Targeted Therapies for HIV-Associated Kaposi Sarcoma and Lymphoma

摘要 感染艾滋病毒的人可以预期接受抗逆转录病毒治疗后可以过上接近正常的生活。在美国， 癌症已成为老年艾滋病毒阳性人群的主要死亡原因。这包括艾滋病-- 定义癌症Kaposi肉瘤(KS)和淋巴瘤，如原发性渗出性淋巴瘤(PEL)。事实上, KS是当今艾滋病毒阳性人群的主要死亡原因。此外，作为艾滋病毒阳性者， 队列年龄他们患KS的风险越来越高，即使在HIV阴性的人中，KS也是年龄相关的 KSHV携带者。 我们和其他人已经证明，KS和艾滋病相关的淋巴瘤高度依赖于 PI3K/Akt/mTOR信号通路影响生存。雷帕霉素(MTOR)的哺乳动物靶点是一个 丝氨酸/苏氨酸激酶是PI3K和Akt激酶的下游靶标。雷帕霉素是一种变构 MTORC1复合体的抑制剂，我们在HIV的背景下进行了雷帕霉素的第一次临床试验 感染。我们发现雷帕霉素对KS和PEL小鼠模型有效，雷帕霉素对KS和PEL小鼠模型有效。 表现出不依赖于免疫调节的直接抗肿瘤作用。 在这个应用中，我们建议研究KSHV中PI3K/Akt/mTOR通路中的其他靶点 癌症，作为HIV相关癌症的一个模型，严重依赖于这一途径 生死存亡。我们建议寻找有效的药物组合，并描述其分子机制。 不同的治疗靶点。这将揭示下一代治疗KS和淋巴瘤的方法 艾滋病毒感染的背景。由于PI3K/Akt激酶也被证明是最佳HIV所必需的 除了感染和复制，我们还将测试这些针对艾滋病毒复制的疗法。重要的是，我们将主要 评估已通过人体第一阶段安全试验的药物，因此将立即用于 HIV相关KS和淋巴瘤的临床试验。

Abstract People infected with HIV can expect a near normal life on antiretroviral therapy. In the United States, cancer has become the leading cause of death in the aging HIV-positive population. This includes the AIDS- defining cancers Kaposi sarcoma (KS) and lymphomas, such as primary effusion lymphoma (PEL). In fact, KS is the leading cause of death in the HIV-positive population today. Furthermore, as the HIV-positive cohort ages they are at an increasing risk of developing KS, which is age dependent even in HIV-negative KSHV-carriers. We, and others, have shown that KS and AIDS-associated lymphomas are highly dependent on the PI3K/Akt/mTOR signaling pathway for survival. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is a downstream target of the PI3K and Akt kinases. Rapamycin is an allosteric inhibitor of the mTORC1 complex and we conducted the first clinical trial of rapamycin in the context of HIV infection. We showed that rapamycin was efficacious in mouse models of KS and PEL and that rapamycin exhibited a direct anti-tumor effect independent of immune modulation. In this application, we propose to investigate additional targets in the PI3K/Akt/mTOR pathway in KSHV cancers, as a model of HIV-associated cancers that are critically dependent on this pathway for their survival. We propose to identify efficacious drug combinations and to delineate the molecular mechanism of different therapeutic targets. This will uncover the next generation of therapies against KS and lymphoma in the context of HIV infection. Since PI3K/Akt kinases have also been shown to be required for optimal HIV infection and replication, we will also test these therapies against HIV replication. Importantly, we will mostly evaluate drugs that have passed human phase I safety trials and thus will be immediately available for clinical trials for HIV-associated KS and lymphomas.