Abstract
If breast cancer is the most common type of cancer worldwide, New Zealand is one of the countries with the highest incidence rate and the highest inequalities within its population. With almost 30% more cases of breast cancer diagnosed and over 20% more death in Māori females in the past year the necessity to find an efficient treatment is even clearer. New types of cancers have emerged in the past few years without any effective treatments.
Oncolytic virotherapy has emerged as a promising new treatment for certain types of cancer. It consists in using a virus to kill cancer cells without harming the healthy ones. Oncolytic viruses have the ability to turn the tumours from “cold” to “hot” by triggering the immune system against the cancer tumour.
Seneca Valley Virus (SVV-001) is a small +RNA picornavirus very promising as an oncolytic virus. SVV has been proven not capable of causing any harm in humans, however, it has the ability to infect and lyse cancer cells specifically. SVV has proven to have a high infectivity, in vitro, in some cancer cell lines, such as lung cancer cells. Its receptor, called TEM8/ANTRX1, is overexpressed in over 60% of solid tumours and barely present at the surface of normal human cells. The presence of TEM8 at the surface of the tumour cells is often associated with poor survival or high chances of relapse. However, most cancer cells, even expressing TEM8, are not getting killed by the virus alone. Every clinical trial involving Seneca Valley virus has failed after phase one, triggering a high cytokine release, the virus gets cleared by the immune system after a couple of weeks.
To overcome these issues, this project aimed to combine SVV with a peptide prodrug to improve cancer therapy. A prodrug is a compound chemically modified to enhance its capacities. In this project, the prodrug is composed of a peptide linked to a highly cytotoxic chemotherapeutic that will inactivate the compound to safely deliver the drug. The peptide sequence is specifically recognized by the 3C protease (3Cpro), highly synthesized by SVV during infection. The SVV 3Cpro cleavage sequence has been identified to be specific to the virus, and not conserved throughout the Picornaviridae family. Once the 3Cpro has cleaved the inactivating peptide, the linker between the drug and the peptide is made to self-immolate, releasing the original chemotherapeutic in the tumour microenvironment.
The drugs used in this thesis are two FDA approved chemotherapeutics: Monomethyl auristatin E (MMAE) and Paclitaxel (PAC).
The principal aim to this thesis was to identify a non-cytotoxic prodrug construct, that when combined to the oncolytic virus SVV, efficiently induce cancer cell death.