Sarah Amend: Great, thanks so much, Andrea. So thanks again for this wonderful invitation and this great opportunity to share this thought piece with you all entitled, Defeating Lethal Cancer, Interrupting the Ecologic and Evolutionary Basis of Death from Malignancy. It's a bit of a mouthful, and today we're just going to be talking about one section of this paper, but I invite you to spend some time to actually sort of go through and read the many different sections. This is a great collaborative effort and I'm speaking today on behalf of my co-authors, including Ken Pienta as well as a prostate cancer patient, Patrick Goodin, who participated with us on this project. So just set the stage really and really what started our way of thinking about cancer as an ecologic and evolutionary process, we're going to stop for a moment and really define what cancer is, and this was published in 2023 as part of a think group of evolutionary ecologists, medical oncologists, cancer biologists, GU chemists, and mathematical oncologists.
And together we updated the definition of cancer to state that cancer is a disease of uncontrolled proliferation. This part of the definition is of course, common to cancer, prostate cancer biologists and clinicians. And really what we're changing here is that it's by transformed cells that are subject to evolution by natural selection. That last part of that definition, subject to evolution by natural selection, invites us to apply the principles of evolutionary ecology to the study of cancer. And very specifically what we do here at the Cancer Ecology Center is we think about cancer in the setting of evolutionary ecology. And evolutionary ecology itself is the study of how interaction shapes species through selection and adaptation, and then the consequences of that resulting evolutionary change. Many of us have thought about evolutionary ecology, but it was a long time ago. So this might be something that cancer biologists and clinicians thought about in high school and in college biology courses. But often we forget these really critical foundational truths about simply life on earth and in fact that hold true in the cells that make up a tumor.
If we apply an evolutionary ecology framework, what types of questions can we ask and can we ask new and different types of questions of the cancer problem to really try to solve the cancer problem for our patients and their families? So first one thing we can think about is how and when species arrive. And in this case we're thinking about species in terms of the cancers and new species in the human body and how do they evolve over time? How do those cancer cells interact with an altar and how are they altered by their ecosystem? And in this case, we're thinking about the whole ecosystem of the tumor and the critical tumor microenvironment cells and stroma that is there. Can we identify common adaptive behaviors that give rise to lethal phenotypes? Things like metastasis and therapy resistance that are common among all patients who die of their disease.
And can we start to understand how and when these cancer species go extinct versus when they go undergo evolutionary rescue giving rise to lethal cancer? And then finally, how can we take all of this into account and actually play into this eco-evolutionary game to intervene for cancer control or one day a cancer cure? So again, they're making different pieces of this story that we introduced in this manuscript and today really what I'm going to be focusing on is this idea of evolutionary rescue and therapy resistance. So we asked a somewhat straightforward question, "Why does therapy fail patients?" And if we look at it from an eco-evolutionary perspective, there are really only a handful of paths to evolutionary rescue, and we're going to walk through these one by one. But really what's important to remember with this is that selection. So what we actually see as the lethal tumor, it's acting on heritable phenotype.
So what those cells do, what they express, what types of proteins and signaling pathways are at play. And if we can understand those adaptive strategies, we can then think about shifting that selective pressure so that we can apply something that that cell is not already responding to. So let's get into it a little bit. The first eco-evolutionary path we're going to talk about is I think the one most cancer biologists think about most of the time, and it's phenotypic heterogeneity or tumor cell heterogeneity. And this is the idea that among all of the different heterogeneous population of the tumor, we know that there are many, many different clones such as this picture here on the right, where each one of these colors is a different cancer cell clone. It's this idea that already within that heterogeneous tumor there already exists a clone that happens to have a trait to confer resistance.
We see this in the natural world. Here I'm showing you examples of diverse breeds of dogs. You also see it in the wild where each of these dogs through selective breeding in this case. But again, if we look to the natural world, this sort of happens through the course of evolutionary ecology. They become specialized. So you can imagine that a rat terrier would not be very successful in the Arctic where perhaps an Alaskan husky would be, but that husky is not going to be very successful in a habitat where they have to burrow down holes to go after rats. Similarly, if we look at tumor cell heterogeneity, an example here is a cell that happens to already express high levels of a drug efflux pump that will remove the toxic therapy. So then there's limited DNA damage that's the cell that will survive and it will give rise to a resistant population.
Another path to resistance and this evolutionary rescue is this notion of evolutionary triage. And this is one of my favorite examples because it allows us to talk about Darwin's finches, which are one of the most famous examples of evolution and adaptation in the natural world. And in this case, individuals with sort of better or more adaptive phenotypic traits are selected over those with a less fit but unnecessarily absent adaptive trait. If we consider these two different Darwin's finches, you can see that their beak shape is very different. One is going to be better at breaking seeds open. That's the finch there on the right, and the other is going to be better at eating insects. And it's not that either one of them don't have a beak, of course, they do. And it's not that the one that's better at eating nuts can't eat fruit or can't eat insects is that they're selected within this particular space to be better at what they do.
Similarly in prostate cancer, we see that tumors that are treated over long periods of time with an anti-androgen therapy, those cancer cells will eventually upregulate the number of androgen receptors. And in that way, they're able to survive simply because they sort of have more of that receptor. It's not that the others are necessarily absent, but that sort of skew of expression is really changing then what the phenotype looks like. And then the picture on the right, it's simply an IHC antigen receptor, and you can see that the one on the right, which is our resistant tumor, has higher levels than the one on the left, though again, it's not absent. Our third example is one of epigenetic plasticity. And we think about this mostly I think as sort of non-evolutionary oncologists. We often think about this in terms of camouflage. In this case, we see a chameleon adjusting their skin coloration to blend in with this branch above.
In this case, the adaptive trait that's selected for is the individual's capacity to alter its phenotype in response to its environment. And I think epigenetic plasticity is really having a renaissance right now where people are beginning to appreciate that how a cell responds will really change depending on its ecosystem and depending on the selective pressures of the particular habitat that it's in. But indeed, that trait, that capacity to change depending on what it encounters is itself a heritable and selectable trait. So in this case, we're showing an example of cancer cells that down-regulate and up-regulate PD-L1 to sort of hide, if you will, from that immune system, similar to how this chameleon is hiding in plain sight by camouflaging itself against that branch. There are many other examples of course, of epigenetic plasticity. Classically, I think we often think of something like an epithelial to mesenchymal transition.
What's really important there is that capacity for that cell to move back and forth along the continuum. Our last example in this case is dormancy. And I think it's really important to note here that when we talk about dormancy in this setting, we're talking about a non-proliferative state. It's not a passive state at all. It's an incredibly metabolically active state. And in this case, the adaptive strategy that is selected for is the lack of cell division. Cancer cells are only susceptible to anti-cancer therapy if they're actually moving through cell division, which is something I don't think we appreciate enough as cancer biologists. And just like a hibernating black bear as sort of hidden from you, it's hidden from hunters, it's hidden from its other predators, and it's sort of hunkering down and staying safe. Similarly, we and as a field, we think about dormant disseminated tumor cells perhaps in the bone or and other tissues is hunkering down, being silent from the immune system as well as not being susceptible to cancer treatment at all.
So those cells would then survive and be the actuators of this evolutionary rescue. So we've walked these four different paths. What does this actually mean in terms of treating the patient? And forgive me, this table is a bit small because we don't have time to go through it one by one, but if we can really appreciate which strategy is taken by each individual tumor within each individual patient, we can then deploy different eco-evolutionary strategies to treat cancer. So for example, I'm going to take this top example here where can we prevent evolutionary rescue at all by using something called an evolutionary double block? So if we know that a cell is highly plastic, for example, can we push them towards expressing or adopting a particular adaptive phenotype that would then also provide a targetable vulnerability? This is really taken advantage of and targeted synthetic lethal approaches where PARP inhibitors will work really well in the setting of BRCA mutated tumors.
Similarly, can we manage that evolution of resistance? And in this case we're talking about that evolutionary triage. Instead of permitting those cells that can then eventually walk up that evolutionary trajectory to express high levels of the AR, can we actually use adaptive therapy and cycle it on and off? And so we never actually select for those lethal clones. There are a number of different strategies we can think about here, and something that I think is really exciting is that in this case, in the setting of evolutionary ecology, we aren't necessarily reinventing the wheel. We are taking strategies that are already in use in the clinic or are already in preclinical development, and we're taking studies that are already being done in the molecular and cell biology spaces, and we're thinking about them in new ways so that we can identify new hypotheses and intervene using different strategies.
And so with this really one of our purposes for this manuscript was to highlight the opportunity that we have as cancer researchers, medical oncologists, and state loudly and clearly this call to action for researchers to really consider these eco-evolutionary forces at play that give rise to the adaptive cancer phenotypes that you observe in the dish or in the mouse or in the patient, and including those that will eventually result in metastasis and resistance. Remember, the tumor itself is not sort of being selected to become resistant or to become metastatic. We only observe what is happening at the very end and to really drive this research forward, really encouraging true collaborative research across disciplines. And this takes a great deal of patience, takes a great deal of humility, but it's really, I think what is going to move the field forward. When we turn to our translation here and think about treatment of cancer patients, can we identify which mechanisms of resistance are at play in each individual patient?
And then if we can, we can thoughtfully tailor treatment regimens to attack different parts of these evolutionary paths. To facilitate this we're starting to see in just a handful of places so far, but I hope that it will gain traction, evolutionary tumor boards similar to the molecular tumor boards that really gained in popularity. In this case, can we take that a step further and look at evolutionary tumor boards to guide clinicians on a per patient basis so that we can look at the evolutionary trajectories of those tumors so we can start to understand new and different and exciting ways to intervene? And so with that, that's sort of the wrap up of our paper today, and I'm really excited that folks want to hear more and please read our manuscript. We look forward to hearing from you all.
Andrea Miyahira: Okay. Well, thank you so much, Dr. Amend, for sharing this with us. So what are your biggest take home messages for how researchers can apply evolutionary ecology research methods to better understand and treat cancer?
Sarah Amend: Yeah, I think in the research setting, it's appreciating that the phenotypes that we see at the end after we apply a pressure of therapy, after we apply different genetic modeling, that those are representing these different adaptive phenotypes. And that if we can understand that whole path of that evolutionary trajectory, we can think about how to shift it earlier. We can think about how to shift it differently. And I think that that's really the opportunity here as again, it's how can we come at the question and a new and different perspective, look at the data a little bit differently, think about how your experiments are designed to incorporate the breadth of this eco-evolutionary.
Andrea Miyahira: Thanks. And are there evolutionary biology approaches to treatment duration and timing to prevent or slow the evolution of more fit tumor cells?
Sarah Amend: There absolutely are. I think a really exciting effort that is underway, again, at a handful of different institutions. But the flagship is really at the Moffitt Cancer Center where they are using these evolutionary tumor boards where you have clinical trials with an N of one patient and sitting down with evolutionary ecologists and mathematical modelers as well as the clinician and the patient on board to understand the trajectory of the patient's tumor. Now, I think that that's a little bit behind, that's not something that a clinician can deploy right now, but I think it's an opportunity to look moving forward. Something that can be applied now are some of these ideas of adaptive therapy, and there are a few papers out and clinical trials that have been done that have shown that if you can track tumor growth over time, can you intervene? And that's really going to be against that adaptive or against that evolutionary triage idea.
So can we prevent that triage from happening? Can we intervene earlier? And then I think the other two places where this is really exciting that can be applied to patients is in addition to those synthetic lethality ideas that we talked about before, is also this notion of bipolar androgen therapy where essentially you are pushing the cells into one adaptive phenotype and then you're hitting them down again. And some of these ideas, I think if we can apply these evolutionary ecology strategies serve on top, but those ideas that are already going on that we can really move.
Andrea Miyahira: Okay, thanks. And are there evolutionary biology approaches to designing clinical trials?
Sarah Amend: Yeah, so in terms of designing clinical trials, I think the biggest thing right now is to sit down and partner with an evolutionary ecologist. There are several that are in the cancer space, and so they're easily findable and they're really eager to work with people. I think the second piece is to think about modeling of the space. I think we are going to need to be thoughtful about the adaptive milieu of each individual tumor, and so I think it's going to be harder, but I think by applying those hypotheses a priori and then building those clinical trials behind them is how we'll be able to gain traction.
Andrea Miyahira: And from this evolutionary biology perspective, what are the biggest questions that cancer researchers need to tackle?
Sarah Amend: Yeah, I think some of the biggest questions from the eco-evolutionary perspective are the dual impacts of metastasis and therapy resistance. I think in the cancer biology field, we really study those two things as independent processes, that cancer cells spread from the primary tumor and then cancer cells are resistant. But from an eco-evolutionary perspective, those are tightly coupled because they are both adaptive responses to stress. We know that cells that are resistant, for example, have higher invasive capacity. We know that metastases are more resistant, but even their actual cellular phenotypes are quite similar. If we drill down to what the adaptive strategy is, I think that again, there's this really beautiful opportunity. Then for whatever your scientific question is, I think we're really pinned in by what we know as molecular and cell biologists, as geneticists, myself included. If we can take a step back and think more broadly about what that adaptive phenotype could be, then you can design experiments and ask different types of questions that will lead us to new and important truths.
Andrea Miyahira: Okay. Well, thank you so much, Dr. Amend, for sharing this with us today, and I hope people go out and read the rest of the paper.
Sarah Amend: Absolutely. Thanks very much.