Last Updated: 3/12/2011
|Dirk P Dittmer, Ph.D.
microRNA profiling in human cancer
By current estimates 30% of all human cancers are of viral origin or require viral infection as an essential cofactor. The goal of my research is to understand viral tumorigenesis; specifically, cancers that are caused by Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8). KSHV is a double-stranded DNA virus of about 120kbp, which belongs to the rhadinovirus family of human herpesviruses. It was discovered in 1994 and is associated with Kaposi's sarcoma (KS) as well as B-cell lymphoproliferative diseases: pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). These diseases are ultimately fatal as they affect internal organs, and in the US are seen in the context of immune suppression such as HIV-positive individuals or transplant patients.
(1) Transcription in AIDS-associated cancers in the context of clinical trials
To determine the contribution of viral genes in AIDS-associated cancers, we have developed real-time quantitative PCR-based arrays, which allow us to analyze patterns of all KSHV transcripts in PEL and KS (Cancer Research 63:2010pp (2003)). Using this technology, we have designed viral arrays for all human herpesviruses.
In collaboration with physicians and researchers at the UNC Lineberger Comprehensive Cancer Center, with 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, we are using this approach to determine the transcriptional responses of EBV and KSHV-associated lymphomas to novel anti-cancer regimens in culture, in mouse models and in patients.
Recently, we expanded this effort to also profile human micro RNAs in the context of AIDS-associated cancers. We can use the micro RNA signature to define stages of cancer progression.
(2) Identification of cancer-associated human viruses
Based on our expertise in high-throughput PCR, we are trying to identify novel cancer-associated viruses in the human population. To test our strategy, we use baboons and, to date, have identified a novel primate KSHV homolog in baboons (J.Virol.77: 8159pp (2003)) as well as a novel SV40 homolog.
We have since established the bioinformatics and robotics infrastructure for rapid screening of primary tumor biopsies and the quantification of virtually all known tumor viruses.
(3) Basic mechanisms of KSHV gene regulation
We demonstrated that the KSHV latency associated nuclear antigen (LANA) is transcribed in every single KS tumor cell. Hence, we surmise 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, which suggests that LANA might be a putative viral oncogene and may contribute to KSHV pathogenesis. Since the LANA promoter is the major promoter of KSHV in tumor cells and since the same promoter also regulates the viral micro RNAs, we are engaged in a detailed investigation of its architecture and regulation by cellular factors, such as p53 as well as LANA itself .
(4) Mouse models of KSHV oncogenesis
We have developed transgenic mice, which express the LANA protein under the control of its own promoter and had previously shown that the LANA promoter exhibits B-lineage specificity in transgenic mice. As we put larger and larger pieces of the virus into mice we find that offspring from multiple independent founder animals develope follicular B-cell proliferative disorders. Thus, our lab has established the first in vivo model for KSHV LANA-dependent tumorigenesis.
Building upon or initial studies of SCID-human mouse models for primary KSHV infection (J.Exp.Med. 190:1857pp (1999)), we established a xenograftmodel for KSHV-associated lymphomas. Using this model we are investigating the anti-lymphoma properties of established and novel anti-viral drugs (Cancer Research 64:4790pp (2004)).
In sum, our cancer-related efforts seek to combine translational studies on KSHV-associated cancers with appropriate mouse models and the 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 are able to rapidly cross-validate the results of these three approaches to cancer research.
Recent Accomplishments and Honors
Member NCI AIDS-associated malignancies working group
Member AIDS-associated clinical trials consortium (AMC)
Chair of network laboratories for the AMC
Member UNC Center for AIDS research
Member NIDCR Oral HIV/AIDS Research Alliance (OHARA)
NCT00450320 "Phase I/II Study of Sirolimus in Patients with HIV-Related Kaposi's Sarcoma"
NCT00096538 "Pilot Study of Valganciclovir in Patients With Classic Non-HIV-Associated Kaposi's Sarcoma"
NCT00427414 "Pilot Study of Liposomal Daunorubicin Citrate in Patients With HIV-Related Kaposi's Sarcoma"
Freie University Berlin (Germany)
Stanford University School of Medicine
UC San Francisco
D. Dittmer, C. Stoddart, R. Renne, V. Linquist-Stepps, C. Bare, J.M. McCune and D. Ganem, "Experimental Transmission of Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) to SCID-hu Thy/Liv Mice ", J. Exp. Med. 190, 1857-1868 (1999)
D. Whitby, A. Stossel, C.D. Wang, C.Gamache, J. Papin, M. Bosch, A. Smith, D. Kedes, G. White, RC. Kennedy and D.P. Dittmer, "A novel Kaposi's Sarcoma-associated herpesvirus (KSHV/HHV-8) homolog in Baboons", J. Virology 77, 8159-8165 (2003)
D.P. Dittmer " Transcription of Kaposi's Sarcoma-associated herpesvirus in Kaposi's Sarcoma lesions", Cancer Research 63, 2010-2015 (2003)
M.R. Staudt, Y. Kanan, J.H. Jeong, J.F. Papin, R. Hines-Boykin, D.P. Dittmer "The tumor microenvironment controls primary effusion lymphoma growth in vivo", Cancer Research 64(14), 4790-9 (2004)
M. Kurokawa, S.K. Ghosh, J.C. Ramos, A.M. Mian, N. L. Toomey, L. Cabral, D. Whitby, G.N. Barber, D.P. Dittmer, and W.J. Harrington, Jr., "Azidothymidine inhibits NF-kappaB and induces Epstein-Barr virus gene expression in Burkitt's lymphoma", Blood, 106(1): 235-40 (2005)
F.D. Fakhari, J.H. Jeong, Y. Kanan, and D.P. Dittmer, ?The latency-associated nuclear antigen of Kaposi?s sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma?, J. Clinical Investigation, 116(3): 1-8 (2006)
S.H. Sin, D. Roy, L. Wang, M.R. Staudt, F.D. Fakhari, D.D. Patel, D. Henry, W.J. Harrington, B. Damania, D.P. Dittmer ?Rapamycin is efficacious against primary effusion lymphoma (PEL) cell lines in vivo by inhibiting autocrine signaling?, Blood 109(5): 2165-73 (2007)
A.D. Mutlu, L.E. Cavallin, L. Vincent, C. Chiozzini, P. Eroles, E.M. Duran, Z. Asgari, A.T. Hooper, K.M. LaPerle, C. Hilsher, S.J. Gao, D.P. Dittmer, S. Rafii, E. Mesri ?In Vivo-Restricted and Reversible Malignancy Induced by Human Herpesvirus-8 KSHV: A Cell and Animal Model of Virally Induced Kaposi's Sarcoma? Cancer Cell 11(3): 245-58 (2007)
Lechowicz M, Dittmer DP, Lee JY, Krown SE, Wachsman W, Aboulafia D, Dezube BJ, Ratner L, Said J, Ambinder RF. Molecular and clinical assessment in the treatment of AIDS Kaposi sarcoma with valproic Acid. Clin Infect Dis. 2009 Dec 15;49(12):1946-9.
O'Hara AJ, Chugh P, Wang L, Netto EM, Luz E, Harrington WJ, Dezube BJ, Damania B, Dittmer DP. Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi sarcoma. PLoS Pathog. 2009 Apr;5(4):e1000389.
O'Hara AJ, Wang L, Dezube BJ, Harrington WJ Jr, Damania B, Dittmer DP. Tumor suppressor microRNAs are underrepresented in primary effusion lymphoma and Kaposi sarcoma. Blood. 2009 Jun 4;113(23):5938-41.
Bhatt AP, Bhende PM, Sin SH, Roy D, Dittmer DP, Damania B. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. (2010)
Address: 804 Mary Ellen Jones Bldg Chapel Hill, NC 27599-7290
Click here to update this profile