The Evolution of Pancreatic Cancer Science: A Look Ahead

Hello, and welcome to Memorial Sloan Kettering Cancer Center. Thank you for joining us. Today, we have CancerSmart: The Evolution of Pancreatic Cancer Science, A Look Ahead. I'm Bill Piersol part of the team here at Memorial Sloan Kettering. If you're joining us, you probably already know, pancreatic cancer is a tough diagnosis. Today, we're going to learn what advances are being made in understanding the disease in the lab and what sort of the directions of therapy are that pancreatic cancer patients and their loved ones should know about.

I'm joined by two of the experts here at Memorial Sloan Kettering. These are folks who know just about all there is to know about pancreatic cancer. This is Dr. Christine Iacobuzio-Donahue. Yes? Got it right?

Yes.

Excellent. And Dr. Eileen O'Reilly. This is your lab that we're in right now, and you're in charge of research here. You are a medical oncologist, as well as also being the Associate Director of Clinical Trials here Memorial Sloan Kettering. And together, they know a lot about this.

Dr. O'Reilly, I'm going to start with you. We all know that pancreatic cancer is a difficult diagnosis. We also know that it's oftentimes caught late. Why is that, and what does that mean for treatment?

Yes. So the late presentation is some of the unique challenge of pancreas cancer that for a lot of individuals there aren't any early warning signs, that the symptoms that they have are sort of nonspecific. For example, some abdominal discomfort, they may have a nag in the back that's investigated for other possible causes, and not thinking that this could be a more serious underlying diagnosis. I think one of the other things we understand about this disease, it has a propensity to spread early. So metastases involving the liver, the inner lining of the abdominal cavity, lymph nodes, and the lung.

So those considerations, along with the fact that there isn't, at least as of now, for the average individual, a routine screening program focused on early detection. Although, I will say that's a big area of research, in terms of trying to identify who might be at risk of developing this cancer.

Dr. Iacobuzio-Donahue, both of you are members of the David M. Rubenstein Pancreatic Cancer Center here.

That's right.

Tell us what you see, in broad terms, as being the direction of research. Where's is it going now, and what do you see happening?

Sure. So there are many exciting things going on. So I can only probably narrow down on two that I think are most exciting right now.

Sure.

One is that there are new ways to grow pancreatic cancer cells from a patient. And this is very important, because it allows us to manipulate the tumor, to treat it with drugs, to look at which tumors are sensitive, which tumors are resistant, and to make personalized models for each patient to understand their tumor and how best to treat them. That's something that we're employing in the center that's very exciting.

The second is it's increasingly recognized here, and at other institutions, that pancreas cancer is not just one disease. But it actually has a number of appearances. And those appearances have different behaviors.

So right now, we're trying to understand how best to recognize those different types, what are the best biomarkers, something that you can look at in the tissue. When patients have those different subtypes, what's the best treatment for them? So there's a lot of interest, both in the lab and the clinic, in understanding that. That's probably one of the most exciting areas, I think, right now.

Dr. O'Reilly, you do a lot with clinical trials. Tell us what's going on with clinical trials right now.

Yes. So clinical trials are a really important area in the field of treating pancreas cancer. And we encourage individuals to think about participation in a clinical trial, because we learn from everybody. And I would echo what Dr. Iacobuzio-Donahue said, that a big theme, in terms of clinical research, is trying to personalize the treatment for a given individual and their unique characteristics of their tumor. We're not there yet for a lot of people, but for some settings we are.

I think the other areas to acknowledge is there is a lot of focus on this disease, there's a lot of advocacy now. We're changing the way clinical trials are being done. There's new models of clinical trials. So looking at multiple things in parallel, consortia focused on pancreas cancer, and focused on certain aspects of treating pancreas cancer. And I think this all creates a synergy between the clinical trial research community, between our colleagues who are at the bench, between the FDA, between advocacy organizations, between industry, and academia. And there's a lot of brainpower, there's a lot of resources, right, that we hope will lead to some real changes for individuals and families affected by this disease.

That synthesis, or sort of that support between the bench, between science and the clinic, that's your wheelhouse.

Absolutely.

Tell us about it, and give us a little demonstration.

Sure, absolutely. Not only do the clinical and research side work together hand in hand and interact frequently, but we also have an example that I like to show everybody of what we call an organoid model. And this is one of the systems that I was referring to when I say we have a new way of growing pancreatic cancers.

So this is one of our very talented staff scientists, Nick Lecomte, who is responsible for making our organoid models. And what an organoid model is, is that it's a way to make the tumor cells grow at the expense of all the other cells that are in a sample. For example, a pancreatic cancer is not just the pancreatic cancer cells, but it has a lot of tissues like scar tissue and inflammation. And if you take a sample and try to study it, it's hard to understand and see what's going on in the tumor, because all the normal cells contaminate that signal.

But with the organoids, you can make the tumor cells grow. You can remove the stromal cells that are contaminating and get a very pure culture. And then you're in a great position to start doing drug testing, to start doing science, to understand how the cells-- why they're malignant, why they're aggressive. But also, the stroma is very important. And we know that it plays a very important role in shaping how a pancreatic cancer behaves.

So when the organoids are grown in this gel-like media, you can control the microenvironment in a way that you can simulate the stromal cells. And you can put that back in a much more controlled way, and take a very complicated tumor and make it in a much more simple, controllable manner of studying it.

So you're literally taking a tumor cell from a patient and then regrowing a tumor.

Yes, yes.

That you can then use for experimental purposes and do things with.

Absolutely.

I want to clarify something you said, as well, to make sure that we're clear. The stromal tissue is noncancerous tissue,

Right.

that can almost form a barrier around the tumor in a way, right?

That's right.

Doesn't that make treatment of pancreatic cancer more difficult?

Yes. So it does a number of things. Is that it's thought to literally make a physical barrier, that the tumor itself is literally very hard if you were to touch it. And it does not have a lot of blood vessels, and it just makes it very hard for drugs to get into a tumor in the patients. So by making the organoids, we can remove that barrier and study how the treatments work.

But the stroma, some data has shown that it makes the tumor grow faster or more aggressively. Other studies have shown that the stroma is actually a good thing and holds the tumor back. But I think what that indicates is just how complicated the stroma is, how we don't fully understand it. There's a lot of science to be done.

And again, with organoid technology and controlling the way that you grow the cells, you can tease apart all those different aspects and understand how the system works.

Well, Nick, you've been doing this, why don't we go and see after the tumor has grown a bit. Show us show us what happens here, and give us a little description of the process by which this happens.

Sure. So I just processed some tumor and placed them into a plate. And after a few days, we can already see this organoid growing from the tumor cell that we have isolated. So this is how it looks like.

So it's grown from a single cell to this.

Yes.

And tell us what each one of those spheres are.

So each of these spheres are growing from a cell that we have isolated, and they grow like hollow spheres with the lumen, like that, in the middle. And they expand dramatically in presence of a cocktail of growth factors. And very rapidly, we can expand these cells and the cell amount that we can use to characterize the tumor from the patient.

And tell me, I mean, you could use this to test the sensitivity to drugs. Tell me what you can do with these once you have them grown.

Right. There are so many things. So first , I'll just show an example of, this is what a biopsy looks like coming from a patient. So that's a magnified view. But it's essentially the size of a very coarse hair, very small. And in many patients who are not able to have surgery, that is the only piece of tissue you would have to study.

Sure.

And for many patients, before organoid technology, you would have to take that little, teeny piece of tissue and many investigators would want to use it. It was not viable. But if you take that and you break it down to single cells, this shows this exact same organoid after three days, after a week, 10 days, and then two weeks. You can see how those spheres are expanding, and it makes a lot of material very fast.

So, suddenly, you can do many experiments in parallel. You can take the organoids and screen them, see how they grow against the treatment the patient themselves are actually receiving, and see if they respond in the same way. And there's evidence to indicate that organoids are good predictors of how a patient will respond.

So you're purifying it.

Right.

And growing it.

Right.

And you can experiment with it then.

Yes. You can experiment with it while you're doing predictive models for the patient themselves. And the experiments mean that when the patient, should their treatments start to fail, you might have data already to know what are the other treatments that the organoid is sensitive to. And that provides options to switch the patients to, again, an example of a personalized model, where you're not just giving any treatment, you're giving the treatment that the organoid is most sensitive to.

So you can literally use this to help shape a patient's therapeutic course.

Absolutely. Absolutely.

That's great.

And that is becoming the paradigm for pancreatic cancer. Many other tumor types as well, but certainly for pancreatic cancer. And patients don't necessarily feel as if they have a lot of time, a lot of options. And they want to make their decision, and have it be the right decision the first time.

And I think this will give the opportunity to have a little more comfort, to feel like I'm receiving a treatment, but my tumor is being tested against other drugs at the same time, and I have a plan B in place.

I understand you have some other insights into the kinds of tumor types that are involved in pancreatic cancer.

Yes.

And you're going to take us and show something about that.

Absolutely. So I am a pathologist by training. So what that means is I've learned how to look at tumors, and look at the patterns that they make, and give that information to clinicians that they can use to try, and, again, we always want to predict how a patient's tumor will behave to give the right treatment.

Sure.

So on the screen is an example. Is a high power view under the microscope. The slide is right here, of what a pancreatic cancer looks like. So it is these little circular structures here which actually, remember, they look like the organoids on the other screen that we're growing as little hollow spheres.

Absolutely.

So they make these circular structures here. These white spaces are fat, because this tumor happens to be growing into the fatty tissue around the pancreas. This pink material is actually the stromal cells that I referred to.

Right.

The stroma that makes that barrier.

Yeah.

That does not get into the tumor. So this is a conventional pancreatic cancer.

Classic pancreatic cancer.

Classic pancreatic cancer. One of the things we've learned recently is that pancreatic cancers do not-- there we go-- they don't look that way the entire time they're growing. So this is the exact same patient, the exact same tumor, about one inch away in the same tumor. And it looks completely different.

Utterly different, yeah.

There are no more of those little circular structures. It's very solid. Some of the cells are getting a little bit more bizarre. These are dead cells here, because it's growing rapidly. So we call this the basal-like phenotype or subtype.

Yeah.

So the thought has been that classical-like and basal-like were two different types of pancreatic cancer. We now understand basal develops out of classical. So a tumor transforms as it's growing in a patient. And that's important, because these two different growth patterns of pancreatic cancer respond differently to the same treatment. So in one person, these two different types of growth patterns, one would respond, one might not.

And while that seems very sobering, how would you get around this, I think the reality is with information comes power, that you can start thinking how to leverage this information to better design our clinical trials, to better sample patients tumors. And really, I think, it gives more hope.

Yeah.

Certainly, to me.

Right. That idea of hope is a useful one. Dr. O'Reilly, for people who are listening to this who are patients or whose loved ones are a patient, what do you see as guardedly optimistic signs in the field?

So I would echo everything that Chris has emphasized, that we're beginning to tailor treatment for an individual. And to give an example of that, we know a lot now about the genetics of pancreas cancer. And for some people, we know why the cancer develops in the first place. And that is helpful for the individual in terms of certain treatment strategies that might have a value for them, but it's also important for the family, because we might identify that family as a family who might be at higher risk for this disease. And we're focused on the potential screening opportunity there.

Yeah.

So to elaborate a little bit further, BRCA genes change. People know them because of their association with breast and ovary cancer, but we want to get it out there that pancreas cancer is also a big one.

Yeah.

And certain classes of drugs, like platinum drugs, have particular effectiveness in that setting. And newer information is PARP inhibitors. That's a class of drugs that we hope to see the first approved in pancreas cancer this year. And that's exciting, to see new drugs in the clinic for people.

Yeah. I know you've been a proponent of screening for BRCA for patients with pancreatic cancer for quite a while.

Yes, we have. And as a courtesy of the center and the interest in the genetics of this disease, we've been able to do that. We've been able to look at the genetic makeup in terms of the family bloodline, so looking for an inherited risk for a given cancer, but also to profile the tumor that Chris' lab and others help us looking for genetic changes in the tumor. And, for example, we know that a majority of pancreas cancer will have KRAS. It's a driver gene. It's involved in the development and the sustenance of the cancer. But we know there's a subset, and maybe more so even in younger people, where we won't see that gene present. But there are other targets that we find for which we have real drugs in the clinic that are being actively explored.

So that all speaks to the theme of an individual person and an individual treatment. We're not there yet. But the field is clearly moving in that direction for this cancer.

Is there a similar theme, and what do you see over the horizon in terms of research? What do you see?

Right. We used to think of pancreatic cancer as all tumors with the same. I think where the field is moving and where research expertise and skills are really being focused right now is trying to best define the molecular subsets of pancreatic cancer. Meaning, some might be best defined by a mutation in the DNA, be it a BRCA mutation. Some might be best defined by this appearance under the microscope. Others might be defined by a certain feature that we have yet to understand.

But I imagine a tumor board, where a patient is presented with their genetics, and the pathology, and our understanding from the organoids for each patient, and we'll come up with a plan. And perhaps there will be four ways that pancreatic cancer are treated based on these molecular features that we're learning about.

Right.

Rather than one treatment for everybody based on how they present. We're, as Eileen said, not there yet, but that is certainly where things are going. So it's a very fast moving time for research on pancreatic cancer. It's very exciting. I think it's very gratifying, both personally and professionally, to see the successes that are happening and for the center to be right in the middle of it, as well. So that's where things are going.

That's wonderful.

Yeah.

That's going to wrap it up for us. I want to thank Dr. Christine Iacobuzio-Donahue, as well as Dr. Eileen O'Reilly. I'm Bill Piersol for Memorial Sloan Kettering. We hope you'll join us at our next CancerSmart. Thank you.