Chapter 22: Studies of Gastro-Intestinal Stromal Tumor


Chapter 22: Studies of Gastro-Intestinal Stromal Tumor



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In this chapter, Dr. Benjamin talks about the area where the greatest advances have been made: gastro-intestinal stromal tumor (GIST). He explains that these advances built on the work of Jeffrey Gottlieb in the 1970s. He explains the successful treatments with Gleevec and notes that this is an example where the "low hanging fruit" idea associated with the Moon Shots paid off. Next Dr. Benjamin explains the value of developing good, non-toxic treatments that will inhibit the majority of pathways that become dominant in cancer. He advocates a poly-targeted approach, acknowledging that the clinician's view is that all drugs have toxicity and putting toxic drugs in combination is not as easy as it looks.



Publication Date



Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Overview; Definitions, Explanations, Translations; Discovery and Success


Tacey Ann Rosolowski, PhD:

I was just curious because it seems like, I mean, it’s a very different model for conducting research than the institution has seen before, and, you know, I mean, I’m not asking for, you know, harpoons or anything. (laughs) I’m just, like, what’s an evaluation of it, and also how, you know, there’s what’s evolving is publicly a slightly different research culture now that that model has been established.

Robert Benjamin, MD:

I think eventually the much more detailed knowledge of cancer biology is going to get us to much more sophisticated strategies for treatment than we currently have, but I don’t know that it’s likely to be quite as straightforward as proposed. But I may be totally wrong in that. I mean, within the area of sarcomas, the place where the greatest advances have been made during my career have been in the treatment of gastrointestinal stromal tumors, and because those are tumors where initially those of us who were smart clinicians paid attention to what Jeff Gottlieb said when he analyzed some of the original studies of Adriamycin and Dacarbazine treating soft-tissue sarcomas and he went back and said, you know, it’s funny that the site of the primary tumor has marked influence on the results of treating metastatic tumors, and the example he gave was that tumors that arose in the gastrointestinal tract responded much less well than tumors that arose in the genitourinary tract. And the pathologists called them all leiomyosarcomas. So this is 1975 that he said there’s got to be something different about these tumors even though they look the same. So it took another twenty years before the concept of GIST was recognized.

Tacey Ann Rosolowski, PhD:

The concept of—

Robert Benjamin, MD:

GIST, gastrointestinal stromal tumor. And that, in fact, the reasons why those GI leiomyosarcomas didn’t respond to therapy were, in fact, that they weren’t leiomyosarcomas at all, they were GISTs, and they had a totally different biology from all other sarcomas. But interestingly, that biology was driven almost exclusively by mutations in the KIT gene, and that KIT mutation just happened to be a mutation that could be targeted by the tyrosine kinase inhibitor Gleevec that was being used in the treatment of chronic myelogenous leukemia. And when we started to use Gleevec for GI stromal tumors—and we didn’t initiate this, but several other people had the same ideas around the same times, and somebody else got there first, but we saw that these tumors that had never responded to anything all of a sudden were melting away with a simple nontoxic pill. So that’s an example of where the low-hanging fruit paid off. But it’s also been said that most cancers are not as stupid as GIST. So when they have abnormalities in a particular metabolic pathway, if you block that pathway, they quickly find an alternative pathway that they can use just as effectively that you haven’t blocked. And I think the majority of cancers fall into that model rather than into the GIST model.

Tacey Ann Rosolowski, PhD:

You know, it’s an interesting terrain, you know, of perspectives on the problem, and because as I’m listening to you, I’m thinking, wow, you know, is there a difference between the perspective that you bring because you’re a clinician versus someone who operates more predominantly out of a laboratory scenario, at any rate, and how that experience makes you frame the problem. And now I’m wondering, well, you’ve got a clinician, you’ve got someone who’s a basic scientist, and you have people who believe in personalized therapy, and the kind of constant ability of cancer to morph itself, that brings an entirely different perspective. So I think the argument of how you best approach a problem can be very complicated indeed, you know. No one answer.

Robert Benjamin, MD:

No, no one answer. But if we can develop good, relatively nontoxic treatments that will effectively inhibit the majority of pathways that end up becoming dominant in different cancers and figure out ways of putting them together, then perhaps the personalized approach will work very well, if we can just say, okay, this is a cancer that has this, this, and this abnormalities, or it has this abnormality, and we know whenever this abnormality is blocked, then we get this next one, come in with a poly-targeted approach to managing it, that’ll be fine. But the practicalities from the point of view of the clinician is that all drugs have toxicity, and putting toxic drugs together is not always as easy as it looks. So, I mean, I think there’s going to be plenty of opportunity to develop things. I have no question that cancer treatment twenty years from now is not going to look like cancer treatment today. But I think there’s some areas, some parts of it, where it may.

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Chapter 22: Studies of Gastro-Intestinal Stromal Tumor