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

描述（由申请人提供）：该项目的目标是确定分子靶点，以开发基于新机制的治疗卡波西肉瘤（KS）的预防和治疗方法。KS是一种新血管肿瘤，通常影响皮肤、口腔黏膜和内脏器官。它是艾滋病毒感染者中最常见的癌症，根据疾病预防控制中心的指导方针，它是艾滋病的定义疾病。不幸的是，这种肿瘤的临床治疗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，KS仍然是一种不治之症。最近发现的KS相关疱疹病毒（KSHV）是KS的病毒病原，这为开发基于发病机制的肿瘤治疗提供了独特的机会。鉴定KSHV肿瘤发生所需的基因，以及介导其致癌潜力的分子事件的性质，是成功开发此类治疗方法的重要第一步。在这方面，我们之前已经证明，只有一种候选的KSHV致癌基因vGPCR在小鼠血管内皮中特异性表达时能够诱导ks样肿瘤。我们进一步发现，vGPCR的表达仅限于少数细胞，但通过旁分泌机制维持KS是必需的。在本研究方案中，我们假设表达vgpcr的细胞分泌的旁分泌是预防和治疗KS的新分子靶点。具体实现以下目标：研究vGPCR旁分泌在卡波西肉瘤发生中的作用；2. 鉴定促进vgpcr表达细胞存活的Akt效应物；和3。研究Akt/TSC/mTOR通路在旁腺肿瘤中的作用。这些研究将为卡波西肉瘤发展和维持的分子机制提供基本的见解，并将进一步揭示关键的分子靶点，以开发基于发病机制的预防和治疗这种疾病的疗法。

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.