Oncolytic Viral Therapy for Prostate Cancer: Efficacy of Reovirus as a Biological Therapeutic

Abstract

Reovirus is a nonattenuated double-stranded RNA virus that exploits aberrant signaling pathways allowing selective cytotoxicity against multiple cancer histologies. The use of reovirus as a potential treatment modality for prostate cancer has not previously been described, and in this study evidence of in vitro and in vivo activity against prostate cancer was seen both in preclinical models and in six patients. The human prostate carcinoma cell lines PC-3, LN-CaP, and DU-145 exposed to replication-competent reovirus showed evidence of infection as illustrated by viral protein synthesis, cytopathic effect, and release of viral progeny. This oncolytic effect was found to be manifested through apoptosis, as DNA fragmentation, Apo 2.7 expression, Annexin V binding, and poly(ADP-ribose) polymerase cleavage were observed in live reovirus-infected cells, but not in uninfected or dead virus-treated cells. In vivo, hind flank severe combined immunodeficient/nonobese diabetic murine xenograft showed reduction in tumor size when treated with even a single intratumoral injection of reovirus. Finally, intralesional reovirus injections into a cohort of six patients with clinically organ-confined prostate cancer resulted in minimal side effects and evidence of antitumor activity. Histologic analysis after prostatectomy found a significant CD8 T-cell infiltration within the reovirus-injected areas as well as evidence of increased caspase-3 activity. These findings suggest that reovirus therapy may provide a promising novel treatment for prostate cancer and also imply a possible role for viral immune targeting of tumor. Cancer Res; 70(6); 2435-44. ©2010 AACR.

Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

“…6 By comparison, targeted virotherapy has the potential to selectively kill cancer cells while sparing normal cells. 8,24 In this regard, our laboratory has previously demonstrated that eIF4E is a good discriminatory factor between normal and cancer cells as eIF4E levels are substantially elevated in the latter. 4,15,20 eIF4E is the rate-limiting subunit of the eIF4F complex, which is comprised of eIF4E, the cap binding protein; eIF4A, an ATPase and RNA helicase; and eIF4G, a scaffolding protein.…”

“…7 In addition, there is clinical evidence that viruses can be used to safely control treatment-resistant prostate cancer. 8 Viruses such as vesicular stomatitis virus often demonstrate a preference to infect and replicate in tumor cells owing to the presence of a faulty interferon response. 7,9 These studies demonstrate the potential use of viruses as an option for targeted therapy.…”

Evolution of Reovirus in Cancer Therapy

“…Of all the clinical trials, six are in partnership with the US National Cancer Institute, and four are in partnership with the National Cancer Institute of Canada Clinical Trials Group. So far, 308 patients have been treated with reovirus in completed studies; approximately 610 patients are currently enrolled in ongoing trials, and it is expected that an additional 631 patients will be enrolled in future trials.Reovirus has been or will be used in 12 ) has been tested in various clinical trials for the treatment of a multitude of cancers, such as prostate cancer, [48][49][50] malignant gliomas, [51][52][53] advanced head and neck cancers, [54][55][56][57] and metastatic ovarian cancers, [58][59][60] among others…”

“…Based on the safety data from this first trial, a translational study was designed to assess the oncolytic activity (ie, the efficacy) of reovirus in preclinical models and in six prostate cancer patients. [48] In this study, the prostate cancer patients first received a single reovirus injection of 1×10 7 plaque-forming units, and 3 weeks later underwent prostatectomies. Importantly, the immunohistochemical analysis of resected prostate tissues from these patients revealed a preference of reovirus to infect cancerous tissue rather than noncancerous tissue.…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…As a monotherapy, revorius administration generates antitumor responses across a broad range of tumor histologies. Tumor regression has been observed in colorectal and ovarian cancer models (36), xenograft breast cancer models and against primary breast tumor samples (37), prostate xenograft models and six organ-confined prostate cancer patients (38), hamster models of liver metastases from pancreatic cancer (39), and glioblastoma stem-like cells (40). Although the initial monotherapeutic results may indicate some therapeutic activity, OVs as standalone therapies have rarely been shown to induce complete, durable regressions of established tumors in vivo (41).…”