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Charles J. Ryan: Hello from the PCF 25th Anniversary Retreat in Carlsbad, California. I'm joined today by Dr. Ken Pienta who is a professor of medical oncology and is the Donald S. Coffey Professor of Urology and Professor of Pharmacology and Molecular Sciences at the Johns Hopkins Hospital. Welcome, Ken.

Ken Pienta: Thanks, it's a pleasure to be here.

Charles J. Ryan: You've been doing some really interesting work, over many years now, looking at tumor microenvironment, and really one of the critical aspects of what makes prostate cancer a lethal disease, which is the process of metastasis. So tell us, if you will, just the state of what we currently know and don't know about the process of metastasis that treating physicians should know.

Ken Pienta: You know, metastasis is an amazing process when you think about it. We know that, for prostate cancer or any cancer to kill you, it has to leave the primary tumor. Because if it stayed in the primary, we would cure everybody by just surgery or radiation. And in fact, as you know, 50% of all patients with cancer are cured because we get the cancer before it spreads.

Charles J. Ryan: I would say many people who undergo radical prostatectomy may actually already have some cells that have escaped their prostate. That's been shown by some I think. But those cells never develop metastasis, or the patient outlives that process. So tell us about the timing of that process. If a man is diagnosed with a metastatic prostate cancer today, how long has it been in his body would you guess?

Ken Pienta: What we guess is that it takes years to develop a clinically relevant metastasis, meaning a metastasis you can see by bone scan or CT scan that's gonna grow up to hurt. We think that, for you to see a piece of cancer, for us to see a piece of cancer that big, it has to about the size of a thumbnail, it has to be about a centimeter around in size. And we think that, if you look at that, that's a billion cancer cells. That's a lot of cancer cells.

We know that that started with one cell leaving the prostate, going through the lymph nodes or through the blood, circulating through the body, and finding, say, a bone to land in. It generally then goes through a period of what we call dormancy, where, just like we think about an invasive species, it sits there for a while learning the new environment. And as it learns it, it finally starts to double. To go from one cell to a billion cells, that's 30 doublings, it's like the rice on the chessboard game, or checkers game, where one to two to four to eight ...

If you think about the fact that, if cancer ... First of all, it's gonna sit for a while, we don't know how long. But then if you think, "Well, it's gonna double every three months." To go from one to a billion every three months, well, that takes about eight years.

So, for a cancer cell that may have escaped the prostate at some point, and let's look at high-risk prostate cancer, guys with Gleason 8, 9, 10, about 30% of them are gonna have a recurrence. That recurrence either happens locally, right where the prostate was, there was a cell leftover, or distantly. That means that that cancer cell escaped sometime many years ago most likely. It's been sitting dormant, and then grows up, we're talking a decade or more.

Charles J. Ryan: So one cell can become a billion cells, can become one metastasis. But, of course, it's not just one cell that escapes the prostate. Any idea, on a typical day, if somebody's living with a Gleason 8 prostate cancer, how many cells might be entering the circulation?

Ken Pienta: That's a fascinating question. A scary question, but a fascinating question for us who think about this stuff. Because if you think about it, there's a lot of technologies now that draw a tube of blood and look for circulating tumor cells. If we find one cell in a tube of blood or let's say five cells, one per mL, milliliter, of blood ... We know that there's five liters of blood circulating in our body at any one time, so if we happen to find one in one milliliter, that must mean there's 5,000 at any given time.

Charles J. Ryan: In that snapshot of time.

Ken Pienta: In that snapshot of time. And what's even harder to understand is that everybody believes the biology is that it only gets to go around the circulation once. Gets released out of the prostate, goes around, goes somewhere, and it's gone because otherwise, it would die. You think about going through the heart, it's like going over Niagara Falls without a barrel. You're not gonna survive that.

That's called first-pass kinetics. So that means every minute you put five liters of blood through your heart. That means your entire blood volume circulates through your heart in one minute, so if there's 5,000 cells at any given time, that means that you have to generate a new 5,000 in the next minute.

So that's all pouring out of the cancer cell, and this tells us why cancer in general and prostate cancer in specific is so inefficient a metastasis. Because literally a cancer is producing 5,000 times 60 minutes times 24 hours, that many millions of cells per day. We know that the vast, vast majority of those die, because if you look 10 years later and there's one met, that literally ... You've put out over a billion cancer cells to get one metastasis that grows up to be seen.

Charles J. Ryan: A billion cancer cells were put out for one of them to seed into the soil, to grow to be a billion-cell tumor.

Ken Pienta: Right, right.

Charles J. Ryan: And you've also shown, your group has shown, the heterogeneity of metastasis, that obviously these cells coming out of the prostate are not clonal, in that you can have multiple clones of metastasis. How do you think that is regulated? Is the immune system in the primary keeping this in check, is it about the stroma, what's the interplay of the cells both in the primary and the metastasis that enable metastasis or prevent metastasis?

Ken Pienta: Great questions that, unfortunately, we don't know the answers to. I think there's an even more fundamental question, which is ... In 1889, over 100 years ago, this guy Stephen Paget, who was a breast surgeon in England, did autopsies on women with breast cancer and determined that cancer cells, breast cancer cells, like to go to bone just like prostate cancer.

And he developed something called the "seed and soil" hypothesis, that you had to generate a cancer cell that was the right seed, that heterogeneity that you're talking about, that would then go to the right soil. Because you never see prostate cancer or very rarely see it, go to a lung. It's bad soil. But bone is good soil.

What we've been fascinated by is why does a cancer cell leave in the first place? What pushes it out, what about that microenvironment pushes it out? Is it a lack of food? Is it that there's a predator immune system nearby that it's trying to escape? Is it a bad environment like low pH, because the cancer cells are growing so fast and outstripping their blood supply? That's what we call the cancer swamp, you develop this swamp that you wanna leave.

We use ecology to talk about that, it's called optimal foraging theory, and it allows us to frame how do these different cells get generated. Are they passively sloughed off into the blood, and they're gonna die? Or are they forced to become something meaner?

Let me give you a fun example from ecology. A grasshopper, cute little bug, stays a grasshopper if there's enough food. The second there's not enough food, it goes through a process, not a mutation, it goes through an epigenetic process where it becomes a locust that can fly away. It's more resistant to drought and flies away to the next place.

So really, what we think about in these cancer cells is, are they grasshoppers that then are forced to become locusts that are gonna escape? We think that the reason why you can have 10 billion cells become one metastasis that's relevant is because all the grasshoppers that fall into the blood, they die. It's that one locust.

Charles J. Ryan: You need to find the cell surface marker of the locusts and target that.

Ken Pienta: That's right.

Charles J. Ryan: And what is that?

Ken Pienta: I don't know. But we're trying to find out. But also, that takes into account ... Again, if you're a squirrel, and you have enough food, and you have a warm nest, and there's no fox nearby, you never leave that little patch of forest. But the minute a fox comes along, it's gonna run.

That gets into this idea of the immune system and the microenvironment, for example, which we're all very interested in, what it is about prostate cancer that stops the cells, the immune cells, from even getting in to become predators to the cancer cells. So really, the microenvironment, that ecosystem that the cancer lives in, is really, really important. And there's lots of cells.

Anytime you have a cancer cell sitting in a prostate, it's interacting with 30 other normal host cells. When we study the tumor microenvironment, the tumor ecosystem, what we're really trying to do is say cancer is more than just gene mutations. It's also about how it's interacting with all the host cells around it, all the patient's normal cells that are either supporting the growth of that cancer or trying to stop it.

And so much of what happens is not the cancer cell continuing to mutate, we know it does that. But why haven't we found very many driver mutations in prostate cancer? It's also because you can become a locust with no change in genes, just by putting pressure on the system that says, "I'm unhappy there."

Charles J. Ryan: Right. So Gleason score, despite billions of dollars spent probably trying to find better markers for metastasis and progression, Gleason score kinda remains the most important factor in the primary tumor that we can look at. Is it, perhaps, that Gleason score is really just a marker of locust, if you will, development? That those are the cells and that's the morphology of those cells that have the propensity to travel and to break out, it's not because they're much higher proliferating. Higher Gleason tumors is the proliferation rate that much higher than-

Ken Pienta: It's not that much higher. I think it's worth pointing out that prostate cancer using the Gleason grading system, it's the only solid tumor grading system based on tissue architecture. As you know, every other cancer is graded by how bad their nuclei look, or how may mitoses are going on. Prostate cancer is the only one that says, "The more disorganized your tissue, the more likely you are to do poorly."

Charles J. Ryan: Yeah, it's always interesting when you talk to trainees, and they'll talk about a metastasis biopsy, and they'll say, "I don't see a Gleason score on this," and then you can explain to them that the Gleason score is about the primary, ti's about how the cancer sits within the normal prostate, for the most part.

It is a fascinating thing, but it's always interesting to see in academic presentations people always coming back to the Gleason score. This pathologist, who 55 years ago sat and just did cartoon drawings of what it looked like, that's potentially one of the factors that drives the appearance of metastatic potential.

Okay, so let me just transition in the final minute we have here about what we do about this therapeutically. We talked about trying to identify markers of cells with metastatic potential. As you look at the limited therapeutic armamentarium we have out there now, how should we be thinking, as clinical trialists and as people developing therapies, how should we be thinking about targeting the development of metastasis?

Ken Pienta: I think really it's about not giving up on the therapies we have, number one, because the hormonal therapies, the super hormonal therapies, the chemotherapies we have are all important parts of our armamentarium. But we all know we're not curing metastatic cancer, and we all know that we still can't figure out how to stop it.

The new immunotherapies are gonna be important to how we get the predator T-cells in. We all know that ... We consider prostate cancer one of those cancers where the T-cells aren't getting in, they're an immune desert. Well, what's keeping them out? One of the things that's keeping them out are these cells called macrophages.

Tumor-promoting macrophages are very prevalent in the primary cancer, and they actually secrete factors that keep cytotoxic T-cells out. So one therapy that, for example, we're working on is to actually stop those tumor-promoting macrophages from getting into the tumor.

Charles J. Ryan: And of course, even neoadjuvant hormonal therapy has been shown to be associated with an influx of immune cells in there. There are studies going back a decade or more looking at [inaudible] and others have shown this infiltration.

But the challenge is, how do we do those studies which require a 10-15 year follow-up to know that we have something clinically relevant in short of-

Ken Pienta: Yeah, and as we know, a lot of those studies fell out of favor because people were treated with antiandrogens and they still had tumor. So people said, "Oh, don't do that," but the reality is, using some of these newer ideas we could look at when people recur. So I think there is room in the neoadjuvant side, and for androgen plus checkpoint inhibitor. We know that guys with Gleason 8, 9, 10 tumors, 30% will fail at three years with a biochemical recurrence. Could easily do some numbers based on that.

Charles J. Ryan: There is a renewed interest in neoadjuvant studies, there are gonna be some phase three trials reporting out in probably the next couple of years, looking at neoadjuvant chemotherapy, for example, we'll get a lot of tissue from those. Mary-Ellen Taplin and Dana-Farber have done a number of things, and others.

So I'm hopeful that we can do in prostate what's actually kinda happening in breast right now, which is developing therapies, looking at the primary tumor, looking at the microenvironment of the primary tumor, and determining what are the factors involved in that short course of therapy that might portend a better outcome long term.

Ken Pienta: I agree.

Charles J. Ryan: I could talk to you all day, but you have other things to do, so I think we'll cut it short there. But thank you so much for joining us.

Ken Pienta: Great, thank you.

Charles J. Ryan: All right.

Ken Pienta: Take care.