Dr. Daniel George Video (Text Version)
Title of Talk: High-Risk/High-Gain Drug Development: Focusing on Novel Targets to Transform the Field of Prostate Cancer
Daniel George, M.D.; Associate Professor of Medicine and Surgery, GU Oncology Program Leader, Director of Oncology Site-Based Research, Duke Cancer Institute
Thank you Pete; that was—that was excellent. I appreciate your—your advocacy work through this last decade and—and beyond that.
I’d like to do a quick overview of today’s session and cover at just a very high-level what—what—how we framed the theme around this session, in particular high-risk, high-gain development—drug development focusing on novel targets to transform the field of prostate cancer. That’s an awfully big title, an awfully big agenda, and—and where—I think this is work in progress, but I think we’re very excited about the kinds of projects you’re going to hear about today and I just want to frame them a little bit for you. If I could have those slides up; okay, great.
Many of you have seen this before; Pete alluded to this as well. Prostate cancer is here to stay; this is a disease that is our most common cancer in American men and it’s interesting to me that after probably almost a—a decade now of—of declines in both the incidents as well as the mortality of prostate cancer, the 2010 projections are up. This is just an actuarial so it’s a little bit of a forecast of what those—the incidents of death of prostate cancer might be in 2010 but it’s based on the prior years and it really does look as if we have reached a plateau in those declines and we in fact may see some—some upward movement now in—in both the incidents and the death rate of prostate cancer.
So though I think we’ve made tremendous progress in our early detection or early treatments and even our treatments of advanced disease, we are far from finished with this mission.
Prostate cancer is a chronic disease in many cases, and it passes through a number of disease states and this is just one pictorial of those disease states from patients presenting in many cases with clinical localized disease, many of which are cured with localized therapy but that third or so of patients that relapse going on to receive hormonal therapy, androgen deprivation treatment of some sort of another and the vast majority will eventually progress through into this what we now term this metastatic castration-resistant prostate cancer state.
And it’s really ultimately that disease state that people are dying from. So all along the way we’re having folks that we’re losing from other causes, other disease causes to death but it’s in that last disease state of castrate-resistant disease that—that the vast majority of patients are dying from prostate cancer now—not from other causes. And so I think that’s really the setting that we’re going to be focused on for today’s session is how do we develop therapies that can impact in this metastatic castrate-resistant prostate cancer knowing that ultimately the goal is also to cure more patients up front. And you know the goal with detection is to be able to do something about it. And—and as we develop you know more specific targets, more specific therapies, and more tolerable therapies in this advanced metastatic setting, the opportunity to move those into the early curable setting for patients to really never get there to metastatic castrate resistance is ultimately the goal. So I think lower toxicity, improved cancer specificity, and select patients at risk for progression are going to be three key themes you’ll hear in the future for drug development in this field.
Now along the way we’ve made tremendous progress and in this last 18 months we’ve—we’ve seen nothing—nothing short of a paradigm shift in the drug development of—of prostate cancer. We’ve essentially gone from one treatment for patients with metastatic castrate-resistant disease to now four treatments. And—and I just list them up here in—in order of—of their FDA approvals; Docetaxel/Prednisone, Sipuleucel-T, Carbazitaxel/Prednisone and soon to be Abiraterone/Prednisone, I should say actually 2011. Sorry about that.
You know no one as far as I can tell has really tested the sequence of all of these therapies. And so when we’re quoting prognosis for patients with prostate cancer, we’re basing it largely on either historical experiences or data we’re deriving from one clinical trial or another developed in parallel. But ultimately and this is probably not actually fully accurate but if you add these survival advantages together we’re going to see even greater survival than we do with any one treatment alone. And I think we—we—you know this is a paradigm we do in—in breast cancer and lung cancer and colon cancer and kidney cancer. And I see no reason why we won't do this in prostate cancer. But ultimately you know different mechanisms will have potentially different mechanisms of resistance, and these strategies very well could be complementary in sequence.
And over the next 5 years we’ll see more and more variations of that sequence come out and how to do that perhaps in the most optimal way.
Well there’s some lessons learned from these new therapies. Prostate cancer is a chemo-responsive disease. We’ve known that. Although I’m not sure we’ve recognized it fully; now we have two chemotherapies in sequence, both improving survival and to me, you know, it just reinforces that message. You know not all chemotherapy regimens are alike and I think patients sometimes struggle with their preconceived notions of this. At the same time, you know chemotherapy is toxic and—and we do need to understand you know how to deliver it better, how to you know—and whom do we need to deliver this in and whom—whom this needs you know an additional treatment too and not just chemotherapy alone.
Autologous cellular-based immunotherapy improves survival in metastatic prostate cancer. That’s a statement but to me that’s also a paradigm shift as well. This is the first ever immunotherapy now—therapeutic immunotherapy for patients with advanced cancer and it’s—it’s great to see that first in prostate cancer. That’s a platform. This is by no means the finished product but I think it’s an opportunity for us to now understand in this disease how do we build on that and in whom is it working and in whom is it not working and how do we do better?
And I think you’ve seen a lot of enthusiasm and passion restored for cancer immunotherapy and I think that’s going to continue in this field. Androgen signaling is critical in advanced metastatic prostate cancer even after castrate progression. You know many of us have believed this for a long time. You’ve seen countless proposals out there around this; now there’s actually level one evidence with—with a secondary hormonal strategy to block androgen synthesis really robustly demonstrating that this is a critical target in the disease. And I think to me it’s reinforcement that there are targets in prostate cancer, specific targets that can benefit the general population even in this advanced chemo refractory state.
So the question for today is how do we improve therapeutic index? And what I mean by therapeutic index is the toxicity to the cancer versus the toxicity to the host. How do we—how do we get therapies to be more effective against cancer and less toxic to the patients? So there’s—we can identify and we can target proteins and genetic alterations that are critical to the cancer but not so critical to the normal cells. And you’re going to hear two presentations on that from both Drs. Chen and Wang both in terms of drug screening and identification as well as development of actual therapeutics. And I think you know one of the things that I think you’ll—you’ll hear and perhaps you know hopefully have some context is how different this is in the academic world than in the private world, I mean in the—in the pharmaceutical world.
And then preferentially deliver therapy to cancer cells; how do we specifically deliver to the—to the prostate cancer cells and not the rest of the body? You’re going to hear two presentations on this from Dr. Denmeade and Dr. Tagawa. And—and I think you’re going to hear—hear some really creative novel strategies for—for treating prostate cancer that ultimately may—may again be a platform for more—for more and more therapeutic approaches.
Okay; so I mentioned Drs. Chen and Wang. They’re going to give you their presentations. I’m not going to go into their data but I just want to frame for you why this is so critical. So academic drug development endeavors are fundamentally different than what we see in our—with our colleagues in industry. These tend to be move novel, high-risk, creative, and potentially high-reward strategies. I’d submit to you that most if not—that the majority if not a significant proportion of our greatest biotech companies really sprung out of early academic strategies and development. So these can be essentially the seeds to what might be a multibillion dollar company some day. Not that that’s the motivation; but that’s the leverage.
Biology-based drug screens, the idea that we’re not just—and not to say that you know chemistry isn’t important; it’s critical to this field as well, but there needs to be more than just chemistry drug screens. There needs to be a biology-based and cancer-specific biology-based approaches; these folks are free to work independent of company time lines and agendas. Their agenda is disease—is treating disease and not necessarily a shareholder. Collaborations are not restricted, so they can go throughout the communities both academic and private. Disease-specific and perseverance is the critical key here and the reason they’ll be on the podium today is because of that.
Regarding a specific targeting to prostate cancer where you know we have some unique benefits in prostate cancer and some of them have to do with the very specific expression of proteins in the surface of this disease or this organ that we don’t see in other tissues. And prostate-specific membrane antigen is one you’re going to hear about today. This is a—I’ve got a little pictorial of it here; it’s sort of two molecules stuck together and it’s a—a transmembrane function; it’s got an extracellular component and actually the enzymatic activity, the catalytic domain of that is on the extracellular component and that’s critical for what Dr. Denmeade will talk to you about. It’s very prostate-specific, 1,000-fold specific for prostate expression and probably another 1,000-fold specific for prostate cancer over normal prostate. So there’s tremendous specificity for this on the surface of prostate cancer cells versus other tissues.
And its functions are you know—are—are a little—little bit varied but they’re enzymatic in—in properties and again that’s going to be critical to how we take advantage of this. PSMA—PSMA is an enzymatic activity mechanism to target prostate cancer; Dr. Denmeade is going to talk to you about his work on how he does this, taking advantage of these very specific features of it in order to release active product locally in the prostate cancer micro-environment. And again the goal of that is to improve drug delivery, minimize toxicity, and increase therapeutic index.
Dr. Tagawa is going to talk to you about the expression of PMSA. Again very specific to prostate cancer; the use of monoclonal antibodies and now sort of the—the optimization of some of these antibodies to specifically bind to PMSA which can allow for again cell targeted and even internalization of those delivery of those warheads to target that cancer cell. And the idea that prostate cancer is also a radio-sensitive disease. We don’t talk about that as much as perhaps some of other treatment strategies but you’re going to see more data in the near future around radio-sensitizing approaches. You’re going to see more data about radio-pharmaceuticals and prostate cancer and I think you know it’s important to know that this is again another important warhead in our—our treatment arm, and finally the ability to bind that radioisotopes to increase therapeutic index specifically to cancer cells.
So I think in summary, you’re going to hear some very creative disease-specific drug development strategies that are going on specifically supported through these mechanisms and we’ve got proof of concept that’s already there. Prostatic acid phosphatase is the antigen we target with sipleucel-T and we’ve seen therapeutic benefit from that—from that target. Now that’s an old target, but it still is a prostate cancer target. Androgen biosynthesis is a very specific you know prostate cancer drug target and now we’ve got proof of concept that blocking that improves survival as well. Blocking other key growth and survival pathways can be critical to prostate cancer, and those aren't the only two examples we’ll see in the future and you—what you hear today very well may be the next one.
Delivery of high-concentration of therapeutics is going to be critical. Ultimately knocking this cancer down is good but to knock it out we’ve got to be able to get more therapy into these cancers and allow for cytotoxic therapies to deliver to prostate cancer cells more specifically—may allow us to move these therapies earlier in the disease and treat these relatively low volume but still critical cancer cells you know before they have a chance to really entrench and can spread.