Dr. Mian on emerging molecular biomarkers for genitourinary cancers

On this episode of Cleveland Clinic’s Cancer Advances podcast, host Dale Shepard, MD, PhD, talks with Omar Mian, MD, PhD, about emerging molecular biomarkers for genitourinary cancers.

On the podcast, Dr. Mian explains the multidisciplinary approach required for effective biomarker utilization, the success of prognostic and predictive biomarkers, and his ongoing research on germline polymorphisms and the use of PET scans with PSMA tracers.

Mian is a radiation oncologist and physician scientist at Cleveland Clinic.

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Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, directing the Taussig Early Cancer Therapeutics program, and co-directing the Cleveland Clinic Sarcoma program. Today I'm happy to be joined by Dr. Omar Mian, a radiation oncologist here at Cleveland Clinic, who is going to talk to us about emerging molecular biomarkers for genitourinary cancers. So, welcome Omar. 

Omar Mian, MD, PhD: Thanks Dale. Good to be here.

Dale Shepard, MD, PhD: So maybe start off, give us an idea, what's your role here at Cleveland Clinic? What do you do here?

Omar Mian, MD, PhD: So again, thanks so much, Dale. I've been a big fan of the podcast for a long time. It's great. It's very exciting to be here. I'm a radiation oncologist in the Taussig Cancer Center, and a physician scientist with a lab that studies genetics and epigenetics of genitourinary malignancies. Primarily we focus on bladder cancer and prostate cancer, a little bit less on kidney cancer and testicular cancer. My clinical focus mirrors that, so I treat prostate and bladder cancer.

Dale Shepard, MD, PhD: All right, excellent. We're going to talk about biomarkers, and their relationship to GU cancers. There's a lot of different people might be listening in, different backgrounds. When you say biomarkers, what does that mean?

Omar Mian, MD, PhD: So, the goal of modern oncology is personalized medicine. And what I mean by that, it's important to understand before we talk about biomarkers. Personalized medicine is really choosing the right treatment at the right dose, at the right time, for the right patient. Which is a tall order. In order to do that, we need a way to risk stratifying patients. Find those patients with certain types of cancer, or certain prognosis from their cancer who we can de-intensify their treatment. And those patients who may need more intensive treatment in order to clear their cancer and have a better outcome. This is where biomarkers have become critical. They're the tool we use for risk stratification, for prognosis, for prediction of who will respond to what type of therapy. And they span an enormously broad range. So, the term biomarker is sort of a catchall term, but this can include clinical and pathologic features.

Classically things like prostate cancer, the PSA or Gleason grade. Or more and more, they're including molecular features. So, these are genes that are expressed by tumors. Or genes that are germline, that you're born with, that may be predictive of a certain type of therapy or put you at risk for a certain type of cancer. We use all of these as biomarkers for personalizing therapy. And just to make one more point around this idea. When you think about risk stratification, I think prostate cancer is a wonderful example, because this is a disease where there's an enormous risk spectrum. You have those men who have the kind of prostate cancer that we watch safely. The best thing for those patients is not to expose them to the side effects of treatment, but rather to observe a cancer that is never going to hurt them.

And on the other end of the spectrum, the complete opposite, that very aggressive and potentially lethal cancer that you don't want to miss. And then everything in between. And in order to best treat those patients, the very first thing we need to do is identify what category they fall into. And that, again, is not always an easy task. Historically, we've done this with those clinical and pathologic features. What is the PSA? Which is a blood test that detects prostate cancer. And what does it look like under the microscope? That's the Gleason grade. And more and more now we're moving into tools that include gene expression classifiers, and molecular determinants of DNA damage response. And even artificial intelligence-based analysis of tissues and imaging studies. And incorporated in all of that are things like PSMA PET, a new kind of imaging modality. So, it's a super exciting time. And more and more for everyone like you and me who treats cancers, biomarkers are becoming the norm of what we do. We need them to be able to treat patients in the best way.

Dale Shepard, MD, PhD: And sort of to understand how to develop these biomarkers and even use them clinically, it's becoming much more multidisciplinary. You need radiology, bioinformatics, and pathology support. Tell us a little bit about how the world changes as we incorporate more of those.

Omar Mian, MD, PhD: You're precisely right. We have to approach this in a multidisciplinary way. We need basic scientists who study the biology of cancer. We need clinicians who treat cancer and know the different therapies that are available, and their nuances. We need pathologists to study the tissue-based characteristics of disease and know that better than anyone. Our radiology colleagues who can tell us so much about a disease from an x-ray, which is incredible. All of these things are incorporated. And the challenge for us now is how do we take that multidimensional data and use it, synthesize it, in a way that we can make decisions as we're sitting across from a patient. In terms of how we are informed to treat them in the best way.

Dale Shepard, MD, PhD: When you think about GU cancers biomarkers, historically, have we had the best success with prognosis, with predicting what treatment might be best for a patient? Or response, and assessing response to therapies? Or has it been kind of a combination of all?

Omar Mian, MD, PhD: It's probably been a combination, but I'd say probably the biggest success we've had is with prognostic biomarkers. Being able to sort of determine which disease is going to behave more aggressively or less aggressively. And to a perhaps lesser extent, we have markers that tell us something about what treatment a patient will respond to, predictive biomarkers. I'll give you an example of each kind. Prognostic biomarkers include things like the Gleason grade, and gene expression classifiers or genomic classifiers that tell us a patient's risk. How aggressive is their cancer? And then you have predictive biomarkers. And those might include something like homologous recombination repair defects, or tumor mutation burden that would tell you about response to a PARP inhibitor, or immunotherapy respectively.

Dale Shepard, MD, PhD: Excellent. GU tumors, wide range. You've got bladder cancer, kidney cancer, and prostate cancer. Which of these tumors have you been working on personally here at the clinic? Which ones have shown the greatest promise for new therapies?

Omar Mian, MD, PhD: It is a wide range of cancers, with a large burden of both morbidity and mortality. I have focused on bladder cancer and prostate cancer. Other genitourinary malignancies, as you know, include kidney cancer and testicular cancer. And a whole spectrum of more rare tumors, including adrenal cancers, upper tract urothelial cancers. A variety of others. Again, my focus has been on bladder cancer and prostate cancer, and this has been the main center of the work that my lab has been doing as well.

Dale Shepard, MD, PhD: So, tell me a little bit about, within prostate, some biomarkers that you're currently working on that you find most interesting.

Omar Mian, MD, PhD: Right. So, I approach my research work in clinical care through the lens of a radiation oncologist. So, I think a lot about how the tool that I have, radiation therapy for both prostate cancer and bladder cancer, can be better. How we can apply it to the right patients. How it can work better. And there's a few aspects of this that I'm particularly excited about. Work that's been done here at the Cleveland Clinic over the last few years that my lab has been privileged to participate in. And that includes studying the biology of a key driver of prostate cancer, which is the androgen receptor. This is the receptor in cells that binds to testosterone. The male hormone, testosterone, is a driver of prostate cancer progression. And we study how both normal tissues and prostate tumors can metabolize testosterone in a way that can sometimes circumvent the therapies we use to block testosterone.

And importantly for me, this leads to a diminishment of the effectiveness of radiotherapy. So said another way, the combination of hormone therapy, testosterone blockers, and radiotherapy, is a very powerful combination. It's synergistic, the two work very well together. And so, when you have a tumor that is resistant to hormone therapy, it's also going to be partially resistant to radiotherapy. And in particular in those higher risk cancers, I described where that combination is the standard of care, or one standard of care. And so, we, along with colleagues here at the Cleveland Clinic, have looked at steroid biosynthesis enzymes, one of which was discovered by my colleague Nima Sharifi. It's hydroxy-3-beta-steroid dehydrogenase-1, which is a mouthful, HSD3B1. This is an enzyme that takes precursors, the building blocks of testosterone, and converts them to testosterone. And it comes in a variety of types and flavors. And depending on which one you inherit from your parents, or which one the tumor might express either normally or perhaps due to a mutation, it can really change the way that patient's prostate cancer responds to hormone therapy and radiation.

One of the more recent projects out of my lab, we just submitted for publication, studies the interaction of germline polymorphism or variant in HSD3B1, and its role in influencing radiation sensitivity. And the sort of takeaway from that work is that, depending on your genotype, depending on the type of this enzyme you have in your prostate cancer cells and, in your body, or a prostate cancer patient's body, that patient has a potentially very different response to the combination of hormone therapy and radiation. They may be very resistant to it. And in those patients, we know that alternative hormone therapies or combinations of hormone therapies may work better. So, this gets back to this idea of using a biomarker, in this case, the germline genotype of HSD3B1, to personalize therapy. And intensify it for those patients with the adrenaline permissive or bad allele, and perhaps de-intensify or use a more standard combination in those patients who have the more favorable genetic profile.

Dale Shepard, MD, PhD: Exactly right. What kind of work has been done within biomarkers, your lab here at the clinic, that has led to clinical trials?

Omar Mian, MD, PhD: So, a variety of things have, I'm very happy to say, moved from the bench to the bedside, as we like to say. So, the laboratory bench work that we've been doing on cancer models, cell lines and the like. To discoveries that we can now use as actionable tools that we can now test in the clinic, with the end goal of changing the way we manage patients and leading to better outcomes. And so, one example I just described is the germline polymorphism in HSD3B1. We now have a prospective trial looking at this polymorphism. And how it influences response to the combination of hormone therapy and radiotherapy in men with higher risk prostate cancer, or even low volume metastatic prostate cancer. So, disease that has spread outside of the prostate, but to a limited number of sites. We now think that in those patients, combinations of hormone therapy and radiation therapy may be effective. And we may be able to use this biomarker to help us pick the right treatment for those patients.

So that's a trial that we have ongoing. We're also looking at gene expression biomarkers, or classifiers, in bladder cancer to identify patients who may have responsive disease from the perspective of radiation therapy and chemotherapy combinations, with the goal of preserving their bladder. So, when they have an aggressive muscle invasive bladder cancer, one option for those patients is chemotherapy followed by removal of the bladder. And as you can imagine, it's a difficult thing sometimes for patients and life-altering. And for those patients who have more localized disease, one alternative for those patients is combinations of chemotherapy and radiation that may allow us to clear the cancer but leave the bladder intact and functional. And hopefully provide a better quality of life for some patients with muscle invasive bladder cancer.

And I would just sort of expand on that more broadly, to say that this is the paradigm across oncology now. Moving away from more radical local treatments to words, multi-modality, multidisciplinary care, combinations of a limited surgery, radiation, systemic therapies like chemotherapy or hormonal therapy. Applying those combinations in the right way allows us to clear the cancer but preserve the organ and their function so that patient ultimately has a better quality of life. Examples include breast cancer, gynecologic cancers like cervical cancer. Head and neck cancers, where we have voice box preservation by the use of chemotherapy and radiation together. And so, this is the same paradigm we like to think about in bladder cancer for the use of combination therapy for organ preservation. Something that I think is important, and that my group is quite passionate about.

Dale Shepard, MD, PhD: And then I guess from the standpoint of responses, tell me a little bit about prostate cancer work with PET scans and tracers, and how that might guide care.

Omar Mian, MD, PhD: One of the perhaps most significant innovations in prostate cancer is the emergence of targeted PET scans, that look for a surface molecule that's specific to prostate cancer cells called the prostate specific membrane antigen, or PSMA. Sounds a lot like PSA. PSMA is expressed on prostate cancer cells almost exclusively. There are a few other places where you'll see it, but what has happened is we've now been able to tag something that finds PSMA to a radiotracer, a positron emitter that we can detect using PET scans. And this allows us for the first time to have a more sensitive, as well as specific imaging study to identify the location of prostate cancer in any individual's body. This has allowed us to do more early detection of disease that may have moved outside of the prostate, to identify local recurrence. For example, after surgery or radiation therapy.

And as I said, with biomarkers of other types, this tool to identify the anatomic location using this molecular radiotracer has completely revolutionized how we're approaching the care of patients with advanced prostate cancers. Along those lines, we're innovating here at the clinic in the space of PET scans and imaging, with our outstanding colleagues in radiology and nuclear medicine. We're developing radiotracers that not only will tell us where the cancer is, but we hope will tell us something about how that cancer will respond to particular types of therapy. One example is a study we have opened, it's a phase 1 pilot clinical trial here looking at chlorphenamine PET radiotracer. Chlorphenamine is an older kind of chemotherapy we use in micro doses, and it's metabolized by the same key enzyme that holds it inside of cells. That is important for sensitivity to a lot of common chemotherapies, cytidine analogs.

These include drugs like gemcitabine, 5FU, ARA-C. And what we hope this PET radiotracer will tell us, in addition to where the cancer is. Because the enzyme it labels, deoxycytidine kinase, DCK, is upregulated in cancer, so we can see the cancer. We hope that the level of this is going to tell us something about whether that patient will have a tumor that's responsive to, for example, gemcitabine. So, whether bladder cancer might be gemcitabine responsive, or perhaps you want to look for a different combination chemotherapy.

So, this is where I think things are going using imaging tools both as diagnostic, as well as predictive of response, and ultimately therapeutic. We've seen that in the clinic as well with PSMA targeted radionuclide. Lutetium PSMA is one example where this PSMA takes a radioactive molecule right to this is the lutetium radioisotope. Takes it right to the cancer where it can be most effective killing the cancer but causing the least possible side effects. So, this is an area where there's a tremendous amount of promise and I personally, I'm very excited about innovation in this space.

Dale Shepard, MD, PhD: So certainly, lots of things have happened recently. Prediction, prognosis, treatments, what are the biggest gaps? What's missing? What's the unmet need still?

Omar Mian, MD, PhD: It's an important question. And as you said, I'm excited about all the innovation. It's changed what we do, but there's quite a bit of unmet need. The main one is that we don't have biomarkers for every type of therapy we have. We don't have biomarkers that are as reliable as we would like. In other words, things like homologous recombination repair defects, and DNA damage response mutations tell us something about whether some patients will respond to therapies like PARP inhibitors radiation chemotherapy. But it's not the full picture. Things like tumor mutation burden, and PD-L1 expression tell us something about whether or not a patient will respond to immunotherapy. But again, the response rates are lower than we would like, and the correlation between these biomarkers and the response rates is not a perfect one, as you know better than anyone. And so, where there's gaps is in refinement of these biomarkers, and discovery of new molecular markers for response to therapy. I think that's probably one of the biggest gaps right now.

And I think one of the areas where there's promise here is we focused on genetic biomarkers, metabolic ones like expression of these proteins. I think where things are going is more functional biomarkers measuring capacity for DNA damage response, incorporating things like epigenetics and methylation, and the like. And so, there's certainly much room for improvement. We need to do better.

Dale Shepard, MD, PhD: Well, this whole concept of personalized medicine and cancer has been kind of bandied around for a very long time. It does look like there's certainly been a lot of progress, and there's a lot of hope for the future. So, appreciate all the work you're doing in this area, and giving us some good insights.

Omar Mian, MD, PhD: Oh, you’re very welcome. Thanks for having me.

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