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Melanie Cole (Host): Ovarian cancer is diagnosed in about 250,000 women each year worldwide. Often referred to as a silent disease because most women do not experience symptoms until its later stages. Ovarian cancer accounts for more deaths than any other gynecologic cancer.

At Penn Medicine, the Ovarian Cancer Translational Center of Excellence is researching novel therapies and earlier detection methods to seek better outcomes for ovarian cancer patients, led by my guest today, Dr. Ronny Drapkin, the Penn Ovarian Cancer TCE links scientists who develop therapies in the lab to patients in the clinic and hospital making it easier to translate new laboratory findings into clinical practice and thereby providing new therapeutic options to patients who desperately need them. Dr. Drapkin is also Director of the Ovarian Cancer Research Center at Penn Medicine and he heads the Drapkin Laboratory at the Perelman School of Medicine at the University Of Pennsylvania. The Drapkin Laboratory focuses on developing a comprehensive understanding of the genetic, molecular and physiological factors that drive the development of cancer focusing specifically on gynecologic malignancies.

Welcome Dr. Drapkin. It is a pleasure to have you with us today. Please, if you would, start by telling us about the current landscape on research of ovarian cancer and why it’s become one of your priorities at Penn.

Ronny Drapkin, MD, PhD (Guest): Well it’s a pleasure to be here. I think I’ll start with answering your question on the priorities because that’s what really drew me to Penn. I actually moved to Penn in 2015 and the reasons that I came wa because ovarian cancer was already a priority. The Ovarian Cancer Research Center at Penn was established in 2007 and it was further strengthened by the creation of the Bastyr Center for BRCA in 2012 and then more recently bolstered with the award from the Abramson Cancer Center of a translational center of excellence to further support our research in ovarian cancer.

So, this is a place that has really made ovarian cancer a priority for a long time and I think it’s been a hotbed for a lot of innovation coming out from the work here.

Host: Isn’t that fascinating and what a great reason for you to go there. So, the Abramson Cancer Center recently awarded as you just said, the Translational Center for Excellence grant to the Ovarian Cancer Research Center. Can you explain what the Ovarian TCE is and your objectives for it?

Dr. Drapkin: Sure. I think our overarching goal is to understand why it is that ovarian cancer initially presents as a very sensitive disease to chemotherapy. It is very chemo-sensitive initially but inevitably; these tumors recur and over time they become resistant to therapy. And we really don’t understand that over time, how does this happen, how does it that the tumor evades our current modalities of treatment. And so one of the overarching goals for the TCE has been to try to really understand that.

Host: So, then tell us about the Core Pillars of the TCE and what is it hoping to achieve?

Dr. Drapkin: Sure. So, in order to answer this question of how does a tumor ever become chemo-resistant and unfortunately claim the lives of many of our patients still; we felt that we had to study this tumor over time. So longitudinally. And in order to do that, we had to create a number of what I call enabling pillars. So, the first one was to really expand on our tissue banking across the entire Penn Medicine System. So, Penn Medicine has the hospital of the University of Pennsylvania, it has Pennsylvania Hospital, it has Chest County Hospital and more recently, Princeton Medical Center. And across these hospitals, we see a lot of patients and a lot of patients have surgery for ovarian cancer every year. Until recently, until we had the TCE, there was really no concerted effort to try to capture that material, those tumors that our patients consent to us. And I felt it was our responsibility to our patients to do as much as we could with that tumor and so our goal has been to try to capture all the cancer cases, all the ovarian cancer cases throughout the Penn Medicine System. That’s pillar one, tumor banking.

Why is tumor banking so important? Because it enables pillar two which is for us to create what we call patient derived tumor xenograft models. This is where we implant patient tumors into mice and have shown over a number of studies over years that these tumors retain their fidelity to the original patient tumor both at the genomic level, also at the morphologic level at the way that these tumors respond to therapy.

So, now you have essentially an avatar of someone’s tumor that you can now do a lot of drug testing on to figure out what it is that they would be sensitive to. Combining that with the knowledge of the genomics of the tumor we are now able to move new concepts, new combination therapies into the clinic by using these PDX models.

And then the third pillar, it’s really a reflection of the sad state in ovarian cancer in that many of our patients do succumb to their disease and for us to really understand how that happens, we need to be able to study that cancer at the time of death. And that means doing what we call a tissue – tumor autopsy program. We call it the Penn Legacy Tissue Program which enables us to harvest tissues at the time of death so that we can really get an opportunity to look at the diversity of tumor, the heterogeneity of tumor, the different metastatic lesions that may exist in a patient at the time of death so that we can then compare it to the tumor that we originally got when the patient presented to us and ask what changed in that tumor at the genomic level, at the metabolic level, at the proteomic level so that the tumor now is resistant to our therapies and could we, through that process, identify new vulnerabilities.

Host: That is amazing. And what a great description of those three core pillars. So, what do we not yet fully know about ovarian cancer recurrence?

Dr. Drapkin: Yeah, that’s a great question. And as I mentioned, it’s really what drives our TCE program. There seems to be a tremendous amount of heterogeneity in this tumor and by heterogeneity, I mean not only within a single tumor, so the cells within the tumor are not all the same. We used to think of cancer as a clonal disease, so all the cells are sort of clones of each other. And that doesn’t seem to be the case. It seems that these cells can be quite different from each other and yet exist in this sort of tumor microenvironment. So, there’s heterogeneity within a tumor and then there’s heterogeneity between tumors. So, no two ovarian cancers are the same. And that makes it challenging, right? Because now you are dealing with a tumor type that is heterogeneous from patient to patient, heterogenous within a patient and so heterogeneity seems to be at the heart of this recurrence. And what we’re trying to figure out is how do these tumors with this idea of heterogeneity, kind of perhaps as a driving force for recurrence, how are they changing? How are our treatments altering those tumors in such a way that they can evade them.

And if we can identify those mechanisms, we could try to thwart them and come up with combinations that prevent those mechanisms from being kicked in in response to our initial therapies. So, that is why for us the tissue is the issue. And we have to have access to that tissue so we can study it longitudinally over time.

Host: I’d really like for you to tell us about your multidisciplinary team that takes advantage of shared resources available through the Abramson Cancer Center and brings together really expert investigators from many different disciplines.

Dr. Drapkin: And none of this could happen without a multidisciplinary approach. So, we have the people in the lab, and these are dedicated MDs, PhDs, MD PhDs, the students, trainees, postdoctoral fellows all working at the molecular level, really trying to understand this cancer. But as I said, a lot of what we need is access to material, access to tissue and so we have to partner with our GYN oncologists, the surgeons who see the patients who bring them to the operating room to perform hopefully lifesaving surgery. We need to work with the pathologists who could tell us that the piece of tissue that we have is actually what we want. It is a particular type of ovarian cancer or it’s not. We need to work with the radiologists who are maybe able to deliver certain therapies in combination with chemo.

There’s a tremendous group of people that have to come to bare on this issue when we are not only trying to bank the tissue, create the models, develop the rapid autopsy program, the tissue legacy program which by the way is a first for Penn Medicine. There hadn’t been this type of program to enable us to study the tissue at the time of death and that required a tremendous orchestration with pathology department, and we have a 50 mile catchment radius so that we can offer this service to people in the 50 miles surrounding Penn Medicine.

So, it’s a tremendous organizational challenge that we’ve been able to meet with support from the TCE and the Abramson Cancer Center.

Host: It certainly is. I was reading about it in my preparation for this segment and what a wonderful program and can expand your research capabilities so greatly. So, while we are talking about research capabilities, Dr. Drapkin, and as we wrap up, what’s next on the horizon? What does the future hold in gynecologic cancer research and treatment?

Dr. Drapkin: Great question. I think it’s a really exciting time. We’ve seen a tremendous number of advances in the last ten, fifteen years. I’ll touch on two areas. One is on early detection and prevention and in that I will say that there’s been a tremendous amount of new insight into how these tumors arise. And we now appreciate that many ovarian cancers actually are tumors that begin in the fallopian tubes, not actually in the ovary and so, this new kind of observation has been a paradigm shift in the field and has made us really rethink how we look at early detection and how do we think about prevention.

So, just to give you an idea, an example, for women who harbor mutations in the BRCA 1 or 2 genes which predispose you to getting ovarian cancer as well as breast cancer; we offer prophylactic surgery or what we call risk reducing surgery where we take out your fallopian tubes and your ovaries if you are a BRC 1 mutation carrier, we recommend that at age 35. If you are BRC 2 mutation carrier, we recommend that slightly later around 40-45. But the problem with that is that by taking out the tubes and ovaries, you are putting these women who are premenopausal immediately into menopause which has its own morbidity associated with it including heart disease and bone disease and so on.

And so, if these tumors really come from the fallopian tubes, the thought now is perhaps we can offer these women what we call interval salpingectomy with delayed oophorectomy. Simply meaning take out the fallopian tubes first and later come back and take out the ovaries once the woman has gone into her natural menopause to make sure everything comes out. And so there’s a clinical trial called the WCSP study which stands for Women Choosing Surgical Prevention. It’s a national study, comes out of MD Anderson and Penn enrolled or began to enroll patients into this study within sometime in the last year.

And so we are now part of this national study that is looking at whether this is A, a safe procedure but also ultimately does it afford women the equal or the same amount of risk reduction as taking out both the tube and ovary. So, that’s one. The other one is a company called Envision Medical that developed what we call a falloposcope so what they are able to now do is actually sample the cells in the fallopian tube and look to see if there’s early cancer cells there that would signal that something needs to be done. It’s essentially like a PAP smear of the fallopian tube. And we’ve opened up a phase two study here in this last six months or so utilizing this approach.

The goal ultimately is to be able to utilize this approach in high risk women. The women with the BRCA mutations. So, there’s a lot of things changing in our ways of thinking about early detection and prevention.

On the therapeutic side, in the last five years; there’s been tremendous excitement about the PARP inhibitors and how successful that’s been in the clinic. What we are realizing now is that single agent PARP is not going to be the key or the answer, but combination therapies are where we are likely to see really great advances. And that’s where the ovarian cancer research center is also making a tremendous impact. Fiona Simpkins who is one of the faulty in the department utilizes PDX models that I described before to come up with new combination therapies. And so she started a trial last year looking at the combination of an ATR inhibitor and a PARP inhibitor and is able to show at least preclinically, that that combination is much more powerful and effective and durable than single agent PARP inhibitor. And she continues to develop those new studies.

Of course, Penn Medicine is the home of the immune-revolution and so immunotherapy is a big part of what we do and Dan Powell who is also in our center has developed CAR-T cell approaches and has been able to target the folate receptor as a target for CAR-T cells and opened up a trial accruing patients for that trial within the last six months as well.

And then one other area that I think is going to be a hot area. It’s kind of really just emerging now. But it’s a handful of observations in the literature across different tumor types suggest that tumors are innervated in ways that normal tissues are innervated, and this is something that hasn’t been appreciated much but what we know clinically is that tumors that are more highly innervated are more aggressive. And what we are learning in the lab is that if you can block innervation, you can actually have a tremendous impact on tumor growth and our response to therapy. So, I think this is going to be another interesting area where two fields kind of overlap, nervous system and tumor cancer biology. That’s going to be an interesting thing to see how it evolves in the next few years.

Host: Do you have any final thoughts, what you would like listeners to take away from this segment about the latest advances in ovarian cancer treatment research?

Dr. Drapkin: I think it’s an incredibly exciting time. I wish we had more people working in the labs. Obviously, we are always cognizant of the need to bring in resources to do all this work so, we work very hard to bring in funding, but I think it’s a very exciting time for our patients, a very exciting time for cancer research. I’m excited to be here at Penn Medicine and look forward to making real progress in the next few years.

Host: What great information. Dr. Drapkin, what an interesting topic. Thank you so much for coming on and sharing your incredible expertise with us today. That wraps up this episode from the experts at Penn Medicine. To learn more about Dr. Ronny Drapkin’s research or to refer a patient, please visit Penn Medicine’s Ovarian Cancer Translational Center of Excellence at www.pennmedicine.org. Until next time, I’m Melanie Cole.