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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