Molecular Targets for the Prevention and Treatment of Kaposi's Sarcoma

描述（由申请人提供）：本项目的目的是鉴定用于开发预防和治疗卡波西肉瘤（KS）的新型机制疗法的分子靶点。KS是一种新生血管肿瘤，通常影响皮肤，口腔粘膜和内脏器官。它是艾滋病毒感染者中最常见的癌症，也是CDC指南中定义的艾滋病疾病。不幸的是，这种肿瘤的临床管理已被证明是具有挑战性的。今天，尽管对其分子病因进行了广泛的研究，但KS仍然是一种无法治愈的疾病。最近确定KS相关疱疹病毒（KSHV）作为KS的病毒病原体，这为开发基于发病机制的治疗方法提供了一个独特的机会。鉴定KSHV肿瘤发生所必需的基因以及介导其致癌潜力的分子事件的性质是成功开发此类疗法的重要第一步。在这方面，我们以前已经表明，只有一个候选KSHV癌基因，vGPCR，是能够诱导KS样肿瘤时，特异性表达在血管内皮细胞的小鼠。我们进一步发现vGPCR的表达仅限于少数细胞，但通过旁分泌机制对KS维持是必需的。在这项研究中，我们假设由vGPCR表达细胞产生的旁分泌物代表了预防和治疗KS的新分子靶点。我们将实现以下具体目标：1.检查vGPCR旁分泌分泌物在卡波西肉瘤发生中的作用; 2.鉴定促进表达vGPCR的细胞存活的Akt效应子;和3.研究Akt/TSC/mTOR通路在旁分泌瘤形成中的作用。这些研究将为卡波西肉瘤的发展和维持所涉及的分子机制提供基本的见解，并将进一步揭示用于预防和治疗这种疾病的基于发病机制的疗法的发展的关键分子靶点。

DESCRIPTION (provided by applicant): The objective of this project is the identification of molecular targets for the development of novel mechanism-based therapies for the prevention and treatment of Kaposi's sarcoma (KS). KS is a neovascular tumor that typically affects the skin, oral mucosa, and visceral organs. It is the most frequent cancer arising in HIV-infected individuals and is an AIDS-defining illness by CDC guidelines. Unfortunately, clinical management of this tumor has proven to be challenging. Today, despite extensive investigation into its molecular etiology, KS remains an incurable disease. The recent identification of the KS-associated herpesvirus (KSHV) as the viral etiological agent for KS presents a unique opportunity to develop pathogenesis-based treatments for this neoplasm. Identification of the gene(s) necessary for KSHV tumorigenesis, and the nature of the molecular events mediating their oncogenic potential, is an essential first step for the successful development of such therapies. In this regard, we have previously shown that only one candidate KSHV oncogene, vGPCR, is able to induce KS-like tumors when specifically expressed in the vascular endothelium of mice. We further found that expression of vGPCR was confined to only a few cells yet was necessary for KS maintenance through a paracrine mechanism. In this research proposal, we hypothesize that the paracrine secretions elaborated by vGPCR-expressing cells represent novel molecular targets for the prevention and treatment of KS. We will accomplish the following specific aims: 1. examine the role of vGPCR paracrine secretions in Kaposi's sarcomagenesis; 2. identify the Akt effectors which promote the survival of vGPCR-expressing cells; and 3. examine the role of the Akt/TSC/mTOR pathway in paracrine neoplasia. These studies will provide fundamental insight(s) into the molecular mechanisms involved in the development and maintenance of Kaposi's sarcoma and will further expose critical molecular targets for the development of pathogenesis-based therapies for the prevention and treatment of this disease.