Targeted Therapies for HIV-Associated Kaposi Sarcoma and Lymphoma

项目摘要摘要 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 已经成为老龄化的艾滋病毒阳性人群的主要死亡原因。这包括对艾滋病的定义 癌症Kaposi肉瘤(KS)和淋巴瘤，如原发性渗出性淋巴瘤(PEL)。在全球范围内，KS是 当今艾滋病毒阳性人群的主要死亡原因。此外，随着艾滋病毒阳性人群的年龄增长，他们 罹患KS的风险越来越大，即使在艾滋病毒阴性的KSHV携带者中，KS也是年龄相关的。 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。我们先前报道了雷帕霉素对mTORC1的抑制作用 在KS和PEL小鼠模型中有效，雷帕霉素显示出直接的抗肿瘤作用 不依赖于免疫调节。这导致了一项成功的临床试验和雷帕霉素的第一线使用- HIV+和艾滋病毒移植KS中的衍生物。 在这项应用中，我们建议研究影响PI3K/Akt/mTOR途径的额外靶点 KSHV相关癌症作为严重依赖这一途径的HIV相关癌症的模型 为了他们的生存。我们还建议利用CRISPR筛分、新化合物和创新组合 阐明不同治疗靶点的分子机制的策略。这些调查将 在艾滋病毒感染的背景下，发现针对KS和淋巴瘤的下一代疗法。重要的是 我们建议主要评估目前处于人体I期安全性试验或已通过I期试验的药物。 安全试验。因此，在本申请中提出的研究取得的进展将立即 可用于HIV相关KS和淋巴瘤的临床试验。

Project Summary 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). Globally, 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. We previously reported that mTORC1 inhibition with rapamycin was efficacious in mouse models of KS and PEL and that rapamycin exhibited a direct anti-tumor effect independent of immune modulation. This led to a successful clinical trial and first line use of rapamycin- derivates in HIV+ and HIV- transplant KS. In this application, we propose to investigate additional targets that impinge on the PI3K/Akt/mTOR pathway in KSHV-associated cancers, as a model of HIV-associated cancers that are critically dependent on this pathway for their survival. We also propose to utilize CRISPR screens, novel compounds, and innovative combination strategies to delineate the molecular mechanism of different therapeutic targets. These investigations will uncover the next generation of therapies against KS and lymphoma in the context of HIV infection. Importantly, we propose to mostly evaluate drugs that currently are in human phase I safety trials or have passed phase I safety trials. Thus, the advances made with the studies proposed in this application will be immediately available for use in clinical trials for HIV-associated KS and lymphomas.