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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要摘要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阳性人群的主要死亡原因。这包括定义的辅助癌症Kaposi肉瘤（KS）和淋巴瘤，例如原发性积液淋巴瘤（PEL）。全球，KS是当今HIV阳性人群的主要死亡原因。此外，随着HIV阳性队列的年龄发展KS的风险越来越高，即使在HIV阴性的KSHV-Carrier中，年龄也取决于年龄。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。我们以前报道了用雷帕霉素抑制MTORC1 在KS和PEL的小鼠模型中有效，该雷帕霉素表现出直接的抗肿瘤效应独立于免疫调节。这导致了成功的临床试验和雷帕霉素的第一线使用在HIV+和HIV移植KS中衍生。在此应用程序中，我们建议调查影响PI3K/AKT/MTOR途径的其他目标 KSHV相关的癌症，作为与HIV相关的癌症的模型，非常依赖于此途径因为他们的生存。我们还建议利用CRISPR屏幕，新颖的化合物和创新组合描绘不同治疗靶标的分子机制的策略。这些调查会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，我们建议主要评估当前正在人类I期安全试验或已通过I期的药物安全试验。因此，在本应用程序中提出的研究取得的进步将立即可用于与HIV相关的KS和淋巴瘤的临床试验。