Kidney Cancer Drug Attacks A Major Type Of Acute Myeloid Leukemia
ScienceDaily (Jan. 29, 2008) — A drug used to treat kidney cancer
also targets a genetic mutation active in about one third of patients
with acute myeloid leukemia (AML), the most common and lethal form of
adult leukemia, researchers at The University of Texas M. D. Anderson
Cancer Center report in the Jan. 29 edition of the Journal of the
National Cancer Institute.
In a Phase I clinical trial, the drug sorafenib reduced the median
percentage of leukemia cells circulating in the blood from 81 percent
to 7.5 percent and in the bone marrow from 75.5 percent to 34 percent
among AML patients whose leukemia includes the FLT3-ITD mutation. Two
patients had circulating leukemia cells, or blasts, drop to zero.
"AML patients with this mutation have a particularly poor prognosis,
so this highly targeted drug appears to be a significant step forward
in leukemia therapy," says senior author Michael Andreeff, M.D.,
Ph.D., professor in M. D. Anderson's Department of Stem Cell
Transplantation and Cellular Therapy and Department of Leukemia.
The JNCI paper reports the drug's effect in lab experiments, a mouse
model of the disease, and in a Phase I study of 16 patients with
relapsed or resistant AML known to have the FLT3-ITD mutation.
There have been no major side effects in the clinical trial to date,
so no maximum tolerated dose has been reached, Andreeff notes. The
drug has little effect on cells with normal versions of the gene and
does not interfere with normal blood cell formation.
A Phase I/Phase II clinical trial for AML is open at M. D. Anderson
that combines sorafenib with the standard of care chemotherapy
combination for AML, idarubicin and cytosine arabinoside. Presently,
the trial is open for relapsed patients and those newly diagnosed
with high-risk disease, says study co-author Jorge Cortes, M.D.,
professor in M. D. Anderson's Department of Leukemia. As safety and
dose escalation research progress, sorafenib will be made available
to other patients and assume a role in frontline therapy.
About 14,000 new cases of AML are diagnosed annually in the United
States and the disease kills about 9,000 people each year. AML is
characterized by swift proliferation of immature white blood cells in
the blood and bone marrow that crowds out normal cells, leaving
patients exposed to infection, severe anemia, and bleeding.
While major progress has been made treating some forms of leukemia
and lymphoma, acute myeloid leukemia has seen less improvement in
recent years. Andreeff says that's because AML exploits multiple
molecular pathways and that these pathways differ from one type of
AML to the next.
Andreeff and colleagues have shown that molecular pathways subverted
and used by AML collude with each other, so when one pathway is
blocked, the others redouble their efforts to fuel the disease.
"Here we have a great response against an important mutation, but
sorafenib alone will not cure patients," Andreeff notes. Combination
therapy will be required. Andreeff and colleagues are planning to
examine other sorafenib combinations against FLT3-mutant disease.
After in vitro tests showed that sorafenib inhibited the growth of
FLT3 mutant leukemia cell colonies, the research team tested the
medication in a mouse model of the disease. Sorafenib-treated mice
had a median survival of 36.5 days compared with 20.5 days in
untreated mice. Bioluminescence imaging showed widespread cancer
growth in untreated mice and barely detectable disease in those that
had received the drug.
Sorafenib, known commercially as Nexavar® and co-developed by Bayer
AG and Onyx Pharmaceuticals, already is approved for advanced renal
cell carcinoma and inoperable liver cancer by the U.S. Food and Drug
Administration. It is being tested against other solid tumors.
The drug targets both tumor cell growth and angiogenesis - new blood
vessels woven by cancer to sustain itself - by targeting two classes
of kinases, which are enzymes that affect proteins by attaching
phosphate groups to them.
Sorafenib's antileukemia effects appear to be superior to early
results of new therapies under development that more narrowly target
the FLT3 gene. Andreeff says the drug's ability to hit multiple
kinases probably accounts for this, but the exact molecular
mechanisms involved require further study.
Co-authors with Andreeff and Cortes are lead author Weiguo Zhang,
M.D., Ph.D., who conducted most of the project's laboratory research,
Marina Konopleva, M.D., Ph.D., Yue-xi Shi, Teresa McQueen, Xiaoyang
Ling, Ph.D., all of the department of Stem Cell Transplantation and
Cellular Therapy; David Harris, Zeev Estrov, M.D., and Alfonso
Quintas-Cardama, M.D. all of the Department of Leukemia; and David
Small, M.D. of Johns Hopkins University School of Medicine.
Research was funded by grants from the National Cancer Institute, a
Leukemia SPORE Career Development Award, and the Cancer Therapy
Evaluation Program.
Adapted from materials provided by University of Texas M. D. Anderson
Cancer Center.
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