Comprehensively Mapping Epigenetic Alterations Promoting Lineage Plasticity to Develop Blood-based Biomarkers to Predict Treatment Outcomes in Prostate Cancer - Martin Sjöström
December 12, 2022
Sjöström refers to the ability to take a blood sample and predict which patient will respond to which therapy, while also detecting treatment resistance earlier, and doing this throughout the course of the disease, being able to take sequential blood samples is the holy grail of precision medicine. Epigenetic modifications of cell-free DNA, DNA that's released from the tumor that can be found in the bloodstream is being used to accomplish this. Sjöström and colleagues are looking specifically at 5-hydroxymethylcytosine (5hmC), a relatively recently discovered epigenetic modification, and sequencing it to investigate treatment resistance and develop liquid biomarkers for advanced prostate cancer.
Martin Sjöström, MD, PhD, Assistant Professional Researcher, Felix Feng Lab, Department of Radiation Oncology, The University of California, San Francisco
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Alicia Morgans: Hi, I'm so excited to be here with Dr. Martin Sjöström, who is visiting us from the University of California, San Francisco, where he was awarded a Young Investigator Award by the Prostate Cancer Foundation. Thank you so much for being here to talk with me about your award and your science and congratulations.
Martin Sjöström: Yeah, thank you so much. Thank you for having me.
Alicia Morgans: Of course. I'm so glad that you're here and willing to take the time to talk through your award and your project. Can you tell us a little bit, Martin, about what your award was? What earned you that Young Investigator Award?
Martin Sjöström: Absolutely. The overall goal of our research is to develop a new liquid biopsy biomarker platform for men with prostate cancer. And I think it's the holy grail for precision medicine for prostate cancer is really to be able to take a blood sample and predict which patient will respond to which therapy, and also detect treatment resistance earlier, and doing this throughout the course of the disease, to be able to take sequential blood samples. The way we're approaching this is to use the epigenetic modifications of cell-free DNA. That is DNA that's released from the tumor and can be found in the bloodstream.
We're looking specifically at something called 5-hydroxymethylcytosine, which is a relatively recently discovered epigenetic modification. It's a chemical modification to the DNA that's not really a change in the structure, but it's a change that regulates gene expression. And a special thing about 5hmC, for short, is that it marks active genes, so genes that are being turned on. And we want to think about this as a liquid biopsy gene expression profiling platform. And the key thing is that we think we can capture more complex cancer phenotypes and to get basically more information than what we can obtain by just the targeted panel of the DNA structure.
Alicia Morgans: I think so importantly too, some of these approaches are being used in cancer screening techniques and others because you can detect very low levels of this in a patient's blood. So can you tell us, how does that affect what you're doing? Does that allow for a bigger spectrum of patient population, early detection of relapse? What are the potential implications of that?
Martin Sjöström: Yeah, absolutely. This is a really sensitive assay and it has gained a lot of interest in the diagnostic setting to be able to diagnose prostate cancer and other cancer types. What we are focused on is the metastatic setting right now where we take blood samples from men with mCRPC before they start the first line therapy for mCRPC, and then we'll look at the modification in their DNA and we can tell... It's really sensitive to detect the prostate cancer DNA and that can be used to tell the ct-fraction, which is the percentage of the DNA found in the bloodstream that's coming from the tumor versus the normal cells. And that correlates well with tumor burden and the aggressiveness of the tumor and can be used as a prognostic biomarker.
We're also looking at different oncogenes and tumor suppressors and we can infer the activity of those genes with 5hmC profiling, which is also very prognostic. But what I think is really the most exciting thing about the assay is that we can also look at the activity of genes that are not part of common targeted panels and get this additional information. And specifically we have looked in the mCRPC setting and seen that this is very prognostic.
Alicia Morgans: Well, I think that's so important and especially as we are dealing with an advanced cancer that may be heterogeneous, this can give us a broader sampling potentially, as well as really get away from the issue of needing to get tissue from patients who may have bone only metastatic disease, which can be an issue for some of our patients. So where does your project stand now? You've been working on it for about a year.
Martin Sjöström: No, absolutely, that's right. And one of the findings we had in the project so far is that we have previously been collaborating with other people and we found two genes, TOP2A and EZH2, that really marked an aggressive subgroup of prostate cancer when they were expressed at high levels. And that was using RNA and gene expression profiling from prostate cancer tissue. So we did the exact same analysis but using cell-free DNA and 5hmC levels instead. And we could see the exact same finding that those that had high levels of 5hmC of those two genes also had a much worse prognosis. And this is the first time this has been shown in cell-free DNA as opposed to taking a tumor tissue biopsy.
Alicia Morgans: Wonderful. Well, where do you go next? What are you and the lab planning for next steps?
Martin Sjöström: We have a number of fantastic collaborators and you are one of them. And what we really want to do is to ask specific questions about different treatments. For example, should a patient be given chemotherapy or AR-targeted therapy? So we're collecting samples from trials and from cohorts specifically asking those questions. And the idea would be to compare the 5hmC patterns from patients who are given chemotherapy versus AR-targeted therapy and look at those that respond or do not respond to therapy to be able to guide that therapy decision.
Alicia Morgans: Well, I certainly am waiting eagerly to hear what your next findings are because I think that this is the kind of technology and technique that ultimately could change practice and really could help us personalize our therapies much more effectively for patients and target the specifics of their cancer rather than being as general as we currently have to be. Thank you so much again for sharing all of this and congratulations again on your Young Investigator Award. We look forward to seeing how you continue to transform the field.
Martin Sjöström: Perfect. Thank you so much.