Advancing Ovarian Cancer Treatment with CD55

Ofer Reizes, PhD and Roberto Vargas, MD

The Cancer Advances podcast is joined by Ofer Reizes, PhD, the Laura J. Fogarty Endowed Chair for Uterine Cancer Research, and Roberto Vargas, MD, Gynecologic Oncologist and Program Director for the Gynecologic Oncology Fellowship to discuss their research on targeting CD55 to combat chemoresistance in ovarian cancer patients. Listen as they give insights into the mechanisms behind chemoresistance, the challenges it presents in treatment, and the potential for innovative therapies to transform patient outcomes.

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-Director of the Cleveland Clinic Sarcoma Program. Today I’m very happy to be joined by Dr. Ofer Reizes, the Laura J. Fogarty Endowed Chair for Uterine Cancer Research, and Dr. Roberto Vargas, a Gynecologic Oncologist and Program Director for the Gynecologic Oncology Fellowship.

They have both been a guest here for previous podcasts and those episodes are still available for you to listen to. They’re here today to talk to us about targeting CD55 as an approach to combat chemoresistance in patients with ovarian cancer. So welcome back, Ofer. Welcome back, Roberto.

Ofer Reizes, PhD: Thank you. Thank you for having me.

Roberto Vargas, MD: Good morning, Dale. Thank you for inviting us.

Dale Shepard, MD, PhD: Excellent. Well, you’ve been here before. Give us a little reminder, what do you do here at Cleveland Clinic? Ofer, we’ll start with you.

Ofer Reizes, PhD: I’m here, I’m Staff, been here for a number of years, Staff in the Research Institute in the Cardiovascular and Metabolic Sciences Department. I’m also Co-Leader of the Cancer Impact Area, and I’ve been working with Roberto and colleagues in gynecologic oncology for I would say about eight years at this point, probably half of my career here at the clinic. And our focus is how do we get our discoveries from the bench and hand it over to Roberto and colleagues.

Dale Shepard, MD, PhD: So good team science. Roberto, what do you do?

Roberto Vargas, MD: As you mentioned, Dale, I’m a gyn oncologist, so I straddle the surgery and the chemotherapy side of our gyn malignancies.

But then in the research realm, I’m considered an early career clinician, scientist, where I mostly focus on this translational realm where I can help get discoveries and concepts that people like Ofer have developed, and get them to a position where then hopefully we can get them to the bedside, to the clinical space. And that’s really an area that I enjoy. It’s really my passion, because I think that’s how we’re going to be able to truly evolve our cancer care this coming decade.

Dale Shepard, MD, PhD: Well, we are going to talk about ovarian cancer. We’re going to talk about chemoresistance. Lot of different people might be listening in, maybe a little more or less familiar with the topic. One thing with ovarian cancer or chemotherapy we hear about sometimes is chemoresistance, we’re going to talk about it. We also hear about refractory disease. So maybe just high level, chemoresistant versus chemorefractory.

Roberto Vargas, MD: Yeah. So in our cancers, I would consider resistant and refractory to be similar, in that a refractory tumor is resistant to the chemotherapy. But refractory for us, the term itself, is someone who, while they’re on their first attempt at the chemo, their cancer has no response to the therapy. As opposed to a resistant cancer, which may have initially the first, second, third time have responded to the chemotherapy, but the cancer subsequently develops resistance.

So you can almost think about a refractory cancer maybe as a cancer that comes with resistance already built in, it’s already there, versus the resistance is something that develops generally over time. That’s the most common scenario that we see it as an evolution of the tumor after repeated treatments.

Dale Shepard, MD, PhD: Excellent. Roberto, let’s stick with you for a second. How many people do you see in-clinic? How common is this problem? So people that develop this resistance, is this something that’s common and a big problem in ovarian cancer or is it a small subset? What’s the scope of the problem here?

Roberto Vargas, MD: It’s the most significant problem in ovarian cancer, in that while when we talk about chemo resistance, the biggest, most important point is resistance to our platinum agents because they are our best, most active agents. That’s the carboplatin that most people get.

And once we treat patients one, two, three times with a platinum-based regimen, they then develop resistance to it. And that changes the entire ballgame because the agents that exist after a platinum have very low response rates traditionally. So it’s the biggest contributor to the bad outcomes in ovarian cancer. So we generally are happy when we can keep someone in their platinum-sensitive type of clinical picture.

Dale Shepard, MD, PhD: Ofer, let’s switch gears and talk specifically about chemoresistance and how we might think about addressing that. We’re going to talk about something called CD55. Give us a little bit of an idea. I mean, we oftentimes don’t get to talk to people who are in the trenches sorting these things out. I mean, there’s millions of proteins and genes in the body, how do you come up with something that you think might be that target?

Ofer Reizes, PhD: In terms of how we come up with our targets, how we prioritize, because as you pointed out, there are hundreds of potential targets that we could be looking at. In this case, we were looking at something that was found at the cell surface, and that was our initiation into this protein that we now recognize is much more complex. But we had been looking at cells that are chemoresistant versus sensitive.

We also were looking at it from the concept of cancer stemness, and I can clarify that in a minute. But the interest was can we find, can we identify proteins that would potentially be markers of chemoresistance. And on top of it, can we find markers of cancer stemness. And those are cells that have been linked, implicated, in tumor recurrence. And this is not just ovarian, it’s across the gamut of gynecologic cancers. And many solid, and even liquid tumors, we know that there are stem cells that pretty much sit at the top of the hierarchy of reestablishing cancers.

In this case, when you treat them with cisplatin, you actually induce the stemness, you induce the chemoresistance. And as it turns out, CD55 is a protein that goes up. So we get more of it after we treat cells with these agents.

Dale Shepard, MD, PhD: Give us a little idea. It’s on the cell surface, mechanistically what’s happening?

Ofer Reizes, PhD: We thought we knew everything.

Dale Shepard, MD, PhD: But that’s an avenue for more research, right?

Ofer Reizes, PhD: Absolutely. We thought we understood it. And as I started, it is known to be a cell surface protein. It is known to be throughout our body in other cells. It’s not just on cancer cells. But what’s interesting about this protein is that we found that it somehow interacts with proteins on the inside of the cells and activates their program of chemoresistance.

Now, as part of our discovery efforts, as we were looking at this protein more closely, we realized in fact it’s not just at the cell surface, but in the chemoresistant cells, it’s in the nucleus of these cells. It somehow traffics from the membrane, the outside of the cell, into the nucleus, and then interacts with a set of proteins that drive chemoresistance.

So the mechanisms were wholly unexpected. It was totally serendipity. And in this case, it opens up a whole new area of research as well as approaches to disrupt development of cancer and development of chemoresistance.

Dale Shepard, MD, PhD: And so when we think about this clinically, what would be the implications of being able to target this?

Roberto Vargas, MD: I think why I’m so excited about this effort and collaboration is that there are multiple different clinical applications that immediately come to mind. And specifically addressing the refractory concept that you brought into the discussion at the beginning, right now we have no way of knowing what patients are going to be refractory. And as I mentioned, you can think about these tumors at ones that already have the resistance built in. They’re not going to respond to therapy. So it’d be fantastic if we could develop a way that I could know before I give a patient chemotherapy that it’s unlikely to work and then move on to a different approach.

To follow that point, it would be fantastic if we could track that slow development of resistance over time and we could tell, “Okay, we are starting to approach platinum resistance. Can we pivot therapies instead of giving you more platinum when we already know that your tumor’s now developed an ability to ignore it?”

And lastly then is the potential to intervene. I think part of the interesting details between that nuclear trafficking is that Ofer has started to be able to tease apart how that’s happening, what’s driving it, and found unique angles that if we can see it happening, can we intervene to prevent it from happening. And I think that’s that third really exciting area that not only can I use it as a marker, but we can use it as a potential therapeutic intervention or an angle, and open a whole nother realm of biologic targeting.

Dale Shepard, MD, PhD: Perhaps not have people develop that resistance, so not actually … You have somebody that comes in and they’re already resistant, you can fix that, but maybe they don’t become resistant in the first place.

Roberto Vargas, MD: And I think in ovarian cancer, if we’re able to avoid the development of platinum resistance, we will change the survival of ovarian cancer drastically.

Dale Shepard, MD, PhD: As we have started to look into this, does this look druggable? I mean, does it look like that there’s going to be some part of that pathway that we can find something that differentiates tumor cells from normal cells?

Ofer Reizes, PhD: Yes. I’ll start by saying yes, but I want-

Dale Shepard, MD, PhD: You’re going to elaborate.

Ofer Reizes, PhD: I’m going to elaborate, but I also want to complement a collaboration that we’ve kicked off, Roberto and I have kicked off on endometrial cancers, and particularly the evolution of resistance in those cancers. So what’s exciting to me is that we’re not just looking at ovarian, we’re looking at, A, other gynecologic cancers as well, but we’re looking at their evolution in an area that really Roberto is pioneering, in my opinion.

And so back to the other piece of the question, do we have a hook, which is basically what you’re getting at, is there a hook using knowledge about CD55 movement into the nucleus as a therapeutic. And that’s work that we’re actually doing with Cleveland Clinic Innovations is developing strategies. We know exactly the region that CD55 uses to get itself into the nucleus. I say that in terms of a teleological, that it actually traffics there because of a specific part of the protein. And we know that if we disrupt that part of the protein, it will not go to the nucleus. It will not develop chemoresistance. It does not promote cancer stem cells.

And so right now in collaboration as I said with Innovations, we are designing both therapeutic strategies, as well as nanobody, antibody approaches to block that region of the protein and disturb and disrupt its ability to get to the nucleus.

Dale Shepard, MD, PhD: That’s great. I guess just from, again, looking behind the curtain, is there anything exciting in terms of new technologies, different approaches, that will enable us to more easily find some of these targets? I mean, there’s all these sort of omics and all these different ways to do single-cell analysis of things. Is there anything that looks bright in the future that’s going to say, “Well, this is going to help us find those additional targets.”

Roberto Vargas, MD: From my perspective, I think the innovation is going to come when we take all those newer technologies, the single-cell sequencing, but we put them in almost like a real time. A lot of the work that we do in the research realm, but also clinically, is more reactive. We wait for an event to happen and we react to it, or we remove a tumor sample and then we look at what’s happening there. And I think that if we can follow tumors real-time and see how they’re changing and track certain features, and that could be using cell-free DNA, using a simple blood sample and seeing what signals we detect there, and at the tumor level as well. I think that that’s when we’re going to be able to start chipping away at staying ahead of the cancer and not really being reactive.

And I think leveraging then the next tier of technologies, which is really the computing power, things like the IBM Quantum computing core that the clinic has in collaboration with IBM and machine learning AI models, that’s really going to give us the power to analyze and crunch all these terabytes of data that we generate and be able to achieve or arrive at a useful, meaningful conclusion.

Because that’s the other piece. We have all these tools and all this data, but until this point it’s been really hard to put it all together in a logical manner. And I think that that’s where this next decade is going to be very, very interesting in all of cancer care, but definitely in the gyn space with people like Ofer driving the innovation.

Dale Shepard, MD, PhD: And, Ofer, you’d mentioned something about modeling changes in cells and you mentioned measuring things over time. I don’t know, do you care to mention anything about the modeling sorts of things that you’re doing to understand resistance?

Roberto Vargas, MD: Yeah, absolutely. Part of breaking up that single-cell component is that now we have ways that we can actually almost tag individual cells in a cancer model. And when we can follow individual cells through time, we can start to learn, well, what are the features of those true stem cells that were there at the beginning and were the only ones that remained at the end once we arrived at resistance. Or what are the features that those stem cells or other cells developed to be able to skirt away from the resistance.

And those technologies are the next level of single cell where it’s not just sequencing, but actually tagging them and sequencing and following them. And we can do that in vitro, and we’ve started doing that now in vivo and animal models, and those concepts really are what are going to get us then to the bedside.

Dale Shepard, MD, PhD: Excellent. Ofer, from a basic science, and this is a great discussion because it’s team science, basic science, clinical science, but more from the basic side, next steps with CD55. And then is there anything else that you or you see others doing that looks particularly interesting that we should be keeping our eye on?

Ofer Reizes, PhD: I don’t think we have enough time for all of that. Yeah, so I’ll start with the immediate, the CD55 piece. Obviously we’re developing therapeutics, we’re looking to find ways to block it. And we’re also looking to find ways of the whole machinery of getting it into the nucleus. And once it’s in the nucleus, what are all the components that it interacts with. And that will give us an opening for additional types of therapeutic strategies to block this interaction. We know that once it gets to the nucleus, all the negative side effects of it getting to the nucleus. So that to some extent is the current effort.

The additional collaborative, Roberto pointed out the models that he’s developed, and we are eager to get more of his models to really ask the question, where does CD55 fit in that equation? The other part, which Roberto also, you alluded to, has to do with the, is it a biomarker. And we’re working very closely to understand whether if the patient comes in and you do the analysis of the tumor itself, the histology of the tumor, if there’s nuclear CD55, does that mean that it’s going to be refractory? Or at what point during the development, during the treatment, does it become chemoresistant? So that to me is an exciting piece of it.

The other is the big data. The AI that is developing in terms of trying to look at, for example, in the case of our protein or other proteins, and look at what’s called the proteogenomics. Once you start modifying and understanding the biology, then can you do a genomic analysis of the protein and its interactome in terms of the genomics of that process. And I think there’s opportunities there in terms of elucidating multiple pathways that we can then drive and block cancer progression.

Dale Shepard, MD, PhD: Can we quickly cover, while we have your expertise here, what are you most interested in from a clinical side in terms of what’s coming up? What’s going to be the next kind of therapeutic break do you see from a clinical side? Any particular pathways that there’s maybe upcoming therapies that you’re looking for approvals and hoping to have available?

Roberto Vargas, MD: Yeah. I mean, there’s been a big push at using a new class of drugs that uses targets on the cell surface, the antibody drug conjugate family of drugs. And uses those targets as a homing beacon and almost like as a dock or a garage. And then once the molecule is at that target, then it injects, introduces, an actual chemotherapy agent into the cancer cell and hopefully leads to cancer cell death.

And that class of drugs has started changing the landscape of almost like a post-platinum era when we now have lost our most active agent. But even within that, I think we’re starting to see resistance to the chemo drug that’s injected into the cancer cell. And again, layering on these concepts of tracking resistance and intracellular trafficking, because those drugs bypass that traffic and they just put it right in the cell, are going to be very useful so that, again, we can be proactive with our approaches and our drugs and not give them and then just wait to see if they work or not.

I think that that’s where a lot of the field is headed. There’s obviously a lot of work in the immuno-oncology realm with immunotherapies, PD-1, PD-L1 inhibitors, and that’s a whole nother aspect. But traditionally, ovarian cancer has not been a disease site that immunotherapy really has been active, so we really shouldn’t walk away from the tried and true efficacious therapies just yet, in my opinion.

Dale Shepard, MD, PhD: Very good. Well, Roberto, Ofer, you’ve given us some great insights into some novel mechanisms for chemoresistance, a little bit of a look into the future of what treatment might look like, and appreciate your insights.

Ofer Reizes, PhD: Thank you for the opportunity. It’s always a pleasure speaking with you, Dale, and highlighting our collaboration. And it can’t be done without a team. And both from the clinical side, the basic research side, translational, it’s a large group. And the opportunity here is fantastic here, here meaning the Cleveland Clinic.

Roberto Vargas, MD: And with leaders in that early phase trial realm such as yourself, that’s the next level of all this. That Ofer has a concept, it gets moved into this translational space, and we develop preliminary data. Then it allows us to come to you and be like, “Can we develop this early phase trial to pilot this?” So I think we have it from beginning to end, even at this podcast table, so we’re excited to see it to fruition.

Dale Shepard, MD, PhD: I’ll be keeping my eye out.

Ofer Reizes, PhD: Definitely.

Roberto Vargas, MD: Now we have a documented commitment-

Dale Shepard, MD, PhD: Yeah, exactly.

Roberto Vargas, MD: … from Dr. Shepard for the phase I. Perfect.

Dale Shepard, MD, PhD: Thanks guys.

Ofer Reizes, PhD: Thank you.

Roberto Vargas, MD: Thank you.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

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