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Gleevec, a drug regarded by many as having "wonder
drug" capabilities in the treatment of chronic myelogenous leukaemia
(CML) and other cancers, has been revealed as having shortcomings in
that some patients have undergone a relapse after building a
resistance to the drug. For others with the advanced stage of the
disease, the drug has failed to produce durable
remissions.
Now however, scientists have discovered that a molecular
understanding of resistance has rapidly led to a new generation of
drugs that might prove even more effective than Gleevec.
Two new studies report that a new compound, known as AMN107, may
one day offer a more potent alternative for treating patients with
acquired Gleevec resistance and others with advanced CML.
In its original conception Gleevec works in CML patients by
selectively deactivating Bcr-Abl, the abnormal tyrosine kinase
protein that triggers rapid growth of leukemic cells and was hailed
as the first approved drug to directly inhibit the activity of an
enzyme known to cause uncontrolled cell growth, and it has been
highly successful for many patients.
But scientists soon recognized that some patients develop
mutations in the Bcr-Abl protein that drastically reduces Gleevec's
effectiveness.
To overcome this resistance to Gleevec, scientists are designing
new compounds and AMN107 is one such drug produced by Novartis
Pharmaceuticals in Basel, Switzerland in collaboration with
investigators at the Dana Farber Cancer Institute.
Basically AMN107 retains half the chemical makeup of Gleevec,
while the other half was designed to create a tighter link to
Bcr-Abl, thus increasing potency and potentially overcoming
resistance due to mutations in Bcr-Abl.
Scientists at the Oregon Health and Science University in Portland
compared the potency of the new compound against Gleevec using a
panel of cell lines expressing 16 different Gleevec-resistant,
mutant versions of Bcr-Abl and their results showed that AMN107 was
at least 20 times more potent than Gleevec against most of the
resistant mutants.
Thomas O'Hare, a research specialist in Gleevec pioneer Brian
Druker's laboratory at the Oregon Health and Science University
Cancer Institute says the results show that 15 of the 16 mutants
were sensitive to AMN107, while one mutant remained insensitive and
would require a different, as yet undiscovered, inhibitor. The
results were equally impressive when the other leading drug in this
field, a Bristol-Myers
Squibb compound called BMS-354825, was also investigated. The
team say that the data indicates that AMN107 is a highly active
Bcr-Abl inhibitor that may have clinical utility in patients with
Gleevec-refractory CML which is great news for patients. They
believe that having several safe and effective drugs available is
the key to controlling acquired drug resistance in CML.
Study leader, Francis Giles, M.D., a professor of medicine at the
University of
Texas M. D. Anderson Cancer Centre say AMN107 appears to
effectively rescue patients with chronic myeloid leukaemia (CML) who
did not respond to targeted therapy with Gleevec, more than 70
percent of advanced CML patients in an international study have
shown a response to the drug, AMN107, and patients with the early
form of the disease have responded at a rate of more than 90
percent.
Giles says "If you can take a pill and rescue people who failed
the current standard of care, that is remarkable, the drug is very
safe, and we are seeing a response that improves daily."
The response rate in over 100 patients enrolled in the clinical
trial to date continues to improve, as doses are rapidly increased.
The first patients began treatment at 50 milligrams, but now all are
taking 400 milligrams twice a day "and we have certainly not reached
a dose-limiting toxicity," Giles says that the "vast majority" of
CML patients do very well on Gleevec, and that AMN107 was designed
to treat the 10 percent of patients who do not respond, either
because of a known mutation that Gleevec does not treat, or because
the cancer has advanced to the point where other mutations in the
cancer arise.
They are about to launch a series of studies testing use of
AMN107 as the first therapy used by CML patients, whether they have
the early chronic stage, advanced "accelerated" and terminal "blast"
stages of the disease to see how AMN107 can fit into the treatment
picture. They expect that patients will benefit from both agents.
Giles says the research represents a new era of medical treatment
where the integration between preclinical researchers and clinical
oncologists is seamless.
The study is being funded by Novartis, which manufacturers both
AMN107 and Gleevec. Giles presented first results of the therapy in
a fewer number of patients last December at the annual meeting of
the American Society of Haematology.
The study, which includes researchers and patients at the
University of Frankfurt in Germany, is still ongoing.
http://www.aacr.org/
http://www.news-medical.net/?id=9343 | 