Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses

Abstract

Tremendous advances have been made in developing oncolytic viruses (OVs) in the last few years. By taking advantage of current knowledge in cancer biology and virology, specific OVs have been genetically engineered to target specific molecules or signal transduction pathways in cancer cells in order to achieve efficient and selective replication. The viral infection and amplification eventually induce cancer cells into cell death pathways and elicit host antitumor immune responses to further help eliminate cancer cells. Specifically targeted molecules or signaling pathways (such as RB/E2F/p16, p53, IFN, PKR, EGFR, Ras, Wnt, anti-apoptosis or hypoxia) in cancer cells or tumor microenvironment have been studied and dissected with a variety of OVs such as adenovirus, herpes simplex virus, poxvirus, vesicular stomatitis virus, measles virus, Newcastle disease virus, influenza virus and reovirus, setting the molecular basis for further improvements in the near future. Another exciting new area of research has been the harnessing of naturally tumor-homing cells as carrier cells (or cellular vehicles) to deliver OVs to tumors. The trafficking of these tumor-homing cells (stem cells, immune cells and cancer cells), which support proliferation of the viruses, is mediated by specific chemokines and cell adhesion molecules and we are just beginning to understand the roles of these molecules. Finally, we will highlight some avenues deserving further study in order to achieve the ultimate goals of utilizing various OVs for effective cancer treatment.

Fig. 1

Cellular apoptosis pathways and intervention by both cellular anti-apoptotic proteins and viral proteins encoded by oncolytic Ad, HSV and VV. A simplified description of intrinsic, extrinsic apoptosis pathways as well as key players (e.g. interferon pathway and p53) and their interactions are included. Also illustrated are mechanisms that viruses employed to block apoptosis, and some cellular anti-apoptotic proteins which are often over-expressed in cancer cells. Two recent dissected anti-apoptotic proteins encoded by VV, F1L [139] and N1L [140], are illustrated. This figure is modified from a figure by Liu and Kirn, 2005 [138].

Fig. 2

Imaging of tumor-selective amplification of an oncolytic VV in tumor-bearing mice after systemic delivery. Subcutaneous tumor (in the back)-bearing nude mice were treated with intravenous injections of wild type WR strain VV (panels 1 and 3), or a tumor-selective oncolytic VV (vvDD; panels 2 and 4) both expressing luciferase. Bioluminescence images are taken 96 hours after treatment. Both ventral (panel 1, 2) and dorsal (panel 3, 4) views are presented. The wild type virus has infected multiple organs and tissues, while vvDD has been removed from most tissues other than the tumor, where it continues to express luciferase. Data are from Thorne et al., 2007 [80].

Fig. 3

The IFN, EGFR/Ras signaling pathways and their interactions with virus-encoded proteins. The kinase PKR is an important downstream effector molecule of the IFN signaling pathway. When a cell is infected by a virus, it is stimulated to produce IFNs that will activate an antiviral defense response of nearby cells. Upon binding of IFNs to cell surface receptors (IFN-R) on neighboring cells, an intercellular signal transduction cascade is engaged, which induces PKR expression. The dsRNA produced by viruses will bind to PKR, and lead to autophosphorylation of the PKR homodimer and activation of its kinase activity. The activated PKR phosphorylates eIF-2α, which in turn inhibits protein synthesis and thereby viral replication in the cells. Ad, HSV and VV encode a number of viral proteins to inhibit the antiviral response. For examples, virus-associated (VA) RNAs produced by Ad; E3L and K3L proteins by VV and NS1 protein by IFA, all can inactivate PKR. Cancer cells have accrued many mutations in these signaling pathways. Inactivating mutations of the IFN signaling pathway can be found in many cancer cells. Oncolytic VSV targets this characteristic for its natural oncotropism. A constitutively activated Ras signaling pathway, another common feature for tumor cells, leads to inhibition of PKR autophosphorylation. Oncolytic NDV and reovirus depend on this characteristic for their tumor cell selectivity. This figure is modified from Everts and van der Poel, 2005 [8].