VSV based virotherapy in ovarian cancer: the past, the present and …future?

Abstract

The standard approach to treating patients with advanced epithelial ovarian cancer (EOC) after primary debulking surgery remains taxane and platinum-based chemotherapy. Despite treatment with this strategy, the vast majority of patients relapse and develop drug-resistant metastatic disease that may be driven by cancer stem cells (CSCs) or cancer initiating cells (CICs). Oncolytic viruses circumvent typical drug-resistance mechanisms, therefore they may provide a safe and effective alternative treatment for chemotherapy-resistant CSCs/CICs. Among oncolytic viruses vesicular stomatitis virus (VSV) has demonstrated oncolysis and preferential replication in cancer cells. In this review, we summarize the recent findings regarding existing knowledge on biology of the ovarian cancer and the role of ovarian CSCs (OCSCs) in tumor dissemination and chemoresistance. In addition we also present an overview of recent advances in ovarian cancer therapies with oncolytic viruses (OV). We focus particularly on key genetic or immune response pathways involved in tumorigenesis in ovarian cancer which facilitate oncolytic activity of vesicular stomatitis virus (VSV). We highlight the prospects of targeting OCSCs with VSV. The importance of testing an emerging ovarian cancer animal models and ovarian cancer cell culture conditions influencing oncolytic efficacy of VSV is also addressed.

Keywords: epithelial ovarian cancer (EOC); high grade serous ovarian cancer (HGSOC); ovarian cancer stem cells (OCSCs); rhabdovirus; vesicular stomatitis virus (VSV); virotherapy.

Figure 1

A schematic overview of the molecular network involved in VSV oncoselectivity. Binding of growth factors to the receptor tyrosine kinase (RTK) activates the receptor complex, which in turn recruits and activates PI3K. Activated PI3K converts PIP2 to PIP3, which subsequently mediates the phosphorylation of AKT. Tumor suppressor PTEN negatively regulates the pathway by removing the 3-phosphate from PIP3, converting it back to PIP2. PTEN is crucial for the activation of IRF3, its import into the nucleus and production of IFN-β. Loss of PTEN leads to over-activation of AKT and subsequently mTOR, which is associated with uncontrolled cell growth, proliferation, and survival. PTEN loss leads also to the development of cancer stem cells (CSCs) and an impaired cellular responses to viral infection. Up-regulation of LDLR in ovarian carcinomas enables VSV to enter cells with altered PTEN function through LDLR. Abbreviations: PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate); PIP3, phosphatidylinositol (3,4,5)-trisphosphate); AKT, serine/threonine kinase; IRF3, interferon regulatory factor-3; mTOR, mammalian target of rapamycin; LDLR, low-density lipoprotein receptor. See text for further details.