Investigator
Ottawa Hospital
Specific Genetic Mutations Impact Chemotherapy Resistance and Therapeutic Efficacy of Oncolytic Viruses in Ovarian Cancer
Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer, and those affected are in urgent need of new therapeutic strategies. Standard treatment is surgery followed by taxane- and platinum-based chemotherapy. However, the rate of relapse is high, and the 5-year survival is only 45%. Oncolytic viruses (OV) are a promising approach to EOC therapy through remodeling the immune composition of the tumor microenvironment. Treatment response in EOC tumors can differ based on the presence of key tumorigenic mutations. This study evaluated the impact of specific tumor mutations on the response to the current standard-of-care carboplatin, two promising OV candidates VSVΔM51 and MG1, an infected cell vaccine (ICV-MG1) regimen, and the antiangiogenic drug Fc3TSR. Mice with tumors harboring constitutive K-Ras activation showed an enhanced response to carboplatin and VSVΔM51 treatment. Additionally, VSVΔM51 treatment prolonged survival of syngeneic mice bearing tumors with mutations in Pten and Kras, Pten and Trp53, or Trp53 and Brca2 with increased activation of CD4+ and CD8+ T lymphocytes in the peritoneal tumor microenvironment. To enhance OV potency, an MG1-based infected cell vaccine inducing the expression of IL21 or IL15 + IL21 was developed and found to enable strong and long-lasting antitumoral immunity in two carboplatin-refractory syngeneic models, ID8-Trp53−/− and STOSE. VSVΔM51 combined with the antiangiogenic Fc3TSR enhanced efficacy in the ID8 model. In summary, OV-based immunotherapy has shown promise in diverse murine models of EOC-bearing clinically relevant mutations, thus laying the foundation for developing new OV-based strategies to target a large spectrum of EOC genotypes.
LY75 Suppression in Mesenchymal Epithelial Ovarian Cancer Cells Generates a Stable Hybrid EOC Cellular Phenotype, Associated with Enhanced Tumor Initiation, Spreading and Resistance to Treatment in Orthotopic Xenograft Mouse Model
The implications of the epithelial–mesenchymal transition (EMT) mechanisms in the initiation and progression of epithelial ovarian cancer (EOC) remain poorly understood. We have previously shown that suppression of the antigen receptor LY75 directs mesenchymal–epithelial transition (MET) in EOC cell lines with the mesenchymal phenotype, associated with the loss of Wnt/β-catenin signaling activity. In the present study, we used the LY75-mediated modulation of EMT in EOC cells as a model in order to investigate in vivo the specific role of EOC cells, with an epithelial (E), mesenchymal (M) or mixed epithelial plus mesenchymal (E+M) phenotype, in EOC initiation, dissemination and treatment response, following intra-bursal (IB) injections of SKOV3-M (control), SKOV3-E (Ly75KD) and a mixed population of SKOV3-E+M cells, into severe combined immunodeficiency (SCID) mice. We found that the IB-injected SKOV3-E cells displayed considerably higher metastatic potential and resistance to treatment as compared to the SKOV3-M cells, due to the acquisition of a Ly75KD-mediated hybrid phenotype and stemness characteristics. We also confirmed in vivo that the LY75 depletion directs suppression of the Wnt/β-catenin pathway in EOC cells, suggestive of a protective role of this pathway in EOC etiology. Moreover, our data raise concerns regarding the use of LY75-targeted vaccines for dendritic-cell EOC immunotherapy, due to the possible occurrence of undesirable side effects.
