Targeted Therapies for HIV-Associated Kaposi Sarcoma and Lymphoma

HIV 相关卡波西肉瘤和淋巴瘤的靶向治疗

• 批准号: 9203895
• 负责人: BLOSSOM A DAMANIA
• 金额: $ 34.28万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9203895
• 关键词: AIDS-Related Lymphoma; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Age; Aging; Antiviral Agents; Biological; Cause of Death; Clinical Trials; Combined Modality Therapy; Complex; Cyclosporine; Cytostatics; Drug Combinations; Exhibits; FRAP1 gene; Funding; HIV; HIV Infections; HIV Protease Inhibitors; HIV Seropositivity; HIV therapy; Heart; Human; Human Herpesvirus 8; Immune; Incidence; Infection; Kaposi Sarcoma; Kidney; Life; Lymphoma; Malignant Neoplasms; Modeling; Molecular; Mus; Non-Hodgkin' s Lymphoma; Organ Transplantation; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Phosphotransferases; Population; Protease Inhibitor; Protein-Serine-Threonine Kinases; Relative Risks; Risk; Safety; Signal Pathway; Signal Transduction; Sirolimus; Solid; Testing; United States; Validation; Viral Load result; abstracting; age related; antiretroviral therapy; antitumor effect; cohort; comparative efficacy; cytotoxic; immunoregulation; in vivo; inhibitor/antagonist; kinase inhibitor; mouse model; next generation; novel; primary effusion lymphoma; research study; standard of care; targeted treatment; therapeutic target

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.

抽象的 感染艾滋病毒的人可能会在抗逆转录病毒疗法上寿命几乎正常。在美国， 癌症已成为衰老的HIV阳性人群死亡的主要原因。这包括艾滋病 - 定义癌症Kaposi肉瘤（KS）和淋巴瘤，例如一级积液淋巴瘤（PEL）。实际上， KS是当今HIV阳性人群中死亡的主要原因。此外，作为HIV阳性 队列年龄，它们的风险越来越高，即使是艾滋病毒阴性，这也依赖于年龄 KSHV-Carrier。 我们和其他人都表明，KS和与艾滋病相关的淋巴瘤高度依赖 PI3K/AKT/MTOR信号传导途径用于生存。雷帕霉素（MTOR）的哺乳动物靶 丝氨酸/苏氨酸激酶是PI3K和Akt激酶的下游靶标。雷帕霉素是变构的 MTORC1复合物的抑制剂，我们在HIV背景下进行了雷帕霉素的第一个临床试验 感染。我们表明雷帕霉素在KS和PEL的鼠标模型中有效，并且雷帕霉素有效 与免疫调节无关，表现出直接的抗肿瘤效应。 在此应用程序中，我们建议研究KSHV中PI3K/AKT/MTOR途径中的其他目标 癌症，作为与艾滋病毒相关的癌症的模型，非常依赖于这种途径的癌症 生存。我们建议确定有效的药物组合，并描述 不同的治疗靶标。这将发现针对KS和淋巴瘤的下一代疗法 艾滋病毒感染的背景。由于PI3K/AKT激酶也已被证明是最佳HIV所必需的 感染和复制，我们还将测试针对HIV复制的这些疗法。重要的是，我们主要将 评估已通过人类I期安全试验的药物，因此将立即使用 HIV相关KS和淋巴瘤的临床试验。