DEVELOPMENT OF NECTIN-4-TARGETING ONCOLYTIC MEASLES VIROTHERAPY FOR THE TREATMENT OF BREAST AND LIVER CANCERS

Abstract

Oncolytic viruses (OVs) are a rapidly emerging treatment platform for various types of cancer that offers several advantages over conventional anticancer therapeutics, including selectivity, potency, and targeted cell death. Recent studies have revealed that measles virus (MV), a member of the Paramyxoviridae family, possesses the ability to selectively target carcinomas by recognizing the tumor cell marker nectin-4, which is highly expressed in many types of cancer. Specifically, wild-type MV targets nectin-4 on the tumor cells and does not engage CD46, which is an additional receptor expressed on all nucleated cells and employed by vaccine strains of MV for infection. The use of MV-based vectors with wild-type glycoproteins is thus justified as candidate for potential development as an oncolytic agent targeting nectin-4. The results in this thesis present as proof-of-concept, the use of a recombinant wild-type MV as an oncolytic agent to effectively target nectin-4-marked cancers, and demonstrate its ability to induce oncolysis of nectin-4-expressing breast and hepatocellular carcinoma (HCC) tumor cells. Specifically, it was observed that MV could dose-dependently and efficiently target and induce cytotoxicity in both cancer models. In addition, the data also demonstrate the feasibility to use a combination of chemotherapeutic agents or anticancer nanoparticles as a chemovirotherapeutic approach to enhance MV’s oncolytic efficacy, while reducing the doses of treatment required and potentially increasing its safety. Results from this study underpin the oncolytic potential of recombinant MV and support the future development of oncolytic virotherapy using MV-based vectors for the management of nectin-4-expressing cancers.