Kaposi' s sarcoma (KS), caused by the KS herpesvirus (KSHV) is an AIDS-associated malignancy (AIDS-KS) and is the most important malignancy of the oral cavity in HIV infected individuals. KS can be treated with local therapy, anti-retroviral therapy and chemotherapy; however, it is estimated more than a half of KS patients will not be cured. KS is characterized by the proliferation of spindle cells and deregulated angiogenesis caused by KSHV genes. The limited success of targeted pathogenesis-based therapies in AIDS- KS such as the use of mTORC1 and PDGFR inhibitors indicate the urgent need to increase our understanding of the interplay of viral and host factors underpinning KS oncogenesis for development of targeted therapies; and more importantly, to inform current therapies. Using animal models of Rac1-dependent and of KSHV- dependent KS oncogenesis developed in our lab, we molecularly delineate an oncogenic paracrine axis connecting the expression of the KSHV oncogene vGCPR with secretion of the paracrine factors in order to define novel therapeutic targets. Novel studies carried out in an unbiased manner led us to: 1) Identify PDGFR- alpha (PGFRA) as the most potent oncogenic driver signaling cascade activated in KS pointing to PDGFRA as a target for anti-KS therapies 2) Identify PDGFRA+ mesenchymal stem cells (MSC) as potential KS oncogenic progenitors. We hypothesize that the prominent activation of PDGFRA and its driver role in the tumors is a consequence of the intrinsic ability of KSHV to target this pathway to increase infectivity, persistence and replication in PDGFRA+ target MSC.
(AIM 1) Will study the role of PDGFRA in KSHV infection of PDGFRA+ MSC KS progenitors and oncogenesis:
(AIM 2) Will Identify host viral interactions conducive to sustained activation of PDGFRA.
(Aim 3) Will seek to use genetic and drug inhibition studies and NGS (RNASeq) to identify and targeting mechanisms of PDGFRA-mediated tumorigenesis in KSHV infected tumors. This work will: 1) Identify phenotypic characteristics of the KS progenitor and how the biology of KSHV in these cells leads to oncogenesis 2) Identify key pathogenic mechanisms and new therapeutic approaches 3) Understand the interplay between PDGFRA and KSHV biology in KS tumors and how it affects pathogenesis and response to therapy

Public Health Relevance

This proposal seeks to understand the molecular mechanisms whereby the Kaposi's sarcoma herpesvirus (KSHV) causes in AIDS patients a particular type of cancer termed Kaposi's sarcoma. By understanding how this virus deploys its molecular machinery to cause this cancer we will be able to develop new approaches able of blocking the ability of the virus to cause cancer and in this way prevent or treat Kaposi's sarcoma tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136387-08
Application #
9210609
Study Section
Special Emphasis Panel (ZRG1-AARR-E (02)M)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2008-07-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
8
Fiscal Year
2017
Total Cost
$411,500
Indirect Cost
$143,421
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Liu, G; Yu, F-X; Kim, Y C et al. (2015) Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene 34:3536-46
Cavallin, Lucas E; Goldschmidt-Clermont, Pascal; Mesri, Enrique A (2014) Molecular and cellular mechanisms of KSHV oncogenesis of Kaposi's sarcoma associated with HIV/AIDS. PLoS Pathog 10:e1004154
Ashlock, Brittany M; Ma, Qi; Issac, Biju et al. (2014) Productively infected murine Kaposi's sarcoma-like tumors define new animal models for studying and targeting KSHV oncogenesis and replication. PLoS One 9:e87324
Mesri, Enrique A; Feitelson, Mark A; Munger, Karl (2014) Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15:266-82
Mesri, Enrique A; Cavallin, Lucas E; Ashlock, Brittany M et al. (2013) Molecular studies and therapeutic targeting of Kaposi's sarcoma herpesvirus (KSHV/HHV-8) oncogenesis. Immunol Res 57:159-65
Ma, Qi; Cavallin, Lucas E; Leung, Howard J et al. (2013) A role for virally induced reactive oxygen species in Kaposi's sarcoma herpesvirus tumorigenesis. Antioxid Redox Signal 18:80-90
Bhatt, Shruti; Ashlock, Brittany M; Natkunam, Yasodha et al. (2013) CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma. Blood 122:1233-42
Bhatt, Shruti; Ashlock, Brittany M; Toomey, Ngoc L et al. (2013) Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest 123:2616-28
Nemeroff, Charles B; Goldschmidt-Clermont, Pascal J (2012) Heartache and heartbreak--the link between depression and cardiovascular disease. Nat Rev Cardiol 9:526-39

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