DR. BENBROOK: Thanks, Bill, for the comprehensive overview of the GOG's work and its resources. Now Dr. Ozols will talk to us about some of the translational activities ongoing in the SPORE program, and then perhaps in the discussion we can see how to best marry these two entities to try to get some collaborative efforts moving forward.

DR. OZOLS: Thank you. I am going to start with the sort of 40,000-foot view and then home in on ovarian cancer, and our ovarian cancer SPOREs.

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Again, this is a SPORE definition of translational research, and I think you are all aware of it, but we should state it again, to use the knowledge of human biology to develop and test the feasibility of cancer related interventions in humans, to determine the biological basis for observations made in individuals with cancer, or in populations at risk for cancer.

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What are SPOREs expected to do? Well, SPOREs are expected to develop critical research infrastructure needed to sustain translational research, objectives for projects within a SPORE, as well as for potential collaborative research with other SPOREs and other research groups in the biomedical research community, and certainly should be in a position to facilitate the complex research objectives inherent in studying human cancer.

So, each of the SPOREs has projects that must have a clinician and a basic scientist, and have translational objectives, and certainly cores to support the project.

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SPOREs are expected to identify the kinds of research questions that can only be accomplished through the research collaborations, networks and consortia.

They are expected to collaborate with other scientists in the field to answer research questions that can full advantage of the SPORE's scientific expertise and infrastructure.

They are supposed to conceive and initiate research that is linked to other key programs of the NCI through the promotion of inter-SPORE research.

I think those are very lofty expectations. I think many of them are successful. Again, we need to look hard at some of them.

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Sharing information is one thing that is clear. We have had excellent SPORE workshops every year for two or three days, now, that have really been facilitating the sharing of information within the organ site networks, as well as other SPOREs, to take advantage of research results that are applicable to various cancer sites. So, again, you all are aware that SPOREs are based on disease specific sites, and the disease specific SPOREs.

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So, the question is, at this point, honing down from the higher view, have SPOREs, including ovarian cancer, met these objectives.

The answer is, not completely. We are not satisfied with the pace of the progress, and Dr. Von Eschenbach, the director of the NCI, has commissioned a translational research working group, as you heard from Dr. Gomez.

This is taken from Dr. Von Eschenbach's recent letter to the SPORE investigators. The reason for this is going to be an inclusive review of NCI's translational research objectives, including the SPOREs.

One of the major questions that I think Dr. Von Eschenbach is addressing in this review is the current disease focused SPORE program, the optimum structure -- these are his words -- to seize the opportunity of the new molecular view of cancer.

This is what we are hearing today over and over again about the molecular aspects of cancer and, again, as you heard over and over again, these are not unique to ovarian cancer.

So, the question is, is the disease-oriented model the appropriate model as we go into more molecular targeted therapies, and maybe there should be SPOREs, for example, in angiogenesis.

Those are the kinds of concepts that I think TRWG will address, and from Dr. Von Eschenbach I think the mandate was for substantial changes in the translational research program for the NCI to come out of the TRWG, including perhaps marked overhaul of the SPORE system.

I personally think that the disease-oriented SPOREs should continue to have a role. There is no drug that has been approved by the FDA, for example, for a targeted therapy. All the drugs approved by the FDA are for specific disease indications. So, I think SPOREs will continue to have that role.

I think the advocates are obviously very important in the SPORE programs, and I don't think we have advocates for signal transduction. We have advocates for the specific diseases, and I think we continue to benefit all the SPOREs from the advocate input.

So, I think we need to have at least some continuous elements of disease-oriented SPOREs, and I hope that will continue.

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Have the current ovarian SPOREs collaborated to promote translational research. You heard from Dr. Fountain that I think we have been very successful. The ovarian SPOREs have collaborated I think more than other SPOREs.

I think most of the clear-cut benefits that have come out of those collaborations that we can tangibly assess are really related, as Dr. Fountain pointed out, to the early detection, to biomarkers, because we have collaborated among ourselves and we have collaborated with the other NCI networks in that regard. So, I think that has been a very fruitful, intensive, continuous collaboration.

The key issue that I want to focus on now, and make some critical comments about is, really, have we collaborated enough on translational treatment approaches, and I think that is the answer, not as much as they should.

I still think that most translational research by ovarian SPOREs should be in the institution's own SPORE projects.

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Now, I don't want you to read this, but this is from the Pacific group from Fred Hutchinson. It just is a list of a whole series of very good, innovative translational research protocols as part of their SPORE.

Well, they are not going to be able to do all those in a timely manner. Fox-Chase has a list like this, UAB has a list like this, M.D. Anderson has a list like this.

We all have lists like this, and that is a problem. We all have individual, good translational research protocols which are accruing at a very slow pace.

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There have been a couple of examples of very good collaborations, and I think they should continue to be the framework.

You heard some of this from Andy Godwin and Rush Schilder about some GOG and SPORE collaborations, and that is one big focus that Bill Beck and I want to talk about and maybe the group wants to talk about, how ovarian SPOREs can work together with the GOG.

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There have been some studies -- I am not going to go into the details of this -- but looking at gefitinib and the clinical trial, and then doing some of the biochemical correlates or molecular correlates to see which patients may respond, and you heard about that, that the EGF mutations in the catalytic domain are present, but rare, in ovarian cancers, three to four percent, and those are the ones that are associated with a drug response.

I think that is a very important observation, that yes, there are some patients who will benefit. It required a collaboration between the GOG who did the study and Andy using SPORE resources to do these analyses, to find out that, yes, some patients may respond and, again, similar to other disease sites as you mentioned.

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This is an example of a study that we talked about earlier this morning, the cetuximab. Again, this was an inter-SPORE phase II clinical trial, and this was a relatively simple trial.

It also points out some of the problems in inter-SPORE collaborations. This was a phase II of single agent cetuximab, dose escalation to rash, to see if we could increase the response rate if all patients with ovarian cancer received cetuximab to the point where they developed the rash.

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This was a primary purpose study, and the objectives were the response rate, inhibition, and there were secondary objectives and, more important, there were translational objectives to look at biopsies from these patients to look at downstream effects, which ultimately then would lead us to the next generation of trials, where we could perhaps learn why patients didn't benefit, what the rash really had to do with perturbations in downstream effects, and then lead, again, hopefully to more specific therapies in the next generation of signal transduction inhibitors.

So, I think this is an example of a good collaboration between GOG and SPOREs, to come up with some quick answers.

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What are the bad parts about this? Well, this took a darned long time to do. We started talking about this over a year ago, and now we have opened a study, and you can see that we felt that we couldn't even get all the SPOREs together to agree on this, and we actually included other centers, such as Memorial and Moffitt and Ohio State , who had a big ovarian cancer program.

So, we developed a consortium that included not only SPORE centers, but non-SPORE centers. This will help to facilitate the study, but one of the problems, of course, is that the approval processes at these individual institutions take time, and sometimes we will complete the study before a center finally gets through the whole process of approval.

So, that has been one of the problems. It just takes too long. We are not satisfied with the pace of the disease. I think there are many good translational research ideas in the individual SPOREs, but we certainly have not been able to implement the facilitation of those trials in a really timely manner.

Again, you heard from Andy about some of the other studies. disadrovid, for example that we felt are really important for GOG and SPORE facilitation, and we need to go forward with those.

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Again, there are some studies that we are working on, but these are just a couple of examples. There should be a lot more examples of this type of collaboration between the GOG and SPOREs.

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So, what are the barriers to increased collaboration among ovarian SPOREs? I think you heard some of these today.

There are certainly institutional barriers. Every institution has its own lawyers that are certainly involved in this, and certainly industry has its own lawyers, as Maurie pointed out.

So, the legal issues about an intellectual property, about signing contracts, they are not getting any easier. They are, in fact, getting worse.

There are barriers about tissue sharing IRBs have. Individual pathology departments have their own rules, and some of them are very intransigent about shipping pathology specimens from place to place.

So, although there are institutional barriers that are very difficult in overcoming at times, there are industry barriers, as I mentioned.

Industry has its own objective. They want to get these studies done as rapidly as possible. They will go to the centers that can do the studies as quickly as possible.

They have problems with different institutions having different legal issues. So, at times, that can delay the activation of a protocol at multiple sites. Again, time is of the essence. They want these studies done yesterday and they want them done fast.

The big barrier, I think, is prioritization. I think that is right now the big problem. We have multiple translational research studies. There are some very innovative studies that George Coukos has, there are innovative studies at all the centers, but we all have menus that are just too long, that are too big and take too long to accomplish.

The logistical aspect, the data management, who is going to be responsible for all this. There is no real support, in many ways, to do all of this except for the cancer center structure. Should we have mini-Cooperative Groups among the SPOREs?

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Just to start the discussion going, these are maybe some a little controversial, but what are some of the potential solutions for increased collaboration?

Well, I think the NCI has got to step up to the plate. I think they have been very supportive of the SPORE system.

I think the SPORE system has been an extraordinary success. I think it can get better, and I applaud Dr. Von Eschenbach for reviewing it. We have got to do better.

The NCI may have to make some mandates, and it may be possible that TRWG may recommend there will be more of a disease-oriented approach, rather than targeting a specific molecular process instead of a disease-oriented approach.

It may be that the NCI may have to decide which trials need to be done and which studies are open simultaneously to all SPOREs.

The SPOREs need to prioritize their studies. I think we need to get together more frequently, we need to be flexible.

We need to perhaps meet and decide, okay, these are the studies that we are going to do. The first study may be M.D. Anderson's and the next study may be Dana-Farber's. So, we need to prioritize studies and we all need to agree upon them, and we all need to get them through our IRBs at the same time, so we can start them, open and close them in a timely manner.

Again, that is going to require flexibility. It is going to require some individuals giving up some of their individual autonomy in some of their studies, but I think that is the only way we can really get these studies ongoing.

Furthermore, I was pleased this morning, we did have -- all the SPOREs met with the GOG hierarchy to discuss how the SPOREs can work together with the GOG and to facilitate this kind of a research.

We raised many of these issues that we discuss now, and some that we talked about already, and the plan is that we are really going to try to get together, mandate us to get together in a locked room, and then come up with a strategy that we can really start to make this happen with perhaps a mini-group from the GOG, which we will do, trials in combination with the SPORE investigators, so that we can really try to accelerate this process.

The goal of this is to do good science, but the goal is also to facilitate the completion of so many good trials that we need to do in a timely manner. Thank you.

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