Prostate cancer is a malignant tumor, which in its aggressive form would spread to the bone and many other parts of the body. The aging male population is especially susceptible to this disease, since from the 5th decade of life the prostate cancer risk rises steadily. In fact, ~ 60% new cases of solid tumors in men over age 70 represent tumors in the prostate gland. Metastatic prostate cancer is the leading cause of cancer deaths among elderly men. The proposed study is expected to provide novel information on the strategy to manage prostate cancer based on selective killing of prostate tumor cells by the oncolytic human respiratory syncytial virus (RSV). Oncolytic virotherapy is an emerging bio-therapeutic platform for cancer treatment, which is based on selective infection and """"""""killing"""""""" of cancer cells. To date, eight oncolytic viruses have been identified. However, recent clinical trials indicated the need for a multi-virus virotherapy approach for the treatment of aggressive cancers and thus, the urgency to identify novel oncolytic viruses. To this end, we have identified RSV as a novel oncolytic virus, since RSV possesses potent anti-cancer activity against prostate tumor cells. Our results demonstrated dramatic enhancement of RSV infectivity in the androgen-insensitive, highly metastatic PC-3 human prostate cancer cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden in PC-3 cells leads to selective """"""""killing"""""""" of PC-3 cancer cells in vitro and in vivo in human prostate tumor xenografts grown in nude mice. We further demonstrated that the possible mechanism underlying the oncolytic function of RSV involves defect in the NF-?B dependent innate anti-viral response in PC-3 cells. Since anti-viral innate immunity constitutes the first line of defense directed to restrict viral infection, we speculate that dysfunctional innate response in PC-3 cells is responsible for the increased viral infectivity and oncolysis. The proposed study will be pursued with two Specific Aims:
Aim 1) Characterize the RSV-mediated oncolysis of prostate cancer cells in vivo in tumor xenografts and in the TRAMP mouse model of prostate cancer.
Aim 2) Study the role of the deregulated NF-?B dependent anti-viral pathway in conferring the oncolytic function to RSV in prostate cancer cells. RSV-mediated oncolysis in vivo will be assessed based on tumor regression;prostate histology;apoptosis in situ;and metastatic spread of PC-3 cells in a fluorescent orthotopic model. Deregulated NF-?B function will be explored using cell biology approaches including knock down of specific NF-?B family members by lentivirus-mediated siRNA expression and chromatin immunoprecipitation. Significance: The oncolytic property of RSV could be developed as an efficient therapeutic tool to specifically target prostate tumors.

Public Health Relevance

Prostate cancer is a leading cause of mortality among elderly population and novel anti-cancer treatment is necessary to control this disease. We have identified respiratory syncytial virus as a novel anti-cancer agent that could selectively destroy prostate cancer cells, but not normal cells. Therefore, this virus could be utilized as a therapeutic to design safe and efficient virus-based anti-cancer agents to specifically target prostate tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA129246-02
Application #
7564763
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2008-05-01
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2009
Total Cost
$200,250
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Echchgadda, Ibtissam; Chang, Te-Hung; Sabbah, Ahmed et al. (2011) Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense. BMC Cancer 11:43
Mgbemena, Victoria; Segovia, Jesus; Chang, TeHung et al. (2011) Kr├╝ppel-like factor 6 regulates transforming growth factor-? gene expression during human respiratory syncytial virus infection. Virol J 8:409
Echchgadda, I; Kota, S; DeLa Cruz, I et al. (2009) Anticancer oncolytic activity of respiratory syncytial virus. Cancer Gene Ther 16:923-35
Sabbah, Ahmed; Chang, Te Hung; Harnack, Rosalinda et al. (2009) Activation of innate immune antiviral responses by Nod2. Nat Immunol 10:1073-80
Sabbah, Ahmed; Bose, Santanu (2009) Retinoic acid inducible gene I activates innate antiviral response against human parainfluenza virus type 3. Virol J 6:200
Kota, Srikanth; Sabbah, Ahmed; Chang, Te Hung et al. (2008) Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus. J Biol Chem 283:22417-29