Grant: Project Grant - PA: Breast Cancer Research

Cancer killing viruses carry a "payload" as a form of a "transgene". This payload is critical for their anti-cancer efficacy. The transgene is often a carbon copy of a human gene, but we know that the human genetics is very different to that of a virus. This is like putting a Ford F150 engine into a Ferrari, it can work but it will not be ideal for the chassis. Our goal is to achieve maximal "payload" expression from "transgenes" encoded by oncolytic viruses - viruses geared towards cancer immunotherapies. We want the most bang for our bucks with these critical therapeutic payloads, so every part needs to be perfectly aligned with the machine. Every virus is unique and we will characterize the distinct blueprints that will provide the greatest powertrain for the transgene and virus, here Herpes Simplex Virus and Vaccinia Virus. Transgenes encoded within viral genomes are mostly taken from the exact coding sequence of human genes. However, many regulatory elements exist within 5'leaders and it is well-known that the codon sequence is critical for high expression. Furthermore, genome location can have many implications. Viruses are unique in their 5'leader, codon usage, and genome organization. The project describes our approach to obtain maximal payload expression by "viro-optimizing - Viralyzing' every parts of the transgenes. Oncolytic viruses are little but extremely powerful machines that can have massive impact for cancer immunotherapies. More than 150 viruses are currently under investigation in labs and companies around the world. For best responses, these viruses are all upgraded with a payload, but this addition has surprisingly not been optimally encoded for their unique racing machine. This project aims to turbocharge transgene expression and apply our findings to clinically relevant cancer virotherapies. Patients want the best machine available and our optimal transgene program will put their oncolytic virus of choice in the pole position.