The most memorable day in my career was the day I was recruited to the BC Cancer Agency as a post-doctoral fellow to work on advanced prostate cancer. It was June 1995. My supervisor, Dr. Nicolas Bruchovsky, was a clinician scientist treating prostate cancer patients. Two years of intense training with him and his staff provided me exposure to patients, basic scientists, pathologists, urologists, and medical and radiation oncologists. This learning environment plus my background in biochemistry/molecular biology were the catalyst for an idea I had about why the current treatments for advanced prostate cancer failed. It was the start of a 20 year journey of research to pursue that idea. It never occurred to me at the time that this path would lead to me starting a biotechnology company and taking my discoveries into clinical trials.
In 1998, the BC Cancer Agency recruited me as a Senior Scientist and shortly afterwards I was appointed Honorary Assistant Professor at UBC. Fortunately I was included in a large Program Grant from NIH with the University of Washington led by Dr. Paul Lange. These regular meetings were exciting with much debate and exposure to translational research and clinical trials on prostate cancer. Being a part of this large program grant had an enormous impact on me.
In 1998, the world believed that advanced prostate cancer was independent of androgen and independent of the androgen receptor, a transcription factor that mediates the effects of androgen. I did not share that view. To me, the data did not support this conclusion.
In 1998, the world believed that advanced prostate cancer was independent of androgen and independent of the androgen receptor, a transcription factor that mediates the effects of androgen. I did not share that view. To me, the data did not support this conclusion. So while most academic institutions and drug companies were focused on developing chemotherapies and looking at survival genes based on the theory that the androgen receptor was irrelevant, I was proposing that the androgen receptor still played a role in driving this then-called “androgen-independent” prostate cancer.
Needless to say as a young scientist with an idea that went against established views the response I received to some grant applications was to re-consider my research focus. Fortunately the US Army Department of Defense’s Prostate Cancer Research Program was looking for high risk, high gain projects and funded my work. In fact, most of my funding over the years has come from the USA, either from the US Army or from the National Cancer Institutes (USA).
Because US funding institutions do not provide dollars for equipment to foreign institutions, added to the fact that I had no start-up funds when I was recruited, I needed to find other avenues to purchase essential equipment. A group of dedicated and passionate men at Country Meadows Senior Mens’ Golf Club jumped in to help and are still continuing to help. Over the past 17 years they have supported my research by providing more than $1 million in charitable dollars. Most of these dollars were to purchase state-of-the art equipment.
The research I pursued over these 20 years involved many steps but all in the same direction leading to clinical trials. The first step was to prove if the androgen receptor could be activated in the absence of androgen by other signalling pathways and then map the region on the androgen receptor responsible for such activation. I discovered that other pathways independent of androgen could activate the N-terminal domain of the androgen receptor. This was an important discovery because all drug development focus had historically been to the C-terminus, ligand-binding domain.
The fact that I had shown that the N-terminus domain of the androgen receptor could drive the cancer independent of androgen was a possible explanation of what could be occurring in men with advanced prostate cancer.
Next I showed that interfering with the N-terminus domain of the androgen receptor would mediate a therapeutic response in vivo. This provided evidence that the N-terminal domain of androgen receptor could become a viable novel drug target. The hurdle associated with this discovery was that this domain is intrinsically disordered and not a folded protein structure. The N-terminal domain of androgen receptor is a hub for interactions with many different proteins that are essential for its transcriptional activity. In the early 2000s, the drug development field was not optimistic about the feasibility of small molecule inhibitors of protein-protein interactions especially when it involved binding to a disordered/unfolded protein region. In spite of this challenge, once again the US Army supported my research.
In 2003, I partnered with Dr. Raymond Andersen, a chemist at UBC, to screen his libraries of natural compounds. With the help of Country Meadows Senior Mens’ Golf Club, I was able to purchase state-of-the-art robotics. This equipment allowed us to quickly move through the enormous numbers of drugs we needed to screen in order to find that one needle in the haystack that would work.
Fortunately with some luck we found EPI-001 and our publication on this discovery caused an avalanche of excitement around the world. Patients, drug companies, and venture capitalists were contacting me about the drug.
Fortunately with some luck we found EPI-001 and our publication on this discovery caused an avalanche of excitement around the world. Patients, drug companies, and venture capitalists were contacting me about the drug. It was clear that we needed to quickly move the drug into clinical trials, but now we were faced with how to raise the required tens of millions of dollars.
The best avenue within our grasp was to spin-out a biotechnology company. In January 2009, we founded ESSA Pharma Inc which is now a public company trading on the NASDAQ and TSX. Today, the prodrug of a single stereoisomer of EPI-001, called EPI-506 is in clinical trials in Canada and the USA (ClinicalTrials.gov Identifier: NCT02606123) for prostate cancer patients with advanced disease.
This clinical trial marks a number of firsts: it is the first clinical trial of a drug that binds an intrinsically disordered region of any protein; EPI-506 is the first antagonist of the N-terminal domain of the androgen receptor to be tested in humans; EPI-506 is a “first-in-class” drug which means it is a completely novel drug scaffold; and the clinical trial is a “first-in-human” trial.
There were a number of factors I would summarize as pivotal in allowing my work to proceed from identifying a novel molecular target, discovering a drug that works on that target, and taking the drug into clinical trials:
- A research environment involving an engaged mentor at the start of my career and exposure to clinical and basic science research.
- Exceptional staff and trainees, of whom there are too many to name but I especially am grateful to Rina Mawji who has diligently worked with me right from the start.
- Community support especially the Country Meadows Senior Mens’ Golf Club who were always there to help and believed in the research.
- The USA Department of Defense’s Prostate Cancer Research Program and their mandate to fund high risk, high gain research.
- Collaborators, such as Dr. Raymond Andersen who was essential in taking the work to the next level.
- Dedicated and respected clinicians like Dr. Kim Chi who supported the clinical development of the drug.