Research interests at Dittmer Lab
By current estimate, 25-35% of all human cancers have viral origin or require viral infection as an essential cofactor. Our research goal focuses on understanding viral tumorigenesis, specifically cancers caused by Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8). KSHV is a double-stranded DNA virus of about 120kbp, belonging to the rhadinovirus family of human herpesviruses.
Discovered in 1994, KSHV is associated with Kaposi’s sarcoma (KS) as well as B-cell lymphoproliferative diseases like pleural effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). These diseases affect internal organs and are ultimately fatal; they are usually seen in the U.S. among immunosuppressed individuals like HIV-positive individuals and transplant patients.
Transcriptional profiling of AIDS-associated cancers
We have developed real-time quantitative PCR-based arrays to determine the contribution of viral genes in AIDS-associated cancers, which allow us to analyze KSHV transcript patterns in PEL and KS (Cancer Res. 63:2010pp (2003)). Using this technology has allowed us to design viral arrays for all human herpesviruses.
We are using this approach, in collaboration with physicians and researchers at the UNC Lineberger Comprehensive Cancer Center, the NCI-AIDS Malignancy Clinical Trials Consortium, the NCI Intramural Viral Epidemiology Group, the Memorial Sloan-Kettering Cancer Center, and the University of Miami Cancer Center, to determine the transcriptional responses of EBV and KSHV-associated lymphomas to novel anti-cancer regimens in culture, in mouse models, and in patients.
Identification of new viruses
Based on our expertise in high-throughput PCR, we are trying to identify novel viruses in the human population. We test our strategy using baboons and have successfully identified a novel primate KSHV homolog in baboons (J.Virol.77:8159pp (2003)) as well as a novel SV40 homolog. We have since established bioinformatics and robotics infrastructures to rapidly screen and quantify virtually all known viruses. Using this approach has allowed us to identify novel West-Nile viruses (J.Clin.Microbio 42:1511pp (2004)) and to continue studying West-Nile inhibitors and novel vaccines.
Basic mechanisms of viral gene regulation
Our studies demonstrated that the KSHV latency-associated nuclear antigen (LANA) is transcribed in every single KS tumor cell, leading us to conclude that LANA is essential for KS tumorigenesis. LANA is required for latent viral replication and proper episome segregation. LANA also binds to the p53 and Rb tumor suppressor proteins, suggesting that it might be a putative viral oncogene and may contribute to KSHV pathogenesis.Since the LANA promoter is the major latency promoter of KSHV, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53, Sp1 as well as LANA itself (J.Biol.Chem. 279:16822pp (2004)).
Mouse models of KSHV oncogenesis
We have developed transgenic mice which express the LANA protein under the control of its promoter, after previously showing that the LANA promoter exhibits B-lineage specificity in transgenic mice (J.Virol 76:11024pp (2002)). Offspring from multiple independent founder animals develop follicular B-cell proliferative disorders. Thus, our lab has established the first in vivo model for KSHV LANA-dependent tumorigenesis.
We established a xenograft model for KSHV-associated lymphomas, building upon our initial studies of SCID-human mouse models for primary KSHV infection (J.Exp.Med. 190:1857pp (1999)). Using this model, we continue to investigate the anti-lymphoma properties of established and novel anti-viral drugs (Cancer Res. 64:4790pp (2004)).
In sum, our cancer-related efforts seek to combine translational studies of KSHV-associated cancers with appropriate mouse models and detailed molecular investigation of a few key viral oncogenes. Using high-throughput real-time quantitative PCR as the signature technology platform for this group, we can rapidly cross-validate the results of these three approaches to cancer research.