Sylvester Comprehensive Cancer Center

Enrique A. Mesri, Ph.D.

Enrique A. Mesri, Ph.D.

Associate Professor of Microbiology & Immunology

Description of Research

Dr. Mesri's laboratory focuses on the mechanisms of viral carcinogenesis by the Kaposi's sarcoma herpes virus (KSHV) or human herpes virus-8. KSHV is the etiological agent of Kaposi's sarcoma, the main type of cancer associated with AIDS. AIDS-KS tumors are characterized by proliferation of spindle cells and blood microvessels (angiogenesis). Elucidation of the mechanisms of viral carcinogenesis and activation of angiogenesis by KSHV is key for the identification of viral and host molecular therapeutic targets and could lead to the development of novel cures for KS. Dr. Mesri’s laboratory has identified the major angiogenic activating viral oncogene of KSHV—the G protein coupled receptor (vGPCR). vGPCR is a viral gene capable of turning normal cells into cancer cells and activating the secretion of growth factors that promote blood vessel growth. More importantly, vGPCR is the only KSHV gene that can solely induce KS lesions in mice. Dr. Mesri's laboratory also recently developed a cell and animal model of virally induced KS—an important step in better understanding the mechanisms of KSHV-mediated viral carcinogenesis and the validation of viral therapeutic targets. In this experimental model, mice were induced to develop highly vascularized tumors that are infected with KSHV and that reproduce all the molecular and biological features of KS. Using this model, researchers employed a gene suppression approach that demonstrated vGPCR is essential for KS tumor growth, and therefore, a very promising therapeutic target. More recently Dr. Mesri collaborated with Dr. P. Goldschmidt in the creation of a KS mouse model based on the sole expression of an activated form of Rac. Using this and the KSHV model, they show that KS could be prevented and treated with anti-oxidants.

Dr. Mesri is working on using drugs and genetic approaches to block vGPCR, in testing FDA-approved drugs that can be used to treat KS. He also is focused on understanding the virus-related or unrelated determinants of the different KS clinical forms. In addition, he is using his novel animal model to understand how KSHV and host genes mediate the paracrine mechanisms of oncogenesis induced by KSHV vGPCR. Dr. Mesri’s laboratory is also currently working in new infectious models of KS, in novel anti-viral interventions based on metabolic inhibitors, and in identifying normal genetic polymorphisms that predispose to KS.



Highlights

  • Identified the viral G protein coupled receptor (vGPCR) as the major angiogenesis inducing viral oncogene of KSHV. Dr. Mesri’s laboratory found expression of vGPCR in cells led to cell transformation and the activation of secretion of the tumor angiogenesis factor VEGF.
  • Developed the first cell and animal model of KSHV-induced Kaposi's sarcoma, which can be used to identify viral genes involved in carcinogenesis and to test anti-angiogenic or anti-viral drugs to treat KS.
  • Validated vGPCR as a viral gene critical for KSHV-mediated carcinogenesis. This defines vGPCR as a very attractive therapeutic target for Kaposi's sarcoma. It also identifies drugs or approaches that could block vGPCR or its activity as promising anti-KS drugs. This laboratory found one of these drugs that can block vGPCR-mediated tumor angiogenesis and KSHV-induced tumors is the cyclooxygenase-2 inhibitor celecoxib.
  • In collaboration with Dr. Goldschmidt, developed a mouse model of oxidative stress dependent KS and developed anti-oxidant experimental therapies to KS
  • Defined a novel mechanism of oncogenesis of KS whereby PDGF signaling drives an oxidative stress mediated paracrine amplification of angiogenesis and tumorigenesis
The most recent new developments of Dr. Mesri's laboratory related to these findings include:
  • Defined the PDGF signaling as novel anti-KS target for KS that could be treated with Tyrosine kinase and antibody inhibitors
  • A new infectious animal model of KSHV-induced Kaposi's sarcoma
  • In collaboration with Drs. Izidore Lossos' and Juan Carlos Ramos' laboratories, the identification of SAHA and Bortezomib combinations as both anti-tumor and anti-viral agents to treat KSHV-lymphomas.
  • In collaboration with Dr. William K. Scott from the Husmman Institute of Human Genetics, the results of the first GWAS for AIDS-KS that identified many genes implicated in viral carcinogenesis as risk factors for KS development in KSHV and HIV infected individuals.
  • In collaboration with Dr. Theodore Lampidis, the use of sugar analogs to target glucose metabolism and viral replication in KSHV sarcomagenesis.

Selected Cancer-Related Publications

  • Ma Q, Cavallin LE, Leung HJ, Chiozzini C, Goldschmidt-Clermont PJ, Mesri EA. A role for virally induced reactive oxygen species in Kaposi's sarcoma herpesvirus tumorigenesis. Antioxid Redox Signal. 2013 Jan 1;18(1):80-90. Read more »
  • Bhatt S, Ashlock BM, Toomey NL, Diaz LA, Mesri EA, Lossos IS, Ramos JC..Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest. 2013 Jun 3;123(6):2616-28. Read more »
  • Croci DO, Salatino M, Rubinstein N, Cerliani JP, Cavallin LE, Leung HJ, Ouyang J, Ilarregui JM, Toscano MA, Domaica CI, Croci MC, Shipp MA, Mesri EA, Albini A, Rabinovich GA.Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma. J Exp Med. 2012 Oct 22;209(11):1985-2000. Read more »
  • Leung HJ, Duran EM, Kurtoglu M, Andreansky S, Lampidis TJ, Mesri EA.Activation of the unfolded protein response by 2-deoxy-D-glucose inhibits Kaposi's sarcoma-associated herpesvirus replication and gene expression. Antimicrob Agents Chemother. 2012 Nov;56(11):5794-803. Read more »
  • Mesri EA, Cesarman E. Kaposi's sarcoma herpesvirus oncogenesis is a notch better in 3D. Cell Host Microbe. 2011 Dec 15;10(6):529-31. Read more »
  • Mesri EA, Cesarman E, Boshoff C. Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10:707-19, 2010. Read more »
  • Sarosiek KA, Cavallin LE, Bhatt S, Toomey NL, Natkunam Y, Blasini W, Gentles AJ, Ramos JC, Mesri EA, Lossos IS. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A 107:13069-74, 2010. Read more »
  • Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, Hale LP, Dong C, Cesarman E, Mesri EA, Goldschmidt-Clermont PJ. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc Natl Acad Sci U S A 106:8683-8, 2009 Read more »

Programs

Collaborating in the Multidisciplinary Research Program(s):

E-mail a Friend