Study of Tumor Pathogenesis and Development of Therapies for AIDS Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

This project is focused on the study of the pathogenesis of HIV-associated malignancies and related diseases and the development of novel therapies for these tumors based on this understanding. Much of the work on AIDS-related malignancies has focused on tumors associated with Kaposi sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD), tumors that most frequently occur in HIV-infected patients. We are also exploring the factors that activate KSHV and in particular, those that directly upregulate certain lytic genes. We have found that Kaposi sarcoma lesions express substantial amounts of KSHV viral IL-6 (vIL-6) and ORF75, and are exploring the mechanism(s) for the constitutive expression of ORF75. We have found that ORF75 expression in latent endothelial cells is mediated by Sp1 and that ORF75 plays an important role in the activation of other KSHV genes. We have found that the KSHV viral load in the central nervous system is a good marker for leptomeningeal involvement of primary effusion lymphoma (PEL). We have also found that some effusions of persons with KSHV multicentric Castleman disease have Castleman plasmablasts in the effusions, and that they can also be found circulating. We have identified a group of patients with KSHV infection but without MCD who have systemic inflammatory symptoms similar to that of MCD and who have high serum levels of various cytokines including IL-6 and IL-10. This represents a new disease entity of KSHV inflammatory cytokine syndrome (KICS). We are also studying the mechanism by which KSHV-encoded vIL-6 induces other cytokines, a potentially important step in the pathogenesis of KSHC-MCD and KICS. We are conducting laboratory studies to assess the levels of cytokines, NanoString analysis, single cell sequencing, and other factors in patients on clinical trials for AIDS malignancies. Also, we are utilizing RNAscope technology to assess the cells producing various cytokines in KSHV-MCD and KICS. We are also exploring other approaches to the treatment of KSHV-associated malignancies, including pomalidomide and related cereblon-binding thalidomide analogs. We have found that pomalidomide prevents the downregulation of surface expression of several immune proteins, including MHC-1 and ICAM-1. In addition, we have found that pomalidomide affects the regulation of MHC-1, ICAM-1, and B7-2 in EBV-infected and HTLV-1 infected cells and cell lines. We are studying the mechanism for these effects, their ability to affect immune function, and the effects of other drugs of interest on expression of thee surface markers. We are also exploring other drugs that can modulate the expression of cellular immune surface proteins in virus-infected tumor cells, including CDK4/6 inhibitors. We have found that abemaciclib, a CD4/6 inhibitor, particularly effective at enhancing expression of surface immune marker, and preliminary results from a trial being conducted with Ramya Ramaswami has shown that it has substantial activity in patients with Kaposi sarcoma. We have found that KSHV LANA is cleaved by certain caspases, and we are exploring the biology of this interaction. We have identified other potential caspase cleavage sites on other KSHV proteins and have shown that K5 is also cleaved. . We are also exploring the activity of a variety of agents that affect putative steps in PEL pathogenesis for potential activity in PEL. In particular, we are exploring agents that affect the JAK/STAT pathway and cyclin-dependent kinases (CDK4/6 ) for activity in PEL and other KSHV-related tumors. We have shown that the anti-CD38 antibody daratumamab can kill PEL cells and are now studying this in a clinical trial.