Saturday, December 21, 2024
12/21/2024
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.
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