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.

项目概要摘要感染艾滋病毒的人可以通过抗逆转录病毒治疗过上接近正常的生活。在美国，癌症已成为老龄化艾滋病毒阳性人群死亡的主要原因。这包括艾滋病定义癌症卡波西肉瘤 (KS) 和淋巴瘤，例如原发性渗出性淋巴瘤 (PEL)。在全球范围内，KS 是是当今艾滋病毒阳性人群死亡的主要原因。此外，随着艾滋病毒阳性人群年龄的增长，他们发生 KS 的风险越来越大，即使在 HIV 阴性的 KSHV 携带者中，这种情况也与年龄有关。我们和其他人已经证明 KS 和 AIDS 相关淋巴瘤高度依赖于 PI3K/Akt/mTOR 生存信号通路。我们之前报道过雷帕霉素抑制 mTORC1 在 KS 和 PEL 小鼠模型中有效，并且雷帕霉素表现出直接的抗肿瘤作用独立于免疫调节。这导致了雷帕霉素临床试验的成功和一线使用 HIV+ 和 HIV- 移植 KS 的衍生物。在此应用中，我们建议研究影响 PI3K/Akt/mTOR 通路的其他靶点 KSHV 相关癌症，作为 HIV 相关癌症的模型，严重依赖于该途径为了他们的生存。我们还建议利用 CRISPR 筛选、新型化合物和创新组合描述不同治疗靶点的分子机制的策略。这些调查将揭示 HIV 感染背景下针对 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正在进行人体 I 期安全试验或已通过 I 期试验的药物安全试验。因此，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。