Research: 2018 – Avalon (Doré)

Project Title:
Engrailed 2 as biomarker and driver of prostate cancer metastasis.
Investigators:
Jules JE Doré, Ph.D., Memorial University of Newfoundland, Faculty of Medicine
 
I am Dr. Jules Dore, born in Calgary, Alberta but grew up in a small farming community south of Vancouver, British Columbia. I gradated from the University of British Columbia, with first class honours B.Sc. in Zoology and continued my education earning a MS degree from the University of Florida and a PhD from the University of Tennessee. Between my two graduate degrees I worked for a venture capital biotech startup company in Vancouver, QuadraLogic Technologies. It is this experience that has given me a unique understanding of both academia and commercialization of biotechnology. After my PhD, I did a Post-Doctoral fellowship at the Mayo Clinic in Rochester, Minnesota, in the Thoracic Disease Research Unit. It was from there that I started my faculty appointment at Memorial University in 2002, in the Faculty of Medicine. In 2012 I took up my present appointment as the Assistant Dean of Graduate Studies in the Faculty of Medicine. My research program has focused on the fundamental nature of how cells growth is controlled, using Transforming Growth Factor-beta as a model since it is able to both stimulate or inhibit growth of cells, dependent on what type of cells it is given too. I have approximately 20 peer-reviewed manuscripts in this area of basic research, with 34 in total. Most cancers originate from epithelial cells, the cell type that is normally inhibited by Transforming growth factor-beta. Most epithelial cancers have lost this necessary “brake system” resulting in their uncontrolled, rapid growth. A number of years ago I joined with Dr. Kao, a member of the Terry Fox Cancer Research Labs and Dr. John Thoms, a Prostate Oncologist with Eastern Health, to help build a team of highly motivated investigators and pool our expertise in order to make significant progress in the fight to cure prostate cancer.

Project Abstract:
In prostate cancer, the major problem is that tumour cells migrate out from the initial site and invade other organs. For prostate cancer, it is primarily brain and bone that are invaded. Patients don’t die from the initial tumour, it is the extra tumours that grow in these distant organs that results in death. Our lab is focused on understanding how and why prostate cancer moves out from the prostate. A few years ago we identified a gene in metastatic prostate cancer that should not be found in the prostate, called Engrailed 2. The normal function of this gene is to direct neurons to connect extensions between one another during brain development. Through research supported by RFD we have identified that Engrailed 2 directs prostate cells to migrate. We have also found that other types of cells can make a natural blocker to Engrailed 2. This proposal is aimed at understanding more about how Engrailed 2 directs prostate cancer to migrate out of the prostate and to identify what this blocker is. Knowing how Engrailed 2 is directing metastasis and the identity of this natural blocker will give us clues into how we can intervene, use this blocker to interrupt the metastatic process, and keep prostate cancer in the prostate. One tumour site will allow surgeons to remove all of the cancer.
Scientific Abstract:
Prostate cancer is the most common cancer in men and accounts for 10% of all cancers humans get. Clinically, research has yet to identify any marker that differentiates the indolent from the aggressive disease, that needs immediate action. The use of changing PSA levels has been useful to identify some instances of the conversion, but it has a 1:5 false positive rate. Based on work previously funded by RFD we have identified Engrailed 2 expression in metastatic prostate cancer cell lines, and recently in tumour tissue, that we believe represents a marker of indolent vs. aggressive initial disease and the conversion from benign to cancer. Preliminary results have shown that Engrailed 2 directs cellular migration and invasion that can be exacerbated by addition of transforming growth factor beta. The present project aims to identify the genes that Engrailed 2 regulates through the use of ChIP-seq methodologies, and determine the nature of the subset of prostate tumour cells that express Engrailed 2 by colocalization of Engrailed2 with a number of marker proteins. In addition, we will define the Engrailed 2 inhibitory RNA molecule we have identified, in order to develop it as a potential therapeutic agent. We believe that Engrailed 2 represents a marker of those cells that will metastasize from the primary tumour and a novel target that will allow us to inhibit metastatic prostate cancer from leaving the primary tumour site.
Impact on prostate cancer patients:
As a marker, Engrailed 2 could alter the way that prostate cancer patients are classified initially for either surveillance or immediate treatment.