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 Groupa group of scientists and
medical professionals in the area who sponsor an organized seminar series
on cancer-related topicsto comment on Gleevec, what it represents
for the future, and whether it has changed their thinking about cancer
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
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
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 heardremission
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
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.
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 interestingand 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.
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
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.
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
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
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.
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 Gleevefrom 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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