Dr. John Isaacs Video (Text Version)
Title of Talk: The Need for Organ Site Specific Cancer Research
Speaker
So we saved the best for last. Dr. John Isaacs is one of the few Professors at Johns Hopkins University and Medical School that doesn’t—doesn’t have an affiliation with 17 departments, but definitely Urology. That’s—that’s it?
Dr. John Isaacs: No.
Speaker: Pharmacology, Pathology—?
Dr. John Isaacs: No; it’s actually Oncology is my primary. Urology even though I grew up there was my secondary. My third one is in the Cellular Molecular Medicine Graduate Program and my—my fourth one which is actually critically important and as you’ll hear, I’m actually a Professor in the Chemical and Bio-molecular Engineering Department.
Speaker: Yeah; so—so John at least from my eyes, I mean he’s a brilliant scientist and his—I mean his—his—the knowledge that he’s added to the fundamental understanding of prostate cancer is indisputable in—in the decades and the coming, but I—I see two things about John that I need to point out. Number one, his tenacity in sticking with his pro-drug concept and you hear Dr. Denmeade speak about it a little bit is nothing less than—than phenomenal and now it’s in patients. So we’re—we’re glad to see that. And number two, I would have to credit you with launching and mentoring the—the early scientific career of the—of our Natasha Kyprianou who you know is—is the Head of the—you know the Chairperson of the Integration Panel right now and in her own right one of the top prostate cancer scientists in the world. So Dr. Isaacs, thank you and we look forward to your talk about the—the missing links and the big holes in research.
John T. Isaacs, Ph.D.; Chemical Therapeutic Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Okay; thank you. So first, it’s—it’s Lent and so I want to apologize for anybody that I’ve upset the last year. I hope your forgive me. Second, I would like to thank Professor Kyprianou and also Wesley Sholes because of the credible organization. I really didn't know what to expect about this meeting but I’ve been impressed for several reasons. One, it’s almost like a homecoming. I get to see family members and my extended family and also I get to be inspired by my heroes.
You know to be in a Phase 1 trial is really daunting because you’re—you’re presented with essentially a consent form that says by the way, this therapy can't help you. But would you please take it so that we can figure out how to give it safely to others. So when I look around I see both survivors and I see people that are advocates, but I also think of the people that are in the Phase 1 trials. They—they always inspire me. That’s one of the great things about being at Hopkins. I’m not at the Roche Institute of Molecular Biology. I’m at an Oncology Center. And so I see those patients come and they are my heroes. So thank you for the rest of the survivors today; you inspire me.
It’s somewhat difficult and almost impossible to end a meeting like this but I grew up in a family of four boys so I’m never without some words to say. You actually might have met my brother who was here, my younger brother, Billy, but anyways what I was realizing as I was getting this talk together, I wasn’t exactly sure how the two unbelievably outstanding clinicians were going to actually face and present the data. But—but what it reminds me of is a very important story; it’s a joke but it’s a very important joke, and it was the joke that in the early essentially ‘60s when we were finding that we were going to go to the moon, President Kennedy defined we were going to go to the moon, so he told the engineers to design a rocket ship to take a man to the moon. And they did. So they made the rocket ship; the man got in and he went up and was on the moon, put the flag there, television was on him, I mean the whole thing, and then the astronaut says and by the way, how do I get home? And the—and the engineer said well you said you wanted to put a man on the moon. You didn't say you wanted to bring him back.
So that was why I pointed out I’m in an Engineering Department. And for engineers it’s always important to give the bounded condition; what are you trying to design? So what I’m going to try to do today is take a little bit different—I’m not going to be that—I don’t want to use the word technically scientific but I’m going to give you a little bit of an overview as to what the problem is that we deal with. And it’s a very important one; it’s—it’s almost a philosophic one and so I chose as my title of my talk The Need for Organ Specific Cancer Research. And you’re going to see why I'm defending this point in a minute.
Now a lot of you have gone into many of these rooms and you’ve been hearing about some incredibly exciting science about the fact of how an epithelial prostate cell can eventually be transformed into a local cancer and then become metastatic and be very aggressive. And you’ve learned that there are many molecular changes; it’s probably made your head spin trying to figure out what this all means.
But there is a practical thing and I’m going to show you in a minute how you can summarize this. All these genetic and epigenetic changes come to down a fairly significant commonality and that’s presented in this slide. Cancer is a lethal disease because you produce more daughter cells than cells die, so in a 170-pound male and I wish I was 170 pounds, but a 170-pound male you will produce 170 pounds of gut, skin, and blood cell every year. That’s not cancer. That’s just turnover; that’s the biology that you spent millions of year evolving to.
In cancer what’s happened is that there’s an imbalance between self-proliferation to replace the cells that we’ve lost and so we have a net gain. And the question is—many—this is true for all cancers okay, but the question is—is there something unique or special about prostate cancer? And let’s look here for a minute; these were a series of studies that we did almost two decades ago now and it shows you an interesting thing. This data was actually published in the first issue of Clinical Cancer Research, which for about 15 years was not available on PubMed. So if you’re a young student there always make sure you’re publishing in a journal that is PubMed accessible because this paper is almost never quoted and it’s an incredibly important one. And what we did is we actually developed methods to determine the rates of proliferation and death in both normal and metastatic cancer from men that had died of prostate cancer. This is the worst form of prostate cancer.
And what you can see is that the normal prostatic epithelial cells are remarkably long-lived. Only about .2% per day are actually proliferating to balance the .2% of the cells dying, so that neither the gland involutes nor overgrows. Prostate cancer is clearly—has an imbalance now where the—the number of cells dying is less than the—sorry, the number of cells dying is less than the cells proliferating. But it’s remarkable as Sam Denmeade showed you this morning, this number of 3%; you have 10 to 15% of your skin cells proliferating per day. So prostate cancer is lethal because it has such a low death rate, and what’s interesting is this 1 or 2% difference seems trivial. What do you think it would take if you had a bank account that was—you had a difference between simple compound—or simple interest versus compound interest? Think of it as a bank account. You’re putting 2% more each day into the bank. It would turn out that you would double your assets in about 70 days. That’s what this tumor does. It actually doubles in size from—oh sorry, it doubles in size—what have I just done—blank—sorry.
It doubles in size about every 30 to 60 days and it turns out that’s really interesting because in order for a cancer to reach the size of a pea it needs about 30 population doubles. So that means it takes about seven or eight years for this cancer to develop into a pea-size. And we think that it takes about another 10 to 15 doublings for it to become lethal. So we think for prostate cancer that the time from the beginning to where it’s actually producing clinical symptoms and is lethal is actually more than a decade and it can even be longer. So this has an extremely lethal disorder when it’s in this metastatic stage but is in fact not growing terribly fast.
Now let me give you a better example of this. Okay; so on the far left is how we all start as a single egg. And we were fertilized and we were then able to produce seven trillion cells. I really didn't know what the word trillion was until our national debt reached that size, so now I actually—I do have something I can compare it to. Okay; but—but the point is there’s seven trillion cells in your body. And those seven trillion cells are absolutely amazing. They do work for the common good. You know we have lots of arguments in our country about what is the common good. But in biology the common good is survival of the host. And so what happens is that there are essentially good and bad neighborhoods. A good neighbor is one that actually involves essentially a series of individual responsibility but also societal observations. So a good neighbor makes sure he takes out the trash, maintains the home, obeys the, you know property laws, and pays taxes. Okay; and taxes are used for the common good. And so I think one of the things we’ve got to get back to about the DoD is where do we want our taxes to go for the common good.
Okay; so society—the societal organization is that you must provide utilities, protection, use your taxes for the common good. So I want to—I want everybody to leave today with one really kind of subliminal idea. Cancer is a societal disease. You’ve heard a lot now at this conference about the cancer cell and you’ve even heard a lot about the micro-environment. But the disease is essentially a societal disease. And here is the good neighborhood; so here’s the normal prostate in which you have a variety of cells all doing different things to help the prostate do its normal function. And what you get is these are the cells that are going to give rise to the cancer but they’re supported by good neighbor cells, the smooth muscle cells; they’ve got blood—this doesn’t project very well but they have blood vessels. They also have nerves. And what those things are doing are essentially just like in a neighborhood. The nerves are like telephone and computer lines whereas the blood vessels are essentially the gas and electric. You’ve got to take things in, and also I should say the sewage system also to take out the waste.
So in this situation you have a good neighborhood; everybody is balanced, okay. This is the result of being a bad neighbor. This is where you no longer respect your own neighborhood and you leave and you go and you corrupt it. But the disease—I’m sorry; the disease is in the patient. So the disease is not just the cell; it’s how the patient responds and how the actual physiology is changed. And I’m going to come back up to that later.
So now the question is what I’ve told you in general has some cancer interesting ideas, but some prostate-specific activities. And one of the fundamental questions about the issue of the rationale for organ site specific research and this is a philosophic profound argument in the scientific community whether we want to have general research discovering basic principles of cancer biology or you want to have specific organ site programs. DoD, this is an organ-site program. And I will tell you I spent the first 15 years of my life probably not in hubris being very humble thinking I could master many topics. I chose to have as my goal, long-term goal the death rate to prostate cancer going down. I spent 30 years doing it. The first 15 years I spent basically as a philosopher learning about the disease. The last 15 I’ve spent as an engineer trying to build molecules. So you heard some this morning. I’m not going to really be talking about that. But what I want to emphasize is that all requires me to become an expert about the prostate. So if anybody comes up and asks me about bladder cancer or renal cancer or breast cancer, I have an opinion on it just like I would predict who will win the next Super Bowl if we have one.
So it turns out that it’s not an expert opinion. I’ve had to spend 30 years to learn about this disease. So there’s an incredibly important thing. Also for therapy, we have issues—the androgen receptor is not going to be working in melanoma. So the—so the targeting of the androgen receptor, melanoma is a very important disease to study but if I study androgen receptor I’m doing it because I’m interested in prostate. And there are issues about prostate-specific markers. PSA is a great marker for prostate cancer. It does very little for glioblastoma. So if I was trying to get a general marker for cancer, this would be not terribly useful but the point is that we have to have specialists working on individual cancers and that’s what the DoD has done incredibly well. We need to maintain that; we need to balance between the generalists studying cancer in general and the organ sites in specific.
Okay; now what I want to point out is I’m not going to really talk about any new drug development because that’s what you’ve been hearing a lot about. But I wanted to tell you our most immediate problems that we have even in drug development. And this relates to biomarkers. We need better biomarkers so that as Joel was saying and—and Oliver was bringing up very beautifully, we need to figure out which patients (a) need to be treated, and we need to figure out which patients need what type of treatment. So that’s really our critical link right now. We’ve got a lot of basic science going on. We’ve got a lot of actually drug development. We’ve got a lot of things exciting. But there’s probably no area where molecular biology or the explosion of our understanding about cancer can be more productive than in the area of biomarkers.
And just to give you an example of how useful—you know we complain about PSA but I can guarantee you if breast cancer had a marker like this they would think for—at least for a couple decades, they would think how lucky they were. Then they would fight about it. But it turns out for prostate cancer that we’ve had PSA almost too long and so we’ve seen warts and all. But it was discovered in the ‘80s and it’s been a remarkable marker actually. So the problem is it’s a canary in the mind. It’s not meant to be—it’s a tripwire, you can either use PSA as a tripwire to say you should figure out what to do next or you can use PSA not just for diagnosis; you can use it for following patients with the disease. So PSA is not the enemy, okay.
But one of the really exciting things that’s come up and I haven't heard a lot of discussion this at this meeting and that is essentially the concept of a liquid biopsy. So what we would love to be able to do is follow patients sequentially so you are your own N of 1. It doesn’t matter if you’re in a group of 100; can we follow you as a patient? So the way to do that is to be able to take your blood and look at the cells that are circulating. So if you have circulating cells, they have markers that can be looked at and when we give therapy we can see how those markers and—and pathways change to see if in fact the therapies we’re going to give you are actually hitting their target. So you can not only evaluate that; you can also use it as an intermediary endpoint. So it’s incredibly important the idea of liquid biopsies.
Now one last point I want to point out—is that we have a real problem in that unfortunately when we were evaluating patients’ responses we say they responded or they didn't respond. And that’s because we have to make a blind decision; we can't individually look at the individual “mets” in a patient for example. And this has really gotten to the problem of throwing the baby out with the bathwater because here’s again that same type of scan. What would happen—let’s just say for a minute that the drug that Sam Denmeade was talking about that we spent way too long getting to clinic, but anyway, okay so it got in the clinic and two-thirds of those lesions went away. But you didn't have a way of detecting those lesions—that they were going away. And the patient then—his PSA was rising; you’d say oh, the therapy didn't work. Well it did work; it worked in a subset of lesions. So we have to figure out a way when we’re talking about these combination therapies, we want to treat the disease and the whole patient with all the heterogeneity—I grew up with heterogeneity and it is the enemy but it’s not insurmountable. So the point is that we can combine things, but we have to have some way to follow the response in the individual patient, so that when we have a lesion that continues to progress we know that.
So really what we need to accelerate—really even clinical development of drugs is some platform for looking at functional imaging. And there’s kind of a problem here. Interestingly enough, bio-tech companies and big pharmaceutical companies are actually not interested in imaging. Now they’ll give lip service to—if they have a targeted drug that hits a specific target that they want to validate that—that target is hit and so if they could image that target they’ll co-develop some type of a marker with their drug, but they’re not doing it for the world. They’re doing it for their drug. So there’s really very little financial support for people trying to develop imaging.
And if you want to get a good story of that you should invite Neil [Vanderback], the man who was working with the—the J-antibody for PMSA. He’s using it for therapy but he has almost no support to use it for imaging and yet it’s a very powerful imaging agent. So that’s a significant problem; we need to figure out how to get support for that.
I want to point out one last thing and I really—I apologize because I don’t mean to make anybody—raise anybody’s blood pressure. But I want to bring up one last point for all of us. I mean I’m not going to live forever no matter what happens, so I can talk about death. And so I don’t mean to upset anybody by showing a death curve. But what I want to point out is that this is a study done with men that have been—that have been given radiation therapy and have failed radiation therapy and their PSA is rising. And they’re—what you can see is there’s basically four groups there. They’re the same type of patient. They were candidates for local radiotherapy. They were given—and then they failed in the sense that they had biochemical recurrence. And this is the mortality of it. And you can look to see; this is actually five years out. There’s a group of people that in 5 years will not be with us. There’s another group that about maybe 30% won't be with us. And there’s a very large numbered group that they’re going to be fine for basically 5 years. So the variability of the disease initially from this period we call biochemical failure is quite large.
Now here’s what is surprising. This is a very large study in which there was almost 1,000 patients. Don’t worry about all the lines; they’re just to show you the variation. This is it when you have failed androgen ablation therapy with metastatic disease and you’ve been given the best therapy we have, essentially taxane based therapy, Docetaxel. And this is the response—this is the survival. And you can see from the best possible group it’s 24 months and the work—I’m sorry, the best possible months is 24 months versus the worst is 13. That’s pretty doggone tight. So you have a disease that can be variable except when it gets to this stage. So it’s remarkably stereotypic in the lethal as far as the last year and a half of life. And so what I’m surprised by is this; I’ve spent my career and I’ve asked everybody that I know this question, but I haven't gotten an answer yet. What really do men die of with prostate cancer?
And here’s a situation from the—that was referred to earlier. These are the results of the Michigan Autopsy Study. So this is where men donated their body after—at the end of their life to have an autopsy so we could figure out really what the lethality of the disease was. And you’ll notice down here bone, okay; we all think of prostate cancer as a bone—as a bone disease. And that’s true; there’s a lower—about 80% of the men had bone disease and often times it was extensive bone disease. But almost the same amount had liver disease and I haven't heard anybody talk about liver disease here. We’re really impressed in our autopsy series at Hopkins at how many men have extensive liver disease which is a different type of scenario okay in soft tissue disease.
So this is an amazingly difficult disease but the question is—what actually converted the man who had metastatic disease, had these sites but was walking around and was fine until that moment when he went over the hill. And then 11 months later things were bad. Believe it or not we haven't studied those men. So for example, if it was a situation that was a cytokine network change or a metabolic derangement of the liver or it was a problem in the relationship between your kidney and your other parts, so I’m impressed with a lot of the men that have changed their lifestyle and have changed their physiology by doing exercise, diet, and other things. They’ve changed something.
But interestingly enough, the medical profession hasn’t caught up with the realization that if we knew more about the last parts of it we could figure this out maybe ahead of time. And what Oliver was bringing up was this idea of—is the goal a cure? It should be if we can, but there’s going to be a large number of men who are going to be in their 70s and 80s that the goal really is getting them back doing active life—quality of life issues and extension.
So one of our—my big passions is I’ve been trying for 30 years to get medical and—and other scientists involved in trying to understand the physiology of prostate cancer death. And I know it sounds like a morbid topic but if we knew more about it and it’s remarkable—I’m an editor of a journal called The Prostate and I get about 500 papers a year submitted to our journal. And not one of them actually has asked the question, which I’m putting up here, what do men actually die of. So I’m looking out at the advocates and that’s why I said I don’t mean to be morbid about this, but one of the things that really inspired me were the autopsy studies. And the way the autopsy studies were done at all three locations; they were done at—essentially at Michigan, at Hopkins, and they were done at the University of Washington, and I apologize if there are other—other ones that are now—that I don’t know about—but all of those required a partnership and it’s actually quite an interesting partner, because you have to partner not only with the patient but with the patient’s family because the patient’s family has to agree also right, with the idea that the—the patient is going to then be part of the warm autopsy.
So I think that we only have 600 patients a year or 700; I think that’s a little low, that number—that are in clinical trials but it’s remarkable how few men—we’ll probably do autopsies on less than 100 men this year. And what I’m suggesting is a situation where people in clinical trials before they get to that stage are monitored all the way through, so we can actually find out the physiology and find out what went on in a cohort of men from the very beginning when the PSA failing to the end. And I think if we did that it would be—it, to me it would be equally exciting as sequencing the human genome; thank you.