Urologic Oncology

SLIDES & TRANSCRIPTS
Friday, December 13, 2002

Special Address
Seamless Urologic Oncology: Mapping the Future

Andrew von Eschenbach, M.D.
Director, National Cancer Institute

Slide 1:

Thanks, Marston.

You know, it has been eleven months since this has been my new home. And I happen to have had the opportunity to be up here a number of times already. But I don't think I've ever felt as much at home as I do right now, looking out at the audience, and seeing so many, many dear and great friends.

I want you to know it's a special moment for me to be able to share with you, the vision and hope that I think we all have for the progress that we are able to make in oncology, and especially be able to focus my remarks on what I have always believed, and that is that at the forefront of that progress in oncology, urologic oncology is in fact our greatest hope with regard to leadership, and with regard to progress.

So what I would like to do over these next few minutes is to share with you a little bit of that vision, if you will, and to kind of put in perspective what I see as our National Cancer Institute agenda, but particularly how that in fact is so incredibly dependent upon the success of the effort that you all are involved in.

Slide 2:

Many of you have heard me at different venues speak about the future of oncology, and the belief that I have that we are at a very, very special moment in time. That at the turn of this 21st century, we actually have within our grasp, the ability to fundamentally change the paradigm of oncology from what we have been used to in the past, namely seek and destroy, to what is the great hope for the future, namely target and control.

And the basis for that belief is because of the tremendous progress that has been made in biomedical research. And the human genome project is just one example of the major breakthroughs and opportunities; that for the first time, are now enabling us to have the tools to unravel the secrets and the mystery of this disease that we have been struggling with.

Slide 3:

We now recognize that the cancer program is in fact extraordinarily complex. But there are unique and specific processes that are associated with the cancer problem. And that in fact, when one thinks about urologic cancers, and one thinks about the portfolio of biologic diversity that exists with regard to prostate cancer, bladder cancer, renal cell carcinoma, and testicular cancer, the entire portfolio of the complexity of oncology is really encompassed by the diseases that we are in fact as a specialty, involved in understanding and treating.

And so when we think about the complexity of cancer, there is probably no other segment in oncology that is better equipped than urologic oncology, to really begin to dissect out the specific elements of the problem. And in that context, then be able to arrive at particularly significant opportunities and interventions.

Slide 4:

The way in which I believe we need to accomplish this new paradigm and seize this new opportunity is to begin to think about the problem with regard to the investigation of its individual components. And the National Cancer Institute's agenda will be very much to continue to enhance our investigation of the fundamental mechanisms that are operative with regard to the development of the cancer cell.

But also importantly, to realize that that cancer cell and its ultimate behavior are determined by the interaction that it has with both its micro and its macro environment.

And so, understanding cancer not only at the level of the cancer cell, but understanding it with regard to the level of the host and host-tumor interactions, and also beginning to understand the problem as it relates to populations are going to be critically important ongoing initiatives. And most importantly is to then take that perspective to a systems biology approach, where we not only understand the individual elements, but understand their dynamic interaction.

Slide 5:

The systems biology approach will need to be fostered again at the cellular level, and many of you are at the forefront of understanding many of the pathways and circuits that are operative within the cancer cell. And our goal in going forward in the future is to not only to continue to elucidate each of these important mechanisms, but most importantly, to begin to see how they interrelate as systems, and then in that context, be able to define appropriate interventions that will in fact be able to alter and change the biologic behavior that needs to be overcome.

Slide 6:

The other important agenda for us, and again, one in which I think urologic cancer has the opportunity to be at the forefront of the development of our new knowledge and understanding is to begin to appreciate not only the changes that are occurring within the cancer cell, but the dynamic interaction the cancer cell has with its environment.

And certainly in this regard, prostate cancer, with regard to the cell-cell interactions that have occurred between bone, as a unique site of metastasis, and the prostate cancer cell are really unraveling for us, the basis of an extremely important part of the portfolio with regard to our ability to intervene in the malignant process.

An area that is really tremendously understudied is our understanding of the macro environment, and the importance of host factors. And again, with regard to urologic cancer, we recognize the importance of hormones, nutrition, and the immune status in this particular regard. And these are going to be important areas of investigation for us.

Slide 7:

In addition to laying out a portfolio that defines important strategic scientific initiatives, I think it is extremely important to also re-emphasize the lesson that we have learned over time within the field of urologic oncology, and that is the need to even more effectively integrate into a seamless approach, the dynamic interaction that has to occur between clinical research, or clinical observations, and basic laboratory investigations.

We recognize that cancer really is a biologic phenomenon, and that in its clinical manifestations, as well as in it basic mechanisms, we have an extraordinary need for fundamental and primary understanding.

Slide 8:

But this understanding can stem from the examples of people like John Grayhack, who have always emphasized for us the importance of observing the manifestation of disease within the patient.

Clinicians and clinical observations are as fundamentally important in this new paradigm of discovery as are laboratory investigations. And we have to think not of the continuum of bench to bedside, but a continuum of patient to bench to patient. It is in a continuum that I think we have the greatest opportunity.

Slide 9:

And observations of clinical significance, for example, the observation of unique predilection of various tumors for certain sites of metastasis actually open for us, extraordinary opportunities for investigation.

In urologic oncology, we have known for decades, the unique biologic manifestations of osteoblastic metastasis and prostate cancer.

Slide 10:

The fact that clinical observation was telling us something extremely important about the biologic manifestation of the disease, mainly that there was a very unique interaction between prostate cancer cells and bone cells, has now been able to be more fully appreciated, because for the first time, we can take clinical observations like that to the laboratory and begin to define their underlying mechanisms.

Slide 11:

And that mechanistic investigation has really led us to be able to refine and in fact replace former hypotheses that explained the clinical phenomenon.

When I began my urologic oncology fellowship at MD Anderson with Bruce Bracken, the explanation for the predilection of prostate cancer to spread preferentially to the axial skeleton, and particularly the lumbar spine and pelvis was because there was a passive dissemination through Batson's plexus.

Slide 12:

We now know that that in fact is a phenomenon of clinical observation that has extraordinarily profound biologic implications, because at the mechanistic level, through work being done by Bernardo Pasqualini and Wadi Arap, we are beginning to appreciate the fact that there are specific ligand receptors in tumor cells that then result in their specific adherence to endothelium within particular organs.

Slide 13:

And that the endothelium does in fact have unique organ specificity that then results in the preferential spread of certain tumors like prostate cancer, to certain sites like bone.

Slide 14:

And that this is in fact an opportunity for us by virtue of understanding these underlying mechanisms, to then begin to develop opportunities to alter or change the cytokines responsible for these specific biologic interactions. And that opens up for us, incredibly important therapeutic opportunities.

Slide 15:

So our mechanistic investigations must then not stop there, but be taken to the point where we can then develop biologic-based intervention.

And again, one of the important agendas with regard to the National Cancer Institute going forward is to be sure that we are in fact continuing this paradigm of mechanistic investigations leading then to the development of biologic-based interventions.

Slide 16:

And one particular proof of principle of the fact that these biologic-based interventions can in fact substantially alter the course of disease in fact the proof of principle that has been made available to us by interventions like Gleevec and herceptin, as mechanistic-based interventions.

Slide 17:

Well, at that point, once the interventions are defined and developed, we must deliver them back into the clinical arena, but do so in a mechanism now of going forward in which we are able to monitor not just simply clinical outcomes of survival or tumor regression, but more importantly, we may be able to measure outcomes having to do with our ability to impact on those fundamental mechanisms that are responsible.

Slide 18:

And again, the NCI's commitment to continuing to develop the tools and the infrastructure in genomics and proteomics that will allow us, both from the point of view of molecular pathology, as well as from the point of view of functional imaging, to be able to monitor and determine in real time, the ability to alter or change mechanisms becomes an extremely important part of our strategic agenda going forward.

Slide 19:

And so I envision that we will see a continued essential requirement of the close collaborative interaction between clinical scientists and basic scientists, working together effectively as teams through an agenda that not only defines what are appropriate and relevant manifestations of disease, but what their underlying mechanisms are at the biologic level, and then our ability to develop interventions that truly change the course of the disease.

Slide 20:

We are beginning to see this play out in only one example that I have time to share with you, with regard to again the story of prostate metastasis in which work that was begun initially at MD Anderson with Leon Chung, in terms of understanding the paracrine and autocrine factors that are responsible for the interaction between prostate cancer cells in the bone stromal has opened up a whole new set of opportunities for us with regard to altering the bone environment.

Slide 21:

And there are currently ongoing clinical trials that are directed at being able to alter or change prostate cancer bone metastasis, not by affecting the prostate cancer cell, but by directly altering the bone micro-environment.

Slide 22:

Similarly, the work done by Bernardo Pasqualini and Wadi Arap in defining ligand-specific receptors on the surface of tumor cells that were homing to endothelial receptors at organ sites, much in the way zip codes get letters to a particular mailbox, is opening up extraordinary opportunities not only to alter or change the zip code to prevent the homing mechanism from being operative, but even thinking of using the zip codes as a way of homing target-specific therapy to sites of metastasis.

Slide 23:

And finally, using mechanistic-based interventions, recognizing for example, the role of PDGF in prostate cancer in a bone metastasizing model, demonstrating the ability to combine mechanistic-based interventions in a way that with the combination, for example here, in this animal model of STI571 and Taxol results in a significant alteration and change in prostate cancer bone metastatic biology.

Slide 24:

Urologic cancers are probably, of all of the diseases that we deal with as a group, extraordinarily well positioned to really help us amplify and expand this approach to the new paradigm. And there are extraordinary opportunities within each of our tumor systems for us to be able to exploit those fundamental mechanisms that I shared with you on the very first slide that are responsible for the malignant phenomenon.

Slide 25:

And a few months ago at the White House in a ceremony to honor cancer survivors, Pres. Bush reaffirmed his commitment to this opportunity and to this agenda. And in the course of that commitment said, "For the first time in human history we can say with certainty that the war on cancer is winnable, and that this nation will not quit until our victory is complete."

And the reason he was able to make that statement is because of the kind of progress that you in this audience, have been responsible for that has enabled us to now begin to think about cancer in an entirely different way than we have been able to in the past, because we are in fact for the first time, really beginning to define those underlying biologic mechanisms that now are amendable to strategic therapeutic interventions.

Slide 26:

The way we will begin to continue to promote and further enhance this new paradigm with new hope is to break the process down into a strategy of a portfolio of discovery, development, and delivery. And within each of these portfolios, to begin to define the unique elements that are relevant for the mechanisms of cancer.

To use that information to develop interventions that will more effectively detect, predict, treat, and prevent the disease, and then in the context of an infrastructure, to be able to deliver that to patients who are in need in a way that extracts the information in a real time and relevant fashion.

Slide 27:

There are a variety of initiatives that we have underway, and I cannot share obviously the entire strategic agenda for you, but I would like to make a few important points about new directions that I think we need to pursue.

Within the area of discovery and our ability to drive the engine of research that is evolving this new knowledge of our understanding of disease at the level of the cancer cell, the person, and the population, there are important strategic opportunities for us.

I think we have the ability to enhance our creativity with regard to research. And we are engaged in a pilot project with one of the other institutes to look at funding mechanisms that are outside of the traditional mechanisms that are currently being employed, that really will allow for creativity and non-traditional thinking to be funded, and to emerge.

We also have to look at mechanisms that go beyond investigator-initiated research, and the traditional RO1 mechanisms to look at the opportunities to not only foster team science, but to recognize the contributions that come from collaborative, interactive, scientific pursuits.

There are important initiatives that we have underway to begin to embrace newer, emerging technologies that up to this point in time have not been necessarily central to biomedical research. And one example is an emerging investment in developing nanotechnology.

And finally, alternative disciplines that are really going to be critically important, for example in terms of proteomics to move to in silico with regard to strategies of computational biology.

There are a host of initiatives with regard to development. We must effectively accelerate the pipeline for drug development, and we have collaborative activities underway with the FDA that will help us with a lot of the regulatory issues, as well as public-private partnerships with the pharmaceutical and biotechnology industry that will enable us to enhance the identification and validation of targets.

And once again, the building of infrastructure around tissue banks and bioinformatics that will enable the more effective and rapid development of interventions based on our enhanced discovery of fundamental mechanisms.

And with regard to delivery, the need to create platforms that will bring these new interventions to the clinical arena, and do so in a context in which we are extracting clinically important and relevant information from a research perspective is another extremely important part of the agenda going forward.

And the expansion of our cancer centers and our SPORE programs, and the integration of those programs is a process that is currently underway, as is a very significant effort of looking at our opportunity to integrate and enhance our clinical trials infrastructure throughout the entire country.

In addition to that, it is extremely important that we expand our infrastructure of the workforce, both in terms of basic scientists, as well as clinical scientists. And our training programs are getting a great deal of attention with regard to mechanisms going forward in the future, particularly around the development of translational scientists.

And obviously, it's extremely important in the delivery agenda that we pay focused attention to the problem of the disproportionate burden of cancer among minorities.

Slide 28:

Urologic cancers have to be an important and critical part of this discovery, development, and delivery portfolio. The prevalence of the diseases that we deal with, the biologic diversity that they present, and the very fact that we have so much opportunity, because of investigators such as yourselves. We do in fact, within this field, have a critical mass of investigators, multidisciplines, and the appropriate resources.

Slide 29:

We will continue to enhance the mechanisms that will enable all of these elements to be applied in a research dimension that take us from original thought, to the point where we actually have impacted on someone's life in a positive and effective way.

Slide 30:

We have made a commitment to enhancing the resources that are being applied to urologic malignancies, and there has been a continued increase in funding for kidney and bladder cancer. And obviously, we have had the opportunity to substantially enhance the amount of funding that has been directed towards prostate cancer. And urologic malignancies are in fact a very significant part of our research portfolio.

Slide 31:

The distribution of those funds is really across the entire continuum, so that we are looking not only at the more fundamental, basic research initiatives in biology, but making sure that we are really providing a full continuum through cancer survivorship and survival.

And each of the portfolios, beginning with prostate, may have a slightly different mix with regard to their current content,

Slide 32:

but our intention is to maintain and create a balanced portfolio across all of the initiatives that we have underway at this point.

Slide 33:

Slide 34:

The SPORE programs have been continuously increasing, because of the enormous success that they have had. And this is an area where GU tumors have had a great opportunity.

Slide 35:

When the SPORE program was first introduced in the early nineties, there were only two prostate SPOREs. We now have more prostate SPOREs than any other single disease site as we go forward in our strategic planning. And we are now at about a level where we are also beginning to introduce GU SPOREs, the first one being focused primarily on bladder.

One of the important issues with regard to the SPOREs, and again where GU tumors have to be at the forefront of leadership is that we are seeing integration occur across the SPOREs in which prostate, especially around the development of clinical trials, has been a leader in this area in which the SPOREs are now interconnecting and collaborating with each other in the development of programs that are applicable.

And in addition to collaboration and coordination with regard to an organ site focus, there is now beginning to develop, collaboration and cooperation across the SPOREs in terms of various disciplines as they focus on mechanisms that are particularly applicable across organ sites. So one of the key elements of the SPORE program going forward will not be just a simple expansion, but most importantly their enhanced integration.

Slide 36:

One very important initiative that GU tumors again has been at the forefront is the ability to integrate the SPORE program with other major initiatives that are underway with regard to basic investigation or discovery. The mouse models of human cancer consortium, which is an effort to develop models of human cancer in the mouse, for the first time had a joint meeting with the prostate SPOREs just about a month ago.

And in that context, there was an extraordinary dynamic interaction between the two that has resulted in over 50 recommendations going forward for the opportunities for increased collaboration and resource sharing. So it's a part of our agenda to drive the integration of these programs.

Slide 37:

You have already heard about our process of progress review groups that are developed to be able to focus and define an appropriate strategic portfolio going forward. And the program review groups have really been quite effective at being able to define for us the strategic agenda going forward in prostate cancer, as well as in kidney and bladder cancer.

Slide 38:

One of the important initiatives out of the prostate PRG has been the fact that we have now defined an NIH-wide prostate cancer research plan that has been disseminated, that includes collaboration and cooperative activities with other elements of the NIH, bringing other institutes into a cooperative, collaborative process to foster prostate cancer.

Slide 39:

The PRG process has defined a very important strategic agenda for prostate that has seven strategic areas for opportunities.

Slide 40:

And the same process has occurred with regard to the kidney and bladder PRG, giving us a road map, if you will, for future strategic resource allocations and investments.

Slide 41:

The concept that I believe is most appropriate for us is to think of this as a collaborative, cooperative effort that involves two levels of integration. The first is the integration that must occur vertically.

And the NCI bears the burden and the responsibility of providing the leadership, and providing the opportunity to disseminate throughout the research community, the opportunities to be able to enhance and affect the discovery development delivery portfolio, but to do so in a way in which there is vertical integration, so that this flows through to the point where we really have impacted on the community and patients who are at need.

In addition to the vertical integration, there needs to be enhanced horizontal integration, both within the NCI, and there is great effort underway to do a number of trans-NCI initiatives that cut across the traditional divisions. And we are also fostering that through many of our programs, for example, an effort that is underway to enhance further collaboration and integration among the cancer centers.

Slide 42:

And so it's a dynamic process, a process that I believe the urologic community remains at the forefront of. And we continue the process of fitting the pieces together in a way that helps us to further enhance what we know, to define what we don't know. And more importantly, to recognize that there is so much that we don't know, that we don't know.

But working together with GU tumors as an important example of leadership for the future, I believe that we have extraordinary opportunity to achieve and to recognize that hope for the future that Pres. Bush committed this country to achieve. And I really can't tell you how proud and honored I am to be a part of this community, and have the opportunity to share with you our ability to work together to achieve that dream.

Thank you.