Overcoming Hormone Therapy Resistance in Prostate Cancer with Sarki Abdulkadir, MD, PhD

“The whole basis of research should be about testing new ideas and testing preconceived notions, because that's really what allowed us to start this project: if we had listened to everybody else, we would never have started.” — Sarki Abdulkadir, MD, PhD 

• John T. Grayhack, MD, Professor of Urological Research
• Vice Chair for Research in the Department of Urology 
• Co-principal investigator, Robert H. Lurie Comprehensive Cancer Center of Northwestern University’s Prostate Cancer SPORE 
  
• Associate Director of Translational Research, Lurie Cancer Center

Abdulkadir details how his research, recently published in Nature Communications, is a significant step toward understanding and treating treatment-resistant prostate cancer. 

• Prostate cancer is very common. In fact, some estimates predict that any man who lives long enough — perhaps into his 70s or 80s — will develop prostate cancer, even if only dormant.  
• Abdulkadir looks at molecular pathways that drive prostate cancer. At the center of his research is the MYC oncogene, a gene that is particularly active in aggressive and drug-resistant cancers, including prostate cancer. 
• After investigating over 30 million compounds, Abdulkadir, alongside collaborators at Rutgers University, identified a handful of compounds that block MYC gene activity, thus making tumors sensitive to hormone therapy.  
• After initial compounds were discovered to be toxic, Dr. Abdulkadir identified what is called compound 975, which is not only well-tolerated but can be administered orally.  
• Abdulkadir emphasizes the necessity of keeping an open mind in biomedical research: even though the MYC gene has historically been considered “undruggable,” he and his team pushed beyond widely held assumptions about the treatability of this gene. 
• Abdulkadir and his team are presently conducting studies they will present to the FDA to gain permission to administer this drug to humans. Expected to take a year or so, Abdulkadir and his team will then begin phase one trials.
• For over 20 years, the Robert H. Lurie Comprehensive Cancer Center of Northwestern University's Prostate Cancer SPORE Program, funded by the National Institute of Health's National Cancer Institute, has fostered collaboration between clinicians and basic scientists. This unique program has allowed for the genesis of innovative research like that of Abdulkadir, who is co-principal investigator of the grant.  
• Abdulkadir says working with students is essential to his research and to the field of biomedical research at large. While some may view young trainees as naive, Abdulkadir views their freshness as necessary in the discovery process.   

Recorded on June 11, 2024.  

Additional Reading

• Breakthroughs Newsletter Feature: Leading Prostate Cancer Research for More Than 20 Years
• News Center Story on the Nature Communications finding
• Cancer Research study about treatment resistance 

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Sarki Abdulkadir, MD, PhD is co-owner of Vortex Therapeutics. Content reviewer, Yang Yi, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Prostate cancer continues to be the most common and one of the most deadly cancers in men in the U. S. Hormone therapy, which suppresses the production of testosterone, is an important tool that can be used to help treat patients with prostate cancer. But unfortunately, some patients will develop resistance to the hormone blocking drugs, which can lead to cancer relapse. Northwestern Medicine's Dr. Sarki Abdulkadir has been working on research to better understand treatment resistance in prostate cancer. In a recent paper published in Nature Communications, Dr. Abdulkadir and his team found that increased expression of specific genes in patients with prostate cancer may predict whether or not the cancer will respond well to hormone therapy. He joins me today to discuss this finding and other prostate cancer focused research being done through the Robert H. Lurie Comprehensive Cancer Center of Northwestern University's Prostate Cancer SPORE Program. Dr. Abdulkadir is a co-primary investigator of the SPORE Program. He's also the John T. Grayhack, MD, Professor of Urological Research and Vice Chair for Research in the Department of Urology. Welcome to the show. 

[00:01:31] Sarki Abdulkadir, MD, PhD: Thank you, Erin. 

[00:01:32] Erin Spain, MS: Well let's start with why prostate cancer? What is it about this disease that drives you and your research? 

[00:01:39] Sarki Abdulkadir, MD, PhD: One of the most important things about prostate cancer you alluded to, it's very, very common. According to some estimates, any man that lives long enough, maybe 70s, 80s, if you look, you may find prostate cancer in them. It may be dormant, but almost all men will develop prostate cancer. So it is very common. And if it is caught early, you can get very good response, but there is a subset of men in which, you know, it is not caught early or it's very aggressive. So just because it's so common, you just have a huge number of men that have to deal with this problem. And I think that is one of the motivating factors for us to study this disease. 

[00:02:23] Erin Spain, MS: And you have been studying this disease for more than 20 years. What brought you into this world of prostate cancer and really got you interested in dedicating your career to studying this disease? 

[00:02:33] Sarki Abdulkadir, MD, PhD: I got into studying prostate cancer I would say almost accidentally, because it all started when I was doing my training at Washington University in St. Louis, my medical training there, residency training, and started looking at a couple of genes that ended up being implicated in prostate cancer. This was the era when there was a lot of human genome sequencing was going on and a lot of that activity. So because of that, then I kind of followed that interest and then it opened up this world of really this important disease for me. 

[00:03:09] Erin Spain, MS: So much of the work in your lab involves looking at the molecular pathways that drive prostate cancer with the hope of making new drugs to treat this disease. And in the paper that we're discussing today, published in Nature Communications, you've focused on one of these genes, the MYC oncogene. Tell me about this gene and the role it plays in cancer, specifically prostate cancer. 

[00:03:30] Sarki Abdulkadir, MD, PhD: MYC oncogene is probably the most significant oncogene in all cancer because it is implicated in many, many cancers and especially when the cancer is advanced, more aggressive, or when it becomes resistant to treatment. In prostate cancer there have been some indication that in more advanced cancers and metastatic disease, the levels of this gene or the activity of this gene is increased. So, we have actually been studying the MYC oncogene and we have been working on making new drugs to it for the last at least 10 years here at Northwestern. And so, this paper actually came a kind of a nice confluence, if you will, of our work trying to develop drugs against MYC and the findings in the paper. The findings in the paper started with our collaborator at Rutgers, Dr. Antonina Mitrofanova, who's a bioinformatics person, a computational expert, and she was just looking kind of just generally to see in the subset of patients that fail hormone therapy with enzalutamide for prostate cancer, what are the genes that are upregulated? So, she saw this gene and she knew that we work on this gene so that we kind of got connected and then did all the remaining studies that we reported in the paper. 

[00:04:56] Erin Spain, MS: We're going to dig into all of that. First, I want to talk a little bit more about the MYC gene. It has been classified as an undruggable target. I mean, that's a huge challenge for you, but yet you've continued to work on this. Tell me about that challenge and what drives you to continue working on targets for this gene? 

[00:05:15] Sarki Abdulkadir, MD, PhD: So, our primary motivation is the fact that if you really look closely at many cancers, including prostate cancer, and also especially when they fail the standard therapy, this gene, MYC, keeps coming up as being very important. So the data are very, very strong that this is a very important gene in cancer. Now, as you said, it has been considered undruggable because it doesn't have the kind of features that traditionally chemists would like to see in a protein or in a gene to develop an inhibitor. But with more recent developments, we and others have kind of been trying to see how we can target this gene. We have been able here at Northwestern to use really computational modeling as a starting point, followed by a lot of additional studies to generate inhibitors that we are preparing for human testing. And the remarkable thing is that, by studying these compounds that we have made, we are actually discovering new things about this MYC protein that people have not noticed before and that makes it more likely, I think, to be targetable, and we hope to be publishing those studies maybe even in the next year or so. 

[00:06:34] Erin Spain, MS: That's very exciting. It could have big implications for all kinds of cancer. So, I want to go back to your collaborators from Rutgers. You were basically contacted — we found this interesting information about a gene that you study. Tell me what happened with the collaboration from there and how we were able to take this information and pursue it further. 

[00:06:55] Sarki Abdulkadir, MD, PhD: We took that also with our collaborator in urology, Dr. Schaeffer. What we needed to do because Antonina is a computational expert, we are the biologist, so to speak, or the cancer biologist. So we needed to now look at this finding and try to do the studies that will determine what this gene is really doing. So the basic finding is that in cancers that have high levels of MYC and also high levels of another protein that regulates MYC, NME2, they don't do well. They don't respond very well to treatment. So what we did is to be able to show that indeed this pathway exists, and if you manipulate this pathway, you can now make the cancer cells to be more sensitive. So our drug that we have been developing came in very handy because we were able to actually use it, you know, in the experiments to show that when you use it to block MYC, now the tumor cells are sensitive to the hormone therapy. 

[00:07:57] Erin Spain, MS: Yes. Tell me more about this compound. This was something that was already in development, and then you said you were able to apply it now with this new knowledge, but what's the genesis of this compound? 

[00:08:06] Sarki Abdulkadir, MD, PhD: So, the genesis of this compound is that we looked at a large library, a chemical library in Silico. So, a virtual library of over 30 million compounds and use an approach to really identify compounds that combined to MYC, thinking that if they bind to MYC they will inhibit it. And then we took the compounds that look positive, then we did a lot of experiments. This took several years, gradually making better compounds, making hundreds and hundreds of new compounds and testing them to really get compounds that not only inhibit MYC effectively, but very importantly, are very well tolerated. So, there's no toxicity. And so that's what we have been working on. Part of our SPORE also is actually to support this work. 

[00:08:57] Erin Spain, MS: This compound, it's called 361, is that right? 

[00:09:00] Sarki Abdulkadir, MD, PhD: Yeah. So, 361 is the first one. We made a better one called 975. And now what is not reported publicly or published yet, we have the one that's going to humans is called 606. So, these are just the names we give to keep track of these compounds. Yes. 

[00:09:18] Erin Spain, MS: In this study, you were able to use the compound 361 in mouse models, is that right? 

[00:09:23] Sarki Abdulkadir, MD, PhD: Yes. And 975. So those two compounds, the 361 and 975, we were able to use them in animal models. Yes. 

[00:09:31] Erin Spain, MS: Tell me a little bit about what we know about the toxicity or the side effects of this compound. What is known so far? 

[00:09:38] Sarki Abdulkadir, MD, PhD: The first compound that we found that we saw has good activity unfortunately had toxicity. So, then we went back and made a lot of changes in the compound to make newer ones, and then we will test them systematically to see, you know, how they perform and how they are tolerated. And then we really major inflection point, if you will, was that compound 975, which was really remarkable because it retained activity. It's orally bioavailable, so it can be taken as a pill, and it's remarkable that it is well tolerated. And this was a surprise because people used to believe that if you really, you know, inhibit MYC in the body, you give it to an animal or a human, you are going to get a lot of side effects because MYC is known to play important roles in many functions like forming your blood cells, for example, the linings of your gut, for example, you know, which turn over frequently are dependent on MYC. So one of the key points in terms of how we were able to succeed in this is we actually did what we call an in vivo screen where we quickly test our compounds in animals so that we can see if there's any negative effect and we quickly drop that. So that allowed us to eliminate a lot of compounds that look really good In vitro or in the cell culture dish, but are not going to be good drugs. So that really saves us a lot of time and money in moving forward. So we found this compound and, empirically, our data shows that it works well, and it's well tolerated. So then we went back and did a number of studies to figure out why. How is it really working in the cell? And what we found, again, was surprising. We found that this compound is not working like a sledgehammer to knock out a cell all the MYC in the cell equally, whether it's in a cancer cell or a normal cell. It turns out that the way MYC works in the cell is actually more sophisticated, more nuanced. And MYC in a cancer cell works differently than MYC in a normal cell. And our compound, fortunately or luckily, is able to inhibit that cancer-related functions of MYC more efficiently and kind of spares, if you will, the more normal functions of MYC. So that is probably why we see this, what we call the therapeutic index, where you see an effect on the tumor much more than the effect on the normal. And so it is well tolerated because of that. And I think the message of that is none of this could have been predicted, a priori, based on what we knew. So, we could only have discovered this by actually going ahead. And even though this is considered an undruggable, you can find a million reasons why you should not do this, right? You can sit on your armchair and that's what a lot of people do. It's not going to work because of all these reasons. But biology and nature are just much more complicated and more sophisticated. Sometimes we need to actually do the experiments and we find that the assumptions we make sometimes are not correct. 

[00:12:59] Erin Spain, MS: And then you were also able to look at a human patient with prostate cancer. Tell me about that analysis. 

[00:13:05] Sarki Abdulkadir, MD, PhD: So, what we did is actually we're able to get data from prostate cancer patients that have received this enzalutamide at the home and treatment and know the response, so we know whether the patient did well or didn't. And then using that information, that's how we were able to show that if the tumor from the patient has high activity of MYC, then the patient doesn't respond very well. So, really highlighting the need to hit this protein and inhibit it. One of the implications of the study is that now you have a biomarker potentially. One of the real issues in prostate cancer therapy , and actually all cancer therapy, is if a patient comes and they have a cancer, breast cancer, or prostate cancer, and what have you, you need to decide how to treat them because you don't want to be giving them a drug that's not going to help them. By us identifying this marker, this MYC activity gene marker as an indicator of lack of response, and because we are developing this drug as well, then, you know, now you can direct those patients to this newer kind of treatment. 

[00:14:23] Erin Spain, MS: Explain to me how you could foresee this being given. You said it could be a pill, so it would be given orally, and would it be given in conjunction with chemotherapy and surgery? Or how would that work? 

[00:14:33] Sarki Abdulkadir, MD, PhD: Right now, it will be as a pill. And I think one of the first scenarios I can envision is the combination, with the, maybe the hormone therapy in where people are not responding well, you add this. So, initially a lot of the new things will come in as a combination and as we learn more and more about the kind of patients that respond well, I think that you can have additional indications. The other thing we have found also is that even the radiation therapy actually is boosted by this compound, it looks like. So again, a lot of the things that are kind of standard of care for prostate cancer you know, could be scenarios where you can do a combination with this new treatment. 

[00:15:21] Erin Spain, MS: So again, this paper was just published. This is really a lot of information that's new that you're adding to the literature. When do you think you could see next steps? You mentioned that there could be a clinical trial coming. When could we see this being incorporated into patient care? 

[00:15:35] Sarki Abdulkadir, MD, PhD: So our timeline right now is that we are doing the studies that we will present to the FDA so that they can give permission to give to humans, and we expect that that should be done in a year. So then you need to do the phase one trial where you check the safety and everything. Then now after that, you go to actually testing in phase two trials where you want to see how effective that is. So that is kind of the timeline we are working with. 

[00:16:06] Erin Spain, MS: Tell me about your role within the Prostate Cancer SPORE Program and how that program has really impacted or helped make this research possible. 

[00:16:15] Sarki Abdulkadir, MD, PhD: The SPORE programs are really nice because the NIH basically wants people to have a collaboration between clinicians and more basic scientists. So all the projects by design need to involve both basic science and clinical research. What that does, it really allows for synergy of ideas. So you are not like in an echo chamber where, you know, the same specialists are talking to themselves. You do have people who have different backgrounds. So this is very interesting because it allows the generation of new ideas and then the ideas can be taken forward to patients. So the SPORE has been really very instrumental in us, working to target, make and develop this new drug that we are trying to develop. So it's like a catalyst, if you will, for us and other investigators. So the SPORE has many investigators both at Northwestern and also University of Chicago and North Shore. And has also a career development component where we try to encourage and nurture some of the more junior investigators like early junior faculty members so that, you know, they can grow their expertise and we meet monthly and really have a good exchange of ideas among ourselves. 

[00:17:38] Erin Spain, MS: This is something that has been part of Northwestern University's research enterprise for a couple of decades. Is that right? 

[00:17:45] Sarki Abdulkadir, MD, PhD: Yeah, Northwestern is really one of those institutions that has been really fortunate to have had a Prostate SPORE for probably one of the longest times since they started. Over 20 years it's been ongoing, started by Dr. Chang Lee as the PI going over the years and now it's my turn and Maha Hussein who I co-lead in this effort. 

[00:18:07] Erin Spain, MS: Collaboration really seems to be a theme in this study. You had folks come to you with research. You've brought in a lot of people, including students, on this paper. Why is that so important to bring in the next generation of scientists to help you with this really important research? 

[00:18:23] Sarki Abdulkadir, MD, PhD: Having good students is just essential actually for success because they are not biased. They tend to have a more open mind in looking at things. I find the conversations I have, the discussions I have with my students are some of the most useful and helpful. Not to say that the most senior people are not helpful, but the younger people don't have a preconceived notion. And they have that, you know, some people may say it's a naivete, which is kind of what you need actually to discover new things because you really have to take a chance and just not listen to the people who think they know it all and they know what the answer is going to be because they have been around for a long time, which is one of the problems we have in science. And then, you know, they are the ones that will take the banner, so to speak, and the next level. So, it's really an honor to be part of their training so that they carry on the legacy, what we are not able to do or what we do wrong, they can do correct and kind of push things forward. 

[00:19:27] Erin Spain, MS: You hold a lot of patents as well. This is technology that you were able to put your name on at the U.S. Patents Office. Tell me about that aspect of your role as a scientist and with this study as well. Is this something that you're able to patent? 

[00:19:40] Sarki Abdulkadir, MD, PhD: It's something that I never used to think about, especially when starting out, but as I get into this, then, you know, obviously the Institutional Intellectual Office, they kind of guide you. As we are working on developing these compounds into something that will benefit people, you realize that without that intellectual property protection, it's never going to move forward. And in fact, some things that the IP life span is short, you know, will not get developed because by the time you finish developing, the IP is gone so nobody's going to invest. So, that's something that I have learned other the years and come to appreciate more and more that that's part of what is needed to really bring benefit to people, to patients.  

[00:20:24] Erin Spain, MS: And really, that's the goal here. That's the goal of the SPORE    program. That's the goal of everything that we're doing is how do we get this to the bedside. As we're wrapping up today, what are the three things that you want listeners to take away about this study and the next steps? 

[00:20:30] Sarki Abdulkadir, MD, PhD: I think my overarching message is that we have hope and don't give up and don't think we know it all. That's the whole basis of research should be about testing new ideas and testing preconceived notions because that's really what allowed us to start this project because if we had listened to everybody else, then we would never have started. That's number one. Number two, collaboration is key. From day one. I'm not a chemist, and I don't have some of the expertise, but we are able to now make new molecules and I can contribute intellectually and hopefully we'll get something that will help patients. So collaboration is key. And the third thing is that I think trainees are very important for carrying things to the future, but really helping you also refine your thinking and your thoughts. I think that we need to keep in mind why we are doing what we are doing. We can't give up and we can't accept the status quo, if you will. If we keep pushing, we will find ways to help people. Because the way this new technology develops is somebody tinkering and trying to discover something, trying to do something. And sometimes they don't get exactly what they are looking for. But then, the progress they've made will lead to new technology that now gets applied in surprising areas that you didn't even think about. Definitely, it's been a really great time where, you know the possibilities are now just so much more than before. 

[00:21:48] Erin Spain, MS: Thank you so much, Dr. Sarki Abdulkadir for coming on the show and talking about this advancement, which is now just leading to so many exciting things in the future. And we can't wait to just take the ride along with you and see what happens. 

[00:22:30] Sarki Abdulkadir, MD, PhD: Thank you so much. 

[00:21:34] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network to hear more about the latest developments in medical research, health care, and medical education. Leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at feinberg.northwestern.edu/podcasts.