: Viral vectors genetically-engineered for replication restricted to cancer cells represent an attractive strategy for prostate cancer therapy because these viruses can replicate and spread in the tumor yet be non-toxic to normal prostate and the surrounding nerves. This overcomes a current challenge of conventional treatments, such as surgery and radiation therapy, and has opened a new avenue for cancer therapy - viral oncolysis- which allows for methods of tumor cell killing that are unique in the field of cancer therapy. Since the mechanisms of viral therapy and the potential toxicities differ from those of standard hormonal or chemotherapy, the possibilities of synergy are worthy of exploration. We have provided data leading to a paradigm shift in thinking about the interactions of pharmaceuticals and/or small molecules with cancer cell pathways and specific oncolytic herpes simplex virus (oHSV) gene mutations. Our overarching hypothesis is that we can identify specific pharmaceuticals and/or small molecules that modulate important prostate cancer cell pathways and, when paired with appropriate oHSV vectors can increase oncolytic cancer cell destruction. We plan to study the following aims:
AIM 1 : We hypothesize that the small molecules identified by our high throughput screen to enhance oHSV spread in human prostate cancer cells, will synergize in vitro and in vivo to kill prostate cancer;
AIM 2 : We hypothesize that histone deacetylase inhibitors will sensitize prostate cancer cells to oHSV bearing appropriate mutations through effects on oncogenic signaling pathways;
AIM 3 : We hypothesize that oHSV's can act as antiangiogenic vectors by attenuating the expression of proangiogenic factors induced by hypoxia and that this effect can be further enhanced by microtubule-spindle poisons.

Public Health Relevance

Current treatment modalities for localized prostate cancer include surgery and radiation therapy, both of which are associated with risks of nerve damage and sexual and/or bladder dysfunction, and other complications. Metastatic prostate cancer also has poor treatment options. In this proposal, we are developing therapeutic modalities to target both local and metastatic disease. This and the lack of good chemotherapeutic responses underscores the public health relevance and importance of developing our proposed strategy as a novel approach to the critical problem of prostate cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102139-10
Application #
8585826
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Daschner, Phillip J
Project Start
2003-07-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2014
Total Cost
$281,834
Indirect Cost
$117,038
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Passer, B J; Cheema, T; Wu, S et al. (2013) Combination of vinblastine and oncolytic herpes simplex virus vector expressing IL-12 therapy increases antitumor and antiangiogenic effects in prostate cancer models. Cancer Gene Ther 20:17-24
Castelo-Branco, P; Passer, B J; Buhrman, J S et al. (2010) Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer. Gene Ther 17:805-10
Kanai, Ryuichi; Wakimoto, Hiroaki; Cheema, Tooba et al. (2010) Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer? Future Oncol 6:619-34
Passer, Brent J; Cheema, Tooba; Zhou, Bingsen et al. (2010) Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication. Cancer Res 70:3890-5
Passer, B J; Castelo-Branco, P; Buhrman, J S et al. (2009) Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells. Cancer Gene Ther 16:551-60
Passer, B J; Wu, C-l; Wu, S et al. (2009) Analysis of genetically engineered oncolytic herpes simplex viruses in human prostate cancer organotypic cultures. Gene Ther 16:1477-82
Liu, Ta-Chiang; Castelo-Branco, Pedro; Rabkin, Samuel D et al. (2008) Trichostatin A and oncolytic HSV combination therapy shows enhanced antitumoral and antiangiogenic effects. Mol Ther 16:1041-7
Liu, Ta-Chiang; Wakimoto, Hiroaki; Martuza, Robert L et al. (2007) Herpes simplex virus Us3(-) mutant as oncolytic strategy and synergizes with phosphatidylinositol 3-kinase-Akt targeting molecular therapeutics. Clin Cancer Res 13:5897-902
Varghese, Susan; Rabkin, Samuel D; Nielsen, G Petur et al. (2007) Systemic therapy of spontaneous prostate cancer in transgenic mice with oncolytic herpes simplex viruses. Cancer Res 67:9371-9
Kuroda, Toshihiko; Rabkin, Samuel D; Martuza, Robert L (2006) Effective treatment of tumors with strong beta-catenin/T-cell factor activity by transcriptionally targeted oncolytic herpes simplex virus vector. Cancer Res 66:10127-35

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