研究将确定各种类型的 NET 常见或独特的分子改变，以及 原发性肿瘤与转移性肿瘤。试点研究已经确定了 RABL6A 和其他特定基因 作为强有力的候选 PNET 生物标志物的改变，拟议的临床前研究将确定疗效 针对 RABL6A 效应途径的独特药物组合，以减轻 PNET 负担。最 该转化项目的直接临床成果将是开发快速且廉价的遗传基因 （基于 FISH）和蛋白质组学（基于 IHC）测试，用于区分患者中各种类型的 NET。这应该 显着提高NET的诊断、分型、预后和治疗水平。

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.