The objective of this project is the identification of molecular targets for the development of novel mechanism-based therapies for the prevention and treatment of Kaposi's sarcoma (KS). KS is a neovascular tumor that typically affects the skin, oral mucosa, and visceral organs. It is the most frequent cancer arising in HIV-infected individuals and is an AIDS-defining illness by CDC guidelines. Unfortunately, clinical management of this tumor has proven to be challenging. Today, despite extensive investigation into its molecular etiology, KS remains an incurable disease. The recent identification of the KS-associated herpesvirus (KSHV) as the viral etiological agent for KS presents a unique opportunity to develop pathogenesis-based treatments for this neoplasm. Identification of the gene(s) necessary for KSHV tumorigenesis, and the nature of the molecular events mediating their oncogenic potential, is an essential first step for the successful development of such therapies. In this regard, we have previously shown that only one candidate KSHV oncogene, vGPCR, is able to induce KS-like tumors when specifically expressed in the vascular endothelium of mice. We further found that expression of vGPCR was confined to only a few cells yet was necessary for KS maintenance through a paracrine mechanism. In this research proposal, we hypothesize that the paracrine secretions elaborated by vGPCR-expressing cells represent novel molecular targets for the prevention and treatment of KS. We will accomplish the following specific aims: 1. examine the role of vGPCR paracrine secretions in Kaposi's sarcomagenesis; 2. identify the Akt effectors which promote the survival of vGPCR-expressing cells; and 3. examine the role of the Akt/TSC/mTOR pathway in paracrine neoplasia. These studies will provide fundamental insight(s) into the molecular mechanisms involved in the development and maintenance of Kaposi's sarcoma and will further expose critical molecular targets for the development of pathogenesis-based therapies for the prevention and treatment of this disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA119911-01A2
Application #
7230886
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2007-04-02
Project End
2012-01-31
Budget Start
2007-04-02
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$282,150
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Montaner, Silvia; Kufareva, Irina; Abagyan, Ruben et al. (2013) Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Annu Rev Pharmacol Toxicol 53:331-54
Hu, Jiadi; Jham, Bruno C; Ma, Tao et al. (2011) Angiopoietin-like 4: a novel molecular hallmark in oral Kaposi's sarcoma. Oral Oncol 47:371-5
Jham, Bruno C; Ma, Tao; Hu, Jiadi et al. (2011) Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma. PLoS One 6:e19103
Ma, Tao; Jham, Bruno C; Hu, Jiadi et al. (2010) Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma. Proc Natl Acad Sci U S A 107:14363-8
Jham, Bruno C; Montaner, Silvia (2010) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor: Lessons on dysregulated angiogenesis from a viral oncogene. J Cell Biochem 110:1-9
Chaisuparat, Risa; Hu, Jiadi; Jham, Bruno C et al. (2008) Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res 68:8361-8