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: 10548401
• 负责人: BLOSSOM A DAMANIA
• 金额: $ 40.01万
• 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 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548401
• 关键词: ABCB1 gene; AIDS related cancer; AIDS-Related Lymphoma; AIDS/HIV problem; AKT inhibition; Acquired Immunodeficiency Syndrome; Africa South of the Sahara; Age; Aging; Animal Model; Biological; CRISPR screen; Caring; Cause of Death; Chemoresistance; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cytostatics; Data; Disease; Drug Efflux; Endothelial Cells; Exhibits; FDA approved; FRAP1 gene; Funding; Generations; Genomics; Goals; Grant; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV therapy; Human; Human Herpesvirus 8; Immunodeficient Mouse; Incidence; Individual; Investigation; Kaposi Sarcoma; Life; Link; Lymphoma; Malignant Neoplasms; Modeling; Molecular; Organ Transplantation; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Phosphotransferases; Population; Publications; Relative Risks; Reporting; Research; Resistance; Resistance development; Risk; Role; SDZ RAD; Safety; Signal Transduction; Sirolimus; Testing; Time; Transplantation; United States; Viral Cancer; Viral Load result; Work; age related; antiretroviral therapy; antitumor effect; cancer cell; cancer therapy; clinical development; cohort; cytotoxic; efflux pump; experimental study; immunoregulation; in vivo; in vivo imaging; inhibitor; innovation; insight; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; mouse model; new therapeutic target; next generation; novel; overtreatment; pre-clinical; preclinical study; primary effusion lymphoma; resistance mechanism; seropositive; standard of care; success; targeted treatment; therapeutic target; therapy resistant; tumor; whole genome

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.

项目摘要 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 已成为老龄化艾滋病毒阳性人群的主要死因。这包括艾滋病定义 癌症卡波西肉瘤（KS）和淋巴瘤，如原发性渗出性淋巴瘤（PEL）。在全球，KS是 是当今艾滋病毒阳性人群的主要死因。此外，随着艾滋病毒阳性队列的年龄增长， 患KS的风险越来越大，即使在HIV阴性的KSHV携带者中也是年龄依赖性的。 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。我们以前报道过雷帕霉素抑制mTORC 1， 在KS和PEL小鼠模型中有效，雷帕霉素表现出直接的抗肿瘤作用 独立于免疫调节。这导致了一个成功的临床试验和雷帕霉素的一线使用- HIV+和HIV-移植KS中的衍生物。 在本申请中，我们建议研究在细胞凋亡中影响PI 3 K/Akt/mTOR通路的其他靶点。 KSHV相关癌症，作为严重依赖该途径的HIV相关癌症的模型 为了生存。我们还建议利用CRISPR筛选，新化合物和创新组合 描述不同治疗靶点的分子机制的策略。这些调查将 在HIV感染的背景下，发现下一代针对KS和淋巴瘤的疗法。重要的是， 我们建议主要评估目前正在进行人体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所取得的进展将立即得到证实。 可用于HIV相关KS和淋巴瘤的临床试验。