Oncolytic Gene Therapy for Prostate Cancer
Abstract
The overall objective of this award was to define novel, clinically-translatable strategies of prostate cancer (PCa) treatment based on the use of adenoviral vectors. Areas of overall research accomplishment during the award period have included development of a replication-restricted, PSA-selective oncolytic Ad5 vector (CV706) by incorporation of a minimal promoter enhancer construct (PSE) from the human PSA gene 5' of E1A. Demonstration of in vitro and in vivo anti-PCa activity by CV7O6 via apoptosis was noted. Clear evidence of in vitro and in vivo synergy was seen when CV7O6 and ionizing radiation are combined. Identification of mechanisms of this synergy were studied and found to include radiation-induced enhancement of viral replication, augmentation of intratumoral apoptosis/necrosis and alteration in vascularization. Pre-clinical studies allowed translation of CV706 to the clinic in Phase I study in men with locally recurrent PCa following radiation, providing validation of this approach, safety and toxicity assessment, identification of viral replication and anti-tumor activity. Subsequently, we are about to begin Phase I study of CV7O6 plus radiation in men with newly diagnosed clinically-localized PCa. Final experiments included exploration of Ad5 E4orf6 protein expression as a radiation sensitizer and identification of HIF-1 expression in PCa and its regulation by the PI3KIPTEN/AKT pathway providing rationale for design of gene therapy strategies based on HIF-l transcription.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA401492
Entities
People
- Theodore L. Deweese
Organizations
- Johns Hopkins University