Peptide Therapy Innovations for Triple Negative Breast Cancer

The Cancer Advances podcast is joined by Ofer Reizes, PhD, the Laura J. Fogarty Endowed Chair for Uterine Cancer Research, and Justin Lathia, PhD, Melvin H. Burkhardt Endowed Chair for Neuro-Oncology Research, Scientific Director of the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, and the Vice Chair of the Department of Cardiovascular and Metabolic Sciences at Cleveland Clinic's Lerner Research Institute to discuss their research on peptide therapy as a targeted treatment for triple negative breast cancer. Listen as they explain their collaborative efforts to develop therapeutic peptides that disrupt cancer stem cell programs, the process of their work, and the potential for expanding peptide therapy to other cancer types.

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 very happy to be joined by Dr. Ofer Reizes, the Laura J. Fogarty Endowed chair for Uterine Cancer Research and Dr. Justin Lathia, the Melvin H. Burkhart Endowed chair for Neuro-Oncology Research, Scientific Director of the Rosa Ella Burkhardt Brain Tumor and Neuro-Oncology Center, and Vice Chair of the Department of Cardiovascular and Metabolic Science at Cleveland Clinic's Lerner Research Institute. Justin was previously a guest on this podcast to discuss mitochondria transfer for glioblastoma, and that episode is still available for you to listen to. Today we're here to discuss peptide therapy as a targeted therapy to treating triple negative breast cancer. So welcome.

Justin Lathia, PhD: Great to be here.

Dale Shepard, MD, PhD: So just to sort of give a little background, let's welcome back Justin. Tell us a little bit about what you do here.

Justin Lathia, PhD: Yeah, so I run a basic science research lab that is very focused on clinical translation and I think one of the things we're excited about here at the Cleveland Clinic is we have an unprecedented opportunity to work side by side with clinical colleagues. So we actually get a lot of clinical samples to generate hypotheses. We get into the lab and test in detail what's going on. And then our home run is really to spin out an early phase clinical trial based on what we've learned in the lab. So my original training is in engineering and I always joke that you don't go to engineering school for fun. You actually go to learn how to build stuff. And I guess in our day and age, I mean this is truly in some ways biomedical engineering. So I know that was a long-winded answer, but that's basically what we do.

Dale Shepard, MD, PhD:

It's all good. All right. Ofer what do you do here?

Ofer Reizes, PhD: So I am staff here at the Cleveland Clinic, also a basic scientist with interest in translation. As you can tell from my endowed title, I work on uterine and ovarian cancers, but I have for years also been working on triple negative breast cancer. And always the interest is how do we develop therapeutics? How do we help our patients?

Dale Shepard, MD, PhD: And so I guess before we dive into this peptide therapy and all, I mean I think this is a really cool thing about the clinic. Right. So based on what you do, mostly gynecologic oncology sorts of things, although you've had triple negative thing, neuro-oncology types of things in terms of a lot of your research yet we're here together talking about breast cancer and new therapies.

Justin Lathia, PhD: Yeah. So I mean this has been a collaboration that I think we've had since I started the group in 2012. Ofer got here a couple years before me. And what's interesting is both of us have been excited about this concept of stem cell programs in cancer. And that's been shown in a variety of advanced cancers, is that you have these cells that have re-emerged in terms of developmental programs. And that has been demonstrated by our groups and others for let's just say a good 15 plus years to be one of the reasons that cancer grows so aggressively, but also resists therapies. And we've just had a focus on trying to understand the machinery that underlies how these cells behave.

Ofer Reizes, PhD: I couldn't have said it better. I agree. The two of us have been collaborating for umpteen years, at least 12, maybe longer, and have successfully looked at programs that are cancer stem cell and designed to identify these therapeutics or ways to disrupt that program.

Dale Shepard, MD, PhD: So the good news is it's been a dozen years and you still like working together.

Justin Lathia, PhD: Absolutely.

Dale Shepard, MD, PhD: So just give us a little bit of an overview, not necessarily deep clinically because this isn't your area clinically, but why triple negative breast cancer? Why is this the topic you guys are trying to look at for this particular therapy?

Ofer Reizes, PhD: I'll take lead on this one. I had been working on triple negative breast cancer for a number of years, looking at it from the angle of obesity, trying to understand why obesity drives triple negatives to become more aggressive. And one of the projects that ended up developing our collaboration was the fact that we identified adipocyte derived hormones that drive the breast cancers, particularly triple negative and turn them more cancer stem like. And that I think is where our collaboration kicked off. Having entered that field and yanking Justin into it, we're looking at new targets, new approaches to disrupt it. And that's where the project that we're talking about today. We recognize that the reason we're interested in triple negative is by virtue of its name, there are no targeted therapies for that cancer subtype.

Justin Lathia, PhD: And I'll kind of take it from there and just kind of talk about the basis of the project initially. Our lab's been interested in what we call the languages and dialects of communication. I probably use those exact words when we talked about mitochondrial transfer.

Dale Shepard, MD, PhD: You did.

Justin Lathia, PhD: Oh good. Okay. So I'm consistent. But one of the things that we've been interested in is these cells are part of an interconnected network and our lab has been interested in the channels that the cells use to talk to one another. And in malignant brain tumors for example, we showed that those channels are absolutely essential. If you block them, you actually slow tumor growth in preclinical models. But triple negative breast cancer for some reason was completely different. Those channels actually were there, but they didn't get to the cell surface.

So what happens is, is if you look at the expression of those channels, you can see them clear as day, but they're not where they should be. And what we actually found was that these channels were in what we call the cytoplasm of the cell. They're not at the cell surface, they're inside the cell and they're binding to two other proteins. One of those proteins is absolutely essential for a cell to make extra copies of itself or self-renew. And that protein is absolutely elevated. It's almost a hallmark of the stem cell program. So we have this channel where it shouldn't be attaching to a really important stem cell factor. And I think that was the initial paper we had published to just describe to the field, hey, there's something weird going on.

Dale Shepard, MD, PhD: And I guess just when we think about that initial finding, the initial paper that you guys put out that talked about this, research is hard and it takes a lot of time and just give us a little bit of an idea. How long ago was that?

Ofer Reizes, PhD: Five years.

Dale Shepard, MD, PhD: Yeah.

Justin Lathia, PhD: So these aren't things that you just go in the lab and go, poof.

Ofer Reizes, PhD: That was five years ago that we published that original paper. And then the intervening years was developing these therapeutic peptide approach.

Justin Lathia, PhD: Yeah. And also to be clear, that initial observation took quite a long time to publish as well. That may have been another five years just to get that paper out because we were actually going against conventional wisdom in a lot of ways. And the peer review process said, okay, well you saw this, now you have to really demonstrate that this is actually the case. We had to do a bunch of different models. We had to do experiments in about four different ways.

Ofer Reizes, PhD: And to show in patients.

Justin Lathia, PhD: Yeah. Actually, and that comes back to the Cleveland Clinic and why this place is so special, is that we were asked by a reviewer, "You guys have done all of this in a tissue culture dish. You've done things in preclinical models. Does this actually happen in patients?" And we were able to collaborate with breast pathology to actually get patient tissue and say, "Hey, this mislocalization, we can see it right here in patients," which is, I think it really lays the groundwork for the next phase of the project, which is why I think you asked us to come today.

Dale Shepard, MD, PhD: Tell us a little bit about this concept of a peptide therapy that can be used to modify these processes.

Ofer Reizes, PhD: So the idea behind it was this complex that forms, there's no obvious way to drug it conventionally. You can't make a small molecule. I have background and Justin does too, in molecular pharmacology that you know what a drug-like molecule should look like and you know the pockets. There was no pocket to play with. And so we had to think through a completely different approach to it, a completely different strategy. And what we came up with was the idea that maybe we designed peptides and to the protein itself that mimic or that act as a decoy for that interaction and can we block that interaction? So that was the beginning of that project and as we discussed. So it was a long process to get molecules, peptides that could interact with the other players of this complex, disrupt those players, and then show that in an in vivo situation you can actually disrupt cancer growth.

Justin Lathia, PhD: I mean, I really don't have much to add. I mean, I think that was the strategy, is that you have this unique biological finding and conventional drug development tells you under no circumstance can you actually make a drug in this way. So we said, okay, but there is actually a lot of peptide therapies out there. And the one thing I would add is it allowed us to get really creative. Right. We thought about the different amino acid sequences, so the different sequences that we would need, but the one thing we did was we actually fused it to a sequence that actually allowed entry into the cell. I think it's awesome exercise in drug development. I mean, the obvious question is what are you guys doing next?

We do have a patent on it. I think we have had conversations with innovations. We do now have necessary data to think, okay, do we partner with someone larger? Can we use the sequence that we have shown to be effective for additional drug development? I want to be very clear, it's early days for us here. We're not going to be able to start a clinical trial in a year, but I think it's a real opportunity to understand the intricacies of the biology involved. And then now that we have at least a starting point, I think we're right for collaboration to expand it out.

Dale Shepard, MD, PhD: So I guess just to clarify a couple of things. You mentioned something about a peptide is a decoy. So how are we using this peptide to disrupt, like what exactly is the mechanism in play here? Because there are a lot of people listening that might not necessarily wrap their head around what, you give a peptide and what really happens.

Ofer Reizes, PhD: So the concept here is that the peptide is made to be equivalent to the original protein. So in this case, we use the connexin protein that Justin described. We use different parts of it to develop these small peptides and show that it interacts with that self-renewal protein with [inaudible 00:12:46] ability to bind to it. So now that you've got this molecule, this peptide that can interact with it, then the idea is that it cannot interact with the endogenous protein. And so your decoy is the concept that instead of binding to the connexin protein, nanog now binds to this peptide. And when it does, it no longer is able to activate the same self-renewal programs that it's able to do in the presence of connexin there.

Dale Shepard, MD, PhD: So essentially sort of sucking up that complex so it can't work,-

Ofer Reizes, PhD: Right. Right. Right.

Dale Shepard, MD, PhD: The way it's supposed to.

Ofer Reizes, PhD: Absolutely.

Dale Shepard, MD, PhD: You talk about clinical trials. You've had some success in animal models, you've had some success in various studies. Tell us a little bit about what you found in the study so far that might suggest in like an animal model, this works.

Justin Lathia, PhD: I mean a couple things, right? We've done all the biochemistry and the biophysics to really understand the dynamics of the binding. We've been able to put the peptide into tumor cells and show that they don't grow as well to show that the genes that are activated for the cell to do what it needs to do are actually silenced. And then in animal models we can put it into tumor-bearing animals and actually shrink the tumors. So I think we're at a good spot there. At least when you think about proof of principle, proof of concept, I think we're definitely there.

Dale Shepard, MD, PhD: You were able to find a protein that's not necessarily important for most other tissues. So that's the key.

Justin Lathia, PhD: Oh, sorry. Yeah, I think we should have been more clear there early on is that is a lot of these stem cell factors aren't present in adult tissues. So when you think about targeting something, you're targeting something that's more cancer unique, which our hope is that will result in less adverse or limited side effects.

Dale Shepard, MD, PhD: Which makes good sense. More specific, less side effects. Is this a concept that you think, I mean certainly most tumors, if they become metastatic, you just can't give enough chemo, you can't give enough targeted therapy, enough immunotherapy, doesn't matter what it is. This whole stemness drives a lot of growth. If we find the right protein complexes, do you think those exist in other tumors that we can do similar? Is this kind of a proof of principle for triple negative breast, but ultimately other tumors as well?

Ofer Reizes, PhD: This complex uniquely in triple negative, we haven't looked exhaustively at other cancers. So potentially the answer is maybe in another solid tumors you'd see it. We looked for it in ovarian cancer, we did not see the same complex. And so the thinking behind that is perhaps there are other complexes that are unique to the different solid tumors. And again, that may also require a peptide therapeutic type strategy to really knock and disrupt those types of interactions.

Justin Lathia, PhD: But to expand on what Ofer said is that once you have this idea of what's in the complex, what the complex looks like, a similar strategy using peptides could be leveraged quite easily actually.

Dale Shepard, MD, PhD: And then I guess just again, for people who might not be aware of kind of peptide therapies and things, how are these typically administered?

Justin Lathia, PhD: That's what we're working on now, right, is you get to a point in drug development where it all comes down to delivery, delivery, delivery. And the short answer is we're still thinking about the best way. Whether we put that in a small particle, whether we put it in a gel that can be sort of placed locally. I think at this point that's where we're at.

Dale Shepard, MD, PhD: Yeah. And I guess that was my next question is kind of where we're at. I mean, first you have to find something to target, find something to impact that. It seems like there's a wide gap between where you go. You mentioned working with innovations for instance.

Ofer Reizes, PhD: Yeah.

Dale Shepard, MD, PhD: What's the next barrier?

Ofer Reizes, PhD: The next barrier, it's to make peptides that are stable in plasma. Because wherever we're going to introduce it, it has to be stable long enough. And so that's actually, it's a leading question, but we are working with innovations and they have funded some of the next phase of the development process in order to understand is it possible to actually convert this into something that will go into the clinic one day? And I think one of the things we've already identified is the peptides are not as stable as we'd like them to be. And so some of the funding that we've received subsequent is to look at that next step. How do you make a peptide stable?

Dale Shepard, MD, PhD: Interesting. So great strides, really interesting way to treat these things and it's just that push to make it something clinically useful. But it sounds like you guys are well underway.

Justin Lathia, PhD: Yeah, absolutely.

Dale Shepard, MD, PhD: So if you think about this whole concept of stemness and triple negative breast and things, do you think there's other complexes within triple negative that might need to be addressed as well? Or do we think, I mean, redundancy seems to be the bane of our existence when it comes to treatment. Do we think that if we treat this particular complex, this is going to be the answer? Are we looking for other targets as well?

Justin Lathia, PhD: I mean, we're constantly looking for other targets. There's another aspect of cancer that we don't think enough about, and that's this idea of evolution. Right. So everything we're doing, we're putting a pressure on the cancer cell to change, to adapt, to evolve. So it's something we've thought about, is that can we be intelligent about our peptide and the complex and ask? There's probably going to be a subset of cells that don't respond. Well, what state are they moving into? And that may help us think about potential resistance mechanisms.

Dale Shepard, MD, PhD: Well, fascinating work. It's an important problem to solve and seems like it has some important implications for other tumors as well. So appreciate your insights.

Justin Lathia, PhD: Yeah, thanks for having us, Dale.

Ofer Reizes, PhD: Yeah.

Dale Shepard, MD, PhD: Absolutely.

Ofer Reizes, PhD: Thank you.

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