Project Title: Targeting pancreatic cancer with
oncolytic virotherapy and cytotoxic drugs; identification of
cellular mechanisms and biomarkers for treatment responses
Research Aims – Current treatments for pancreatic cancer have negligible effects, necessitating development of novel treatment strategies for this incurable cancer. We have developed a different strategy for treatment by modifications of the common cold virus (adenovirus) to selectively kill cancer cells but not normal cells. Recently we found that our modified viruses could kill pancreatic cancer cells very efficiently and further improve on the efficacy of gemcitabine, the current chemotherapy of choice in the clinic for treatment of pancreatic cancer. One of these mutants, named AdΔΔ, was selected for further investigations based on its high selectivity for cancer cells leaving normal cells unharmed.
Our overall objective is to further investigate safety, efficacy and mechanisms of actions of this modified virus alone and in combination with gemcitabine for future translation into early clinical trials. Additional chemotherapeutics with potential to treat pancreatic cancer will also be included in these studies. Through testing in our collection of pancreatic cancer cell lines and normal healthy cells we will determine the degree of cell killing by each treatment. A major focus of the proposal is to identify specific biomarkers to monitor the response to combination treatments. We will determine which small ribonucleic acid (RNA) molecules called microRNAs are differentially expressed in progressing versus regressing (treatment responsive) pancreatic cancers. Our previous studies indicated that microRNAs were increased or decreased specifically in response to treatment and that these microRNAs could regulate essential cell growth and death programmes in the cancer cells. Identification of specific microRNAs as biomarkers both for disease detection and treatment responses would greatly improve on both diagnosis and choice of therapy for pancreatic cancer patients.