Joel Nowak
Hello, I’d like to welcome you to another Malecare telephone conference. My name is Joel Nowak, and I am Malecare’s director of advocacy and advanced prostate cancer programs. I am given the honor of moderating our teleconference programs.
Today’s teleconference is going to be a little different than some of our prior ones. Today, we have the great fortune to have a personal friend of mine in a real live and absolutely brilliant prostate cancer researcher to talk with us about an investigation drug that she has invented, or I should say developed, to treat prostate cancer. My guest, Dr. Mary Sadar is the distinguished scientist at the British Columbia Cancer Agency having received her Ph.D. from the University of Bradford in the United Kingdom in biochemistry. She also has done post doctoral work at AstraZeneca in molecular biology and at the British Columbia Cancer Agency, the department of endocrinology with her post doctoral works specifically in prostate cancer.
She has served on over 50 grant panels including five years at the NIH study session for drug discovery and molecular pharmacology and has been and is still the chief scientific officer of a biotechnology company which she has founded called ESSA. Dr. Sadar discovered a novel drug target for prostate cancer. She screened drugs against this target and brought a clinical candidate of this drug into clinical trials that are currently ongoing in both the United States and in Canada. This is the first drug in clinical trials targeting an intrinsically disordered protein region in a first in class drug of the end terminus of the androgen receptor. We’re going to come back to what that all means in a few seconds. Her work is a first in type to the entire field of steroid hormone receptors with no other small molecule inhibitor reported to bind to the end terminus. During this teleconference, Dr. Sadar will hopefully help us understand what it is she has done.
Dr. Sadar is also the 2017 chair of the United States Department of Defense programmatic review panel for prostate cancer. She is the first Canadian to serve as chair of this conference. That’s a heck of an introduction because you are a heck of a researcher and heck of a person. I’d like to welcome you, Dr. Sadar. It’s really good to talk with you.
Dr. Sadar:
Thank you very much.
Joel Nowak:
Dr. Sadar, I was wondering if you could tell us a little about your research, specifically maybe translate what it is that I said so that we can understand it.
Dr. Sadar:
My research is focused on advanced prostate cancer. It’s focused on the protein in the human body that causes most prostate cancer to grow and rapidly proliferate, to increase in number. The treatment for advanced prostate cancer is unfortunately castration which is to reduce the male sex hormone and that male sex hormone works on this protein called the androgen receptor that I have been studying for 20 years.
What I’ve been doing is trying to figure out how this androgen receptor continues to fuel advanced prostate cancer even though these men are castrated. That’s really what I’ve been doing for the past 21 years and trying to find therapeutics, trying to find drugs that will benefit these men for a longer life, hopefully, improve their quality of life.
Joel Nowak:
Are there are other drugs that target this particular protein, the androgen receptor?
Dr. Sadar:
Yes. When men with advanced prostate cancer are treated for advanced disease, they receive LHRH analogs which reduce their testosterone levels, and that really targets androgen receptor because it reduces testosterone levels, male sex hormones that binds to the androgen receptor. There is also abiraterone which is used which reduces the amount of androgens, steroids, in men that are receiving it, and that has beneficial effect, and it works again on reducing testosterone or these steroids that bind androgen receptor.
There’s also anti-androgens. There’re a number of anti-androgens. Probably the most well known one now is enzalutamide, but there’s also the whole family which is the bicalutamides, flutamide, nilutamide. There’re a lot of these anti-androgens. They work on the opposite end of where my drug works. They work in the same spot that testosterone and other steroids will bind to androgen receptor. It’s like a competition. They’ll fill the spot that testosterone normally would fit on androgen receptor to prevent the testosterone from working on the androgen receptor.
It is a well known target. What’s unique about my research is that’s not the important part of the androgen receptor because in advanced disease that part of the androgen receptor where testosterone interacts with the androgen receptor it might not be made anymore and it might be a truncated androgen receptor. That would mean all of these therapies, all the anti-androgens, abiraterone, castration, wouldn’t have any effect on these truncated androgen receptors. Where my research fits in this is we are targeting the part of the androgen receptor that isn’t lost in the disease, and that’s called the end terminal domain. It’s present on all forms of androgen receptor that cause the disease to keep proliferating and growing.
Joel Nowak:
The time that this drug would probably be used would be at the time that a man becomes castrate, and these other drugs stop working.
Dr. Sadar:
That’s where we’re starting. We’re starting our clinical trial that’s ongoing right now. It’s a dose escalation study. It’s a phase I that we’re doing right now. It is in men that have become resistant to abiraterone or to enzalutamide or some men received both of these therapies, so both treatments. That’s where we’re looking now. We’re looking at quite late in the disease, so after men have received a lot of treatments and those treatments no longer work, that’s where our drug has been slotted in to see if we can help those men.
In the event that our drug works, well hurrah, but then we’ll try to move the drug earlier. We’ll try to move it into earlier disease because theoretically if it is having the effect that we see in the laboratory it should help men with earlier disease as well.
Joel Nowak:
How do you see this effect in the lab?
Dr. Sadar:
We have a lot of different models. You can never truly mimic human disease like treating a patient, so we have cell lines. We have many different cell lines. These cell lines were made from men that had metastatic disease, and that metastatic disease was removed and their cells were then grown in a culture dish, and then we try our drugs on these cells that are growing in culture dishes. We have a lot of molecularly engineered cells that have readout systems on them, so if we know if our drug is working.
For example, we engineered our human prostate cancer cells. These were cells that were originally from a man with a prostate cancer metastases to his lymph node and his clavicle region. We engineered those cells so that when the androgen receptor, which is the target, when the androgen receptor was pushing proliferation and causing cells to grow and dive, that the cells would emit light. How we screened for drugs was let’s see which drugs can turn off the light.
There is specific equipment for that. There’s assays for that, but that was really one of our assays. We screened I think about 36,000 drugs. That’s actually relatively low, but we got lucky. Always with a bit of luck helps. The drug that we found was this EPI-506 is the drug that’s in the clinic. It turned off the light of these cells that we engineered. Then there was a whole battery of tests. Then we test how specific the drug is. Does it kill other cells which wouldn’t be good because we only want to kill prostate cancer cells. We don’t want to kill bladder cells or epithelial cells in the intestine and all those things. You start to check how specific the drug for prostate cancer.
Then, of course, we do our animal studies which most closely mimics human disease, and that’s where you take these human prostate cancer cells and you grow tumors in animals, unfortunately, you have to do this because that’s the closest to human. These tumors will grow in these castrated animals just like what happens in human disease, and then we give the animals our drugs, our EPI-506, and we would see this wonderful effect on the tumor stop growing, reduced tumor growth. It’s sort of the full line from in the bench to animal testing, and then of course, in order to get into the clinic we had to do the FDA protocols for safety and toxicity.
Joel Nowak:
What’s involved in that?
Dr. Sadar:
Oh boy. It’s very expensive. I couldn’t do that in my lab. Now the biggest hurdle first was money because I can do the molecular biology as an academic, so I received grants, a lot of grants, lots from the US Army, from NIH, to the biochemistry molecular biology. Now in order to get the dollars to create a drug that goes in the clinic and to pay for all of the tests that the FDA required, all the safety, toxicity, chemistry. It’s all chemistry. You have to have a chemical compound that’s safe going into humans. We had to spin out a company just to get private money, so from angel investors, from venture capitalists, from investment banks, et cetera. That was the point of where we had to now look at other places for money to look at commercialization of this technology. That was the first step.
It cost a lot of money to do all these tests. Then once we had the company in place, many very qualified people in areas that I have no expertise were hired. They started to do the chemistry. They started to look at the toxicology of the compound. How long does the drug last in animals? Does it stay in the blood long enough to potentially effect the tumor, or does it just go through the body immediately and never really get absorbed? All of these factors have to be considered before creating a drug.
It’s extremely expensive. Like I said, you can’t do this with academic dollars. It’s very difficult. The company was formed. People were hired to interact with the regulatory people at the FDA. A chief medical officer was hired, Frank Perabo, who is the superstar in the field. He did many of enzalutamide clinical trials. It now became a little bit of a monster that in order to get in the clinic you have to now have so many different areas of expertise well beyond my lab, my little teeny lab. It bloomed.
Joel Nowak:
You’ve created or certainly were the impetus to start this thing. It’s kind of your baby. What’s it like to, I guess, to somewhere lose some control of your baby? I’m making an assumption. I don’t know if that’s correct, but do you feel that way?
Dr. Sadar:
Absolutely, I feel that way. It’s having to build trust. This is my baby. I’ve worked for 20 years on this. To then pass it over into hands that aren’t my hands I have to have trust that those are good hands that it’s going into, that they’re going to do everything they can to make sure it was the best shot possible of succeeding in the clinical trials. I’ve done everything that I could here in my lab. Over 20 years, I’ve had at least 10-13 people working on it every single day for those 20 years. It’s a lot of time and effort.
There is the trust. There is the learning to let go a little bit. I can’t run the clinical trials. I can’t do the chemistry, so I have to believe that it’s in good hands, and it is. The people that ESSA have hired are absolutely outstanding. They’re superstars. I’ve only mentioned one, but there’s a whole number of superstars that were hired into this company. I can breathe easy. I can realize it’s in good hands.
Joel Nowak:
Great. Actually, I want to go back a little bit to something you’ve said when you described the trial which is, as you said, a phase I trial. If you would for those people who may not know what phase I trial is, if you give a brief description of that. You also mentioned the words dose escalation. If you could describe what that means I would appreciate it.
Dr. Sadar:
Yes. When you go on to patients, this is the first in human clinical trial meaning this drug that we’ve made has never ever been put into humans before. What you have to do is you have to make this enormous leap. Everything we’ve done has been in animals. Animals have much faster metabolism. They handle drugs differently than humans. How do you decide what dose should be the first dose in humans that will be safe?
That’s really what a phase I is. It’s figuring out what dose is safe in humans, what is the highest dose you can put into humans that are still safe meaning you’re not getting a lot of really horrible toxic effects that would compromise the patient’s health or compromise the patient from continuing on the drug. That’s what a phase I is. The FDA actually tells the company which dose they can start with, and that’s based on their animal studies, their toxicity studies that they had to give the FDA so the FDA can decide what dose is the first dose that you give patients.
In our clinical trial, they’re all prostate cancer patients. None of them are healthy. There’s not a placebo arm. There’s nothing like that. All of them are patients. All of them receive the drug. You start with three patients per cohort. The first three patients have been dosed at the lowest dose, and for us that was 80 mg in a patient. Once they go through 30 days, I believe it was 30 days, and there’s no adverse, there is adverse event, then another group of patients can then start on a dose that’s higher. You keep doing this. You keep testing three patients moving up the amount of drugs that they’re receiving until you start to see some toxicity.
It’s cancer, so you want to get as much drug as you possibly can into patients because you want every chance possible of affecting the tumor. You really want to have what’s called a maximum dose, maximum tolerated dose. That’s what a phase I is. It’s finding the dose.
It’s not really about seeing whether the drug works or not. The dose that we’re starting at it with right now that we’ve finished the first three patients was a very low dose. It’s not predicted to be efficacious because it’s so low, but you may get some clinical data because we are monitoring blood levels, we’re monitoring PSA. We’re doing all these things. Once we get to an efficacious dose, which keep your fingers crossed that we do, and that we can put a lot of this drug into patients we should get some sort of read out about whether we’re having any effect on PSA levels. Plus patients they will tell you if they’re feeling well or not. You get a lot of feedback from patients.
Once you ….
Joel
Nowak:
Do you have the opportunity … I’m sorry, go ahead.
Dr. Sadar:
I was going to say, so once you find that dose then you start the phase II studies. The phase II is really to give an indication of whether the drug has any effect on the tumor, and you increase the numbers of the patients.
Joel Nowak:
How do you evaluate in the phase II whether or not it’s had an effect on the tumor?
Dr. Sadar:
In our trial, of course, there’s always PSA. That’s one of the major readouts. It’s usually a 50% drop in PSA. PSA, of course, is measured in the blood of patients, prostate specific antigen is what that stands for. We also look, I believe, we’re looking at tumor volume. I think we are doing some analysis of how much tumor burden these patients have. I’m not sure what else actually, probably the quality of life as well and maybe morphine use. I’m blurry here on our on all the aspects of the clinical trials because I’m not the clinician. Our chief medical officer, Frank Perabo, designed all those clinical trials.
Joel Nowak:
Right. Are you still working on this drug in the lab, or is that something that is not happening anymore?
Dr. Sadar:
We are working on this drug in the lab. What my academic research is looking at is we know that prostate cancer forms resistance to drugs. That’s been the problem. You treat men with these therapies and eventually they develop resistance, so you switch to another drug and eventually develop resistance. Of course, we’re thinking what if our drug develops resistance? What resistance would that be? What mechanism would that involve?
To try to address that what my lab did is we incubated these human prostate cancer cells with our drugs for very long period of time. It was about a year and a half. Eventually  we saw resistance, so eventually the prostate cancer cells started to grow in the presence of our drug. That’s resistance. The good thing is that it took a year and a half. If you put this into perspective, in tissue culture enzalutamide causes resistance with long-term culture in three months. Ours causes resistance in a year and a half, so six times longer. If that panned outs clinically that would be wonderful.
We still need to understand how the cancer cells are forming resistance to our drugs. We’re now analyzing these cells, and we have picked up one potential pathway that is manageable. I’m not going to describe more here because the work’s just not completed enough. I would like to make sure I’m standing on really firm ground, but in everything that we’ve looked at we have a resistance mechanism that we seem to be able to halt. That’s the whole theory behind us. If you can understand the resistance you could potentially do combination therapies in order to prolong the efficacy of the drug or maybe even potentially cure the patient if you do a cocktail.
Joel Nowak:
That’s an amazing word to use when we talk about prostate cancer, metastatic prostate cancer. It’s a word I don’t like to use, but it’s really optimistic and potentially so exciting sounding. It really is.
Dr. Sadar:
That’s my goal.
Joel Nowak:
Appreciate that. I’m sorry.
Dr. Sadar:
That’s always been the goal of my lab. We would really like to just get rid of the prostate cancer, just get rid of it out of these men.
Joel Nowak:
Which, of course …
Dr. Sadar:
We don’t want to lose sight of that.
Joel Nowak:
Which brings me to the question, how did you get into prostate cancer? Why prostate cancer? Why not breast  cancer, kidney cancer or arthritis?
Dr. Sadar:
I was very interested in cancer. My sister died of cancer when I was a child, so I was very aware of cancer. I knew that I just wanted to work in cancer. To me, there weren’t different types of cancer. Just cancer. That’s all you heard. You don’t hear it’s leukemia. You don’t hear it’s whatever.
As a child, I wanted to be a cancer researcher. When I went off to do my Ph.D. I did it on the dioxin transcription factor, dioxin receptor in fish, and had a wonderful Ph.D. experience. When I came back to Canada, I never thought I was smart enough to do human medical research, but I wanted to stay in Vancouver because that’s where I was living. My friends and family pushed me into applying for a position with Dr. Nicholas Petrovsky who Dr. Nicholas Petrovsky he was and M.D., Ph.D. He was the discoverer of dihydrotestosterone which is really what fuels prostate cancer and intermittent androgen suppression. He was the pioneer.
He was a real superstar in the prostate cancer field. I applied with him, and I was lucky enough that he hired me. What I did my Ph.D. on was the dioxin receptor which is the transcription factor, and actually there were things that I did with that transcription factor which was very similar to what I went on to do with the androgen receptor. Androgen receptor is also a transcription factor. What a transcription factor is is it’s something that binds to DNA to turn on lots of genes to turn on the production of making lots of  different things in the nucleus cells.
It wasn’t a big jump, but for me, I still remember when Dr. Petrovsky offered me the job and first day on the job. It was the best feeling ever. It was a gorgeous day in Vancouver. I walked down the road by the BC Cancer Agency happier than ever that I was in medical research, and I had a chance to make a difference.
Joel