Targeted Therapies for HIV-Associated Kaposi Sarcoma and Lymphoma

摘要 感染艾滋病毒的人可以期待通过抗逆转录病毒治疗获得接近正常的生活。在美国， 癌症已成为老龄化HIV阳性人群的主要死因。其中包括艾滋病- 定义癌症卡波西肉瘤（KS）和淋巴瘤，如原发性渗出性淋巴瘤（PEL）。事实上，我认为， KS是当今艾滋病毒阳性人群的主要死亡原因。此外，由于艾滋病毒阳性 年龄越大，他们患KS的风险越大，即使在HIV阴性的人群中，KS也具有年龄依赖性。 KSHV携带者。 我们和其他人已经表明KS和AIDS相关淋巴瘤高度依赖于 PI 3 K/Akt/mTOR信号通路对存活的影响。雷帕霉素的哺乳动物靶蛋白（mTOR）是一种靶蛋白。 丝氨酸/苏氨酸激酶是PI 3 K和Akt激酶的下游靶标。雷帕霉素是一种变构药物 mTORC 1复合物的抑制剂，我们进行了第一次雷帕霉素在HIV背景下的临床试验， 感染我们发现雷帕霉素在KS和PEL小鼠模型中是有效的， 表现出独立于免疫调节的直接抗肿瘤作用。 在本申请中，我们建议研究KSHV中PI 3 K/Akt/mTOR通路中的其他靶点。 癌症，作为HIV相关癌症的模型，这些癌症严重依赖于这一途径， 生存我们建议确定有效的药物组合，并描绘的分子机制， 不同的治疗目标。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PI 3 K/Akt激酶也已被证明是最佳HIV感染所需的。 感染和复制，我们还将测试这些疗法是否能对抗艾滋病毒复制。重要的是，我们将主要 评估已通过人体I期安全性试验的药物，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.