SLIDES & TRANSCRIPTS
Wednesday, February 16, 2000

Can Treatment Be Tailored to Biologic Characteristics?
James Abbruzzese, MD

DR. MAYER: Let us begin this morning's session, and our first session is entitled "Can Treatment Be Tailored to Biological Characteristics." This session will be chaired by Dr. James Abbruzzese.

Jim is Chairman of the Department of Digestive Diseases at the M.D. Anderson Cancer Center in Houston.

Jim?

DR. ABBRUZZESE: This morning's session is going to in many ways recapitulate a lot of the concepts and ideas that were presented yesterday. I have identified three speakers whom I hope can try to begin to bring some of these issues directly to the level of the individual patient.

May I have the next slide?

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How can we use biologic characteristics -- and we have talked about many of these, both the molecular as well as clinical characteristics to the individual patient -- and how can that drive specific treatment decisions? I think the three speakers are going to be able to address this exceedingly well.

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Next slide, please.

So, in answer to the question, like the colorectal PRG, I think the short answer to this question is yes. I think it has to be. We have got to get to a level of understanding of colorectal cancer, as well as other neoplasms, that can allow us to drive and individualize therapy for patients, to select from what I hope will be a very large number of therapeutic options and select those that are going to uniquely benefit that patient and hopefully produce improved survival.

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Next slide.

I wanted to re-emphasize, and I think again this will repeat some of the issues that we have talked about previously yesterday, what we need to do to accomplish this overall goal. As Eric Fearon showed, evolving on a daily basis, we need to have detailed understanding at a biochemical level of colorectal carcinogenesis. We need to fill in all the gaps and identify the important targets through that understanding.

We talked a lot about identifying and validating appropriate targets for therapy, for prognosis, for prediction. That is going to take an enormous effort, and I think you can see that how to do that in sort of response to the question I asked, how to do that is not obvious -- absolutely obvious -- at this point in time.

We talked a lot about techniques to assess targets in tumor in surrogate tissue. I would argue that we need to look at the tumor in particular, if we can, either through invasive or non-invasive techniques.

Next slide, please?

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The technology is obviously evolving very quickly. This is a slide of confocal microscopy of a colorectal crypt taken from patients in a trial we recently completed of celecoxib in patients with familial adenomatous polyposis. This is the sort of technology I think that we will be able to utilize more and more effectively. This is a fairly simple approach where we were able to triple stain these crypts for apoptosis which is a white staining cell, and mitotic proliferative fraction of cells using the yellow stain, and I think over time we are going to be able to translate more and more of these more tissue-based assays into assessing the effects of our therapy. This is just one simple example.

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Eric Fearon yesterday talked about some of the pathways that contribute the signal transduction pathway to genetic pathways that contribute to colorectal carcinogenesis, and we are constantly filling in the details. In fact, it is a moving target. I think that is one of the biggest challenges, that simple concepts such as inhibiting Cox II with a compound such as celecoxib or non-specifically with sulindac now it is interesting that may be the way it works, but there are other targets.

PPAR delta which is a target of the beta catenin APC pathway seems to be an important target as well, maybe more important than Cox.

This is data from a recent paper published in Cell by the Kinzler-Vogelstein group. So, we need to keep aware of these new targets that are going to be changing.

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What do we need to more rapidly accomplish these goals of individualizing therapy? Obviously I think we need effective targeted therapy. My personal view is that the two or three drugs that we have right now are not targeted, and they are not particularly effective.

We need to do better. I think we sort of pat ourselves on the back. We have a couple of new drugs that we can play around with in combination, but in reality we are nowhere near where we need to be to try to individualized therapy based on the sort of concepts that have been talked about yesterday.

We talked about establishing large tissue banks. I think that is fairly straightforward. How to do that, how to fund it, Carolyn talked extensively about that. That is a potential problem, a barrier that we need to overcome. We need extensive clinical data on cohorts of patients treated in uniform fashion to try to make sense of all these data and, of course, we talked extensively about the pathology and laboratory infrastructure, the costs associated and the techniques associated with trying to accomplish this.

Next slide, please?

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Just for an understanding of the underlying pathologic biochemistry of colorectal cancer to be relevant to the management of human malignancy, specific biologic characteristics must convey clearly defined prognostic or predictive information that impacts individual patient management.

I think that is what we are trying to achieve. The challenge for us: I put 100 years because I am a little bit pessimistic that we are going to be able to accomplish this in 10 or 20 years, although I think Len, who is going to be the first speaker, has a little bit different perspective, and I would like to see this happen. I think this is going to take some time to sort this all out. I hope we can do it faster.

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Next slide, please?

I have selected three people that I think are working very hard to accomplish this goal, are working at the level of both the clinic and the laboratory, and I think we will learn a lot from these three presentations.

So, first up, Len Saltz, then Al Benson will speak on some of his work, and I have asked Dr. Peter Danenberg to kind of update the state of the science and look a little bit into the future.

Thank you.

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