title: 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.
authors.affiliation: Departments of Oncology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chandini M
authors.initials: CM
authors.lastname: Thirukkumaran
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nodwell
authors.forename: Kensuke
authors.initials: K
authors.lastname: Hirasawa
authors.forename: Zhong-Qiao
authors.initials: ZQ
authors.lastname: Shi
authors.forename: Roman
authors.initials: R
authors.lastname: Diaz
authors.forename: Joanne
authors.initials: J
authors.lastname: Luider
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Magliocco
authors.forename: Patrick
authors.initials: P
authors.lastname: Lee
authors.forename: Sandra
authors.initials: S
authors.lastname: Nishikawa
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.forename: Matt
authors.initials: M
authors.lastname: Coffey
authors.forename: Kiril
authors.initials: K
authors.lastname: Trpkov
authors.forename: Kevin
authors.initials: K
authors.lastname: Fonseca
authors.forename: Jason
authors.initials: J
authors.lastname: Spurrell
authors.forename: Don G
authors.initials: DG
authors.lastname: Morris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D023041:Xenograft Model Antitumor Assays