Abstract

Herpes simplex virus-1 (HSV-1) has many attractive features for further development as an oncolytic and gene transfer vector for prostate cancer therapy. Although many advances have been made in this field in the past decade, we now describe methods to increase the efficacy of treatment using relevant transgenic prostate cancer models mimicking human metastatic prostate cancer. We hypothesize that appropriately chosen chemotherapeutic agents combined with oncolytic HSV vectors will improve anti-tumor efficacy, including after systemic delivery, and that this combination will permit the use of lower, less toxic doses of chemotherapy. We will explore the mechanisms of targeting and anti-tumor efficacy of oncolytic HSV following intravenous delivery. We will study the immune mechanisms of HSV vectors expressing cytokines that can act synergistically to elicit immune destruction of prostate cancer. We hypothesize that oncolytic HSV vectors exert some of their anti-tumor effects by inhibiting angiogenesis within the tumor and that the expression of appropriately chosen cytokines will enhance this anti-angiogenic effect. We will explore these mechanisms of action following both intra-neoplastic and intravenous administration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102139-04
Application #
7228054
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Daschner, Phillip J
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2007
Total Cost
$340,161
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Peters, Cole; Rabkin, Samuel D (2015) Designing Herpes Viruses as Oncolytics. Mol Ther Oncolytics 2:
Playa, Hilaire; Lewis, Timothy A; Ting, Amal et al. (2014) Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2). Bioorg Med Chem Lett 24:5801-5804
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
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
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
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
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

Showing the most recent 10 out of 17 publications