Study of Tumor Pathogenesis and Development of Therapies for AIDS Malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

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 Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans 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 spliced X-box binding protein-1 (sXBP-1) can directly activate production of viral interleukin-6 (vIL-6) and ORF21, a viral thymidine kinase. 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. We have found that KSHV LANA is cleaved by certain caspases, and we are exploring the biology of this interaction. 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 are also exploring the ability of daratumumab to kill primary effusion lymphoma cells. 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 KSHV-encoded viral interleukin-6 (vIL-6). This represents a new disease entity of KSHV interleukin-6 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 KSHV-associated inflammatory cytokine syndrome (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. Finally, we are utilizing RNAscope technology to assess the cells producing various cytokines in KSHV-MCD and KSHV-inflammatory cytokine syndrome (KICS).