Science Talk: Gleevec and Beyond

Last month, the Food and Drug Administration (FDA) approved the drug STI571 (Gleevec from Novartis) as an oral treatment for chronic myelogenous leukemia (CML), a chronic disease in which too many white blood cells are produced in the bone marrow. Approved by the FDA after an expedited review, Gleevec is the first drug that turns off the signal of a protein known to cause a cancer.

In the wake of the approval and the news coverage it garnered, News&Views asked half a dozen faculty members of The Scripps Research Institute (TSRI) who belong to the Cancer Affinity Group—a group of scientists and medical professionals in the area who sponsor an organized seminar series on cancer-related topics—to comment on Gleevec, what it represents for the future, and whether it has changed their thinking about cancer targets.

 

Immunology Professor Ralph Reisfeld One has to use the word "breakthrough" carefully, because it has been used in the past, and, in my opinion, false hopes were given. Not intentionally, but it resulted in false hopes in patients. Having had cancer in my own family, and knowing what it means to those people afflicted by it, I am very careful not to raise any false hopes. More work has to be done, but what is terribly exciting, at least to my understanding, is that Gleevec is the fruit of extensive work on the Philadelphia chromosome by many scientists who learned to target abnormal proteins on tumor cells with molecular-targeting drugs. In fact, in the early 1990s, scientists at CIBA-Geigy, later Novartis Pharmaceuticals, were able to use a well-defined target, the bcr-abl gene, located at the place where chromosomes 9 and 22 are fused together. [They] characterized its aberrant, cancer-causing protein. They created Gleevec and designed it to shut off the BCR-ABL protein in patients with chronic myelogenous leukemia, or CML. This is an exciting area of research since the powerful molecular technology now available to scientists should lead to the discovery of correct targets in other cancers. Several initiatives are underway at the National Cancer Institute, such as the Cancer Genome Anatomy Project, the Molecular Targets Initiative, and the Molecular Classification of cancer. A number of questions still need to be answered. These include: How long does Gleevec control CML? Does Gleevec actually cure patients of CML or does the drug delay the onset of more advanced forms of cancer? If [the latter], how long does Gleevec keep CML in check? Can the effectiveness of Gleevec be increased in combination with other drugs? Gleevec may also target other cellular proteins such as C-Kit and platelet-derived growth factor receptor (PDGFR). A number of clinical trials are underway to find other tumors that may respond to Gleevec, such as gastrointestinal stromal tumor, glioma, and soft tissue sarcoma.

Immunology Professor Gary Bokoch Gleevec is a good example of how our current knowledge about how signaling pathways contribute to diseases [can allow scientists] to target these pathways. It's an amazing drug from what I've heard—remission rates that are unheard of and very few side effects so far. It opens up a lot of promising new areas of research. I'm hoping that this will serve as an example for [those in] the drug industry and will stimulate them to think more deeply about going after signaling molecules. What Gleevec targets is a tyrosine kinase. It appears that it is possible to get quite specific inhibitors of kinases, and I think that we are going to be able to use that fact to target a lot of different types of kinase pathways regulated by proteins such as GTPases. There are something like 100 tyrosine kinases, and there are about 400 serine and threonine kinases, and [molecules like the] GTPases are using these kinases to regulate cell function. The drug has proven what a lot of people in the signaling field have tried to say to people working in therapeutic areas: that signal transduction provides viable targets to intervene in many types of disease processes.

Chemistry Professor Chi-Huey Wong [Gleevec] was developed to target a tyrosine kinase associated with a leukemia. The time to FDA approval was very short. It's quite an impressive story. I think that kind of approach is very interesting—and even more so in the future because of the information we will get from genomic research. We may be able to identify unique sequences or molecules associated with cancers and those could be interesting targets for drug development. The other important thing is to understand how cancers are formed. It's still a puzzle.

Chemistry Professor K.C. Nicolaou Gleevec is a fantastic success story by Novartis. The drug will help a population of patients suffering from certain types of leukemia and gastrointestinal cancer. Its widespread applicability remains to be seen, however. The science behind this discovery is exemplary of the modern drug discovery process in which biology identifies and validates a target responsible for a given disease, and chemistry designs and synthesizes small molecules to bind and knock out the action of the culprit protein target. With the human genome now deciphered, we will have many more such biological targets to go after, and with the sharpening of the tools of chemistry, the drug discovery process will be faster and more precise. New drugs will come out at an accelerated pace and will possess more selective action and fewer undesirable side effects. With so many more anticancer drugs in the pipeline and so much research underway, I am very optimistic about the future. I am afraid, however, that magic drug we need to cure cancer will not come tomorrow or all at once. Such new drugs will continue to reach the patients steadily, and, hopefully, sooner rather than later.

Molecular and Experimental Medicine Professor Bernard Babior I think that [Gleevec] certainly changes the outlook in terms of cancer chemotherapy, because it has a defined target. Most chemotherapeutics are like hitting the cancer with a sledge hammer. Gleevec is a much more delicate approach. It has the potential to be a very useful drug. One thing I do have to say, though, is that it is overrated. It has been advertised as the cure for chronic myeloid leukemia (CML). Maybe it is and maybe it isn't, but we won't know for some time to come. There are a lot of treatments for CML. None of them are specific like Gleevec, but all of them work for awhile and then stop working. I imagine that there may be a mutation in the BCR-ABL protein that would make it insensitive to Gleevec, and then Gleevec would stop working. Then the question is, "Is Gleevec going to turn out to be better than, say, hydroxy urea or the interferon, which are used now?" Interferon works for awhile and then it stops working. And Gleevec could work for awhile and then stops working. If it doesn't, then it would be wonderful. It's conceivable that you could even have a cure, but, to me, that would be a big surprise because cancer cells can mutate to evade treatment. My money would be against it. The question is how long Gleevec works. If it works longer than the present therapy, then you are in good shape. You may not have a cure for cancer, but you would likely have a much improved prognosis.

Molecular and Experimental Medicine Professor Ernest Beutler [Gleevec] represents the most concrete realization of what medical scientists have been expecting to happen: as we identify the molecular basis of cancer we will be able to target some of the causative molecules. Thus, this development hardly comes as a surprise. In fact, maybe the most surprising thing is that it has taken so long to find a target. Of course, we've been treating targets all along but we haven't previously had as clear an idea of what the targets were and how the drugs worked. What's particularly elegant about this story is that it demonstrates how basic understanding of a type of cancer can ultimately lead to an effective treatment. This story goes back about 40 years, and it has been a succession of findings over those 40 years, not a sudden insight, that has led to Gleeve—from morphology to molecular biology to protein chemistry, and, finally in the end, to the design of the drug. This could be a model for other types of cancer. Most medical scientists have the conviction that there will not be a single cure for cancer. Cancer is due to a series of perturbations of cell growth control, and there are many different causes. As these causes get identified, one can think seriously about interfering or replacing the aberrant function and, in that way, curing the cancer. It's a first of sorts. It's an expected first, and hopefully there will be a lot of others. This is the reason why it is important to support basic research.

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