Development of oncolytic HSV-1 as an anticancer therapeutic for extracranial neural tumors and cancer stem cells.

摘要

Cancer has plagued mankind since the beginning of time. In order to improve patient survival, innovative therapeutic approaches are urgently needed. One such therapy, using "oncolytic" viruses, has demonstrated wide tumor applicability and holds much promise. Advantages of oncolytic viruses include their tumor-selective replication and multiple antitumor mechanisms. As the field of oncolytic viruses progresses toward the clinic, it is crucial to characterize the biology behind the oncolytic virus-cancer cell interaction. Oncolytic herpes simplex viruses (oHSV) have been shown efficacious against many human malignancies. Here, I present evidence that human extracranial neural tumors and their cancer stem cells, are sensitive to oHSV-mediated tumor destruction. Because xenograft models for human malignant peripheral nerve sheath tumors (MPNSTs) did not exist, I generated and characterized novel MPNST xenograft models that allow for preclinical evaluation of anticancer agents. Human MPNST cells were efficiently transduced, supported virus replication and were killed by oHSV in a non-Ras dependent manner. This result was in stark contrast to oHSV infection of untransformed, normal human Schwann cells that did not support virus replication. While the antitumor efficacy of oHSV was not enhanced by combination with a small molecule epidermal growth factor receptor inhibitor, an oHSV that expressed a matrix metalloproteinase inhibiting transgene significantly improved antitumor potency. In efficacy studies with this novel oHSV, designated rQT3, I discovered a novel mechanism of oHSV-mediated antitumor activity via disruption of tumor vasculogenesis. To characterize the transcriptomic affect of oHSV infection in human cancer cells I performed a functional genomic analysis and identified a gene signature that correlates with productive oHSV infection. Because cancer stem cells may play major roles in tumor escape from therapy, metastasis and disease relapse, I sought to isolate these cells and determine if they were sensitive to a transcriptionally-targeted oHSV. Neuroblastoma cancer stem cells were identified based upon marker expression and functional assays. As predicted, oHSV effectively infected and replicated within tumor cells possessing stem cell properties. This finding holds therapeutic implications for cancer relapse. The multiple antitumor mechanisms and clinical safety profile of oHSV suggest that these viruses hold much promise to improve outcome for cancer patients.