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Tumor-specific targeting using oncolytic herpes simplex virus type 1 for prostate cancer treatment

University of British Columbia

Prostate cancer is the most common non-skin cancer, and the second leading cause of cancer-death in men. Current treatments, including androgen withdrawal therapy, are not curative for advanced metastatic disease and new treatment strategies are urgently required. In this regard, oncolytic virotherapy offers a promising new approach. This project aims to provide a proof-of-principle that an oncolytic herpes simplex virus type-1 (HSV-1) virus can be engineered to replicate in a tissue- and tumor-specific fashion through both transcriptional and translational regulation of an essential viral gene. Using the amplicon/helper system, we first generated a prostate-specific amplicon virus by inserting the ARR2PB promoter in front of the ICP4 gene, and two tumor-specific amplicon viruses by incorporating multiple copies of miR-143 or miR-145 complementary target sequences in the 3’ untranslated region (3’UTR) of ICP4. Finally, we generated two prostate tumor-specific recombinant viruses using the bacterial artificial chromosome and the recombineering method. Our results showed that an amplicon system containing a prostate-specific promoter upstream of an essential viral gene can complement a helper virus for lytic replication specifically within prostate tumor cells. We also showed both in vitro and in vivo that viral replication and cell killing occurred only in tumor cells with abundant eIF4E protein or low levels of miR-143/miR-145 when viral gene expression was controlled by a modified 5’UTR or 3’UTR, respectively. Nude mice bearing LNCaP tumors treated with local or systemic injections of these tumor-specific viruses had a >85% reduction in tumor size at day 28 post-viral injection and without extensive toxicity to normal tissues. Quantitative real-time PCR analysis also showed that the majority of the virus was detected in the tumor mass and not within normal tissues. In conclusion, the incorporation of a tissue-specific promoter or a tumor-specific element in an oncolytic HSV-1 virus is a viable strategy to restrict viral replication and oncolysis selectively to tumor cells while sparing normal tissues. This work provides a basis for the development of novel oncolytic HSV-1 viruses for local and systemic treatment of locally advanced and metastatic prostate cancer.

Thesis/Dissertation

application/pdf

2009-10-02

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/13552

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/