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Researchers Develop New Strategy For The
Treatment Of CML
Main Category:
Lymphoma / Leukemia News
Article Date: 22 Jan 2007 - 21:00 PST
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Virginia Commonwealth University Massey Cancer
Center researchers have identified an approach
to enhance the activity of a new anti-cancer
agent that has already shown impressive efficacy
in the treatment of chronic myelogenous leukemia.
Chronic myelogenous leukemia, or CML, is a
cancer of the bone marrow caused by a specific
genetic abnormality and is one of the more
common forms of leukemia. Imatinib mesylate
(Gleevec) is a highly effective anti-cancer
agent that has revolutionized the course of
therapy for patients with CML. It works by
inhibiting the activity of a mutant protein,
known as Bcr/ABl, which is responsible for this
disease. However, despite initial success,
patients eventually become resistant to imatinib
mesylate.
According to Steven Grant, M.D., Massey's
associate director for translational research
and co-leader of the cancer center's cancer cell
biology program, and senior author of the study,
resistance to imatinib mesylate has prompted the
development of newer generation inhibitors, such
as a compound known as dasatinib, which are not
only considerably more potent than imatinib
mesylate, but also are active against cells
expressing many of the mutations that make them
resistant to the latter agent. Dasatinib also
inhibits another important survival protein
known as Src. However, Grant said that not all
patients respond to dasatinib, and the risk
remains that patients will develop resistance to
this agent as well.
To address this problem, Grant and colleagues
examined the effects of combining dasatinib with
PD184352, another clinically relevant small
molecule inhibitor of a critical cellular
survival pathway that inactivates an important
survival protein known as ERK1/2
(extracellular-signal regulating kinase1/2). The
article was pre-published as a First Edition
Paper in Blood, the journal of the American
Society of Hematology, which appeared online
Jan. 11.
By blocking this pathway, PD184352 reduces the
survival and proliferation in numerous tumor
types, including leukemia cells. The team found
that combining extremely low concentrations of
dasatinib with PD184352 resulted in a dramatic
increase in apoptosis, or programmed cell death,
in association with inactivation of multiple
survival signaling pathways. Notably, enhanced
lethality occurred in CML cells displaying
various forms of imatinib mesylate resistance,
said Grant.
"While the development of newer, more effective
kinase inhibitors such as dasatinib for diseases
such as CML is a clear priority, resistance of
leukemia cells to these novel agents may also
develop," said Grant.
"Addition of a second, targeted agent that
potentiates the activity of dasatinib may reduce
the leukemic burden further, and thereby reduce,
or possibly even prevent the emergence of drug
resistance. If validated, this concept could
have significant implications for the treatment
of CML and possibly other hematologic
malignancies," said Grant.
This work was supported by grants from the
National Institutes of Health, the Leukemia and
Lymphoma Society of America and the Department
of Defense.
Grant, who is also a professor of medicine and
the Shirley Carter and Sture Gordon Olsson
Professor of oncology, worked with a team that
included: Tri K. Nguyen, Ph.D., Mohamed Rahmani,
Ph.D., Hisashi Harada, Ph.D., all in the VCU
Department of Medicine; and Paul Dent, Ph.D., a
professor in the VCU Department of Biochemistry.
About VCU and the VCU Medical Center:
Virginia Commonwealth University is the largest
university in Virginia and ranks among the top
100 universities in the country in sponsored
research. Located on two downtown campuses in
Richmond, VCU enrolls more than 30,000 students
in nearly 200 certificate and degree programs in
the arts, sciences and humanities. Sixty-three
of the programs are unique in Virginia, many of
them crossing the disciplines of VCU's 15
schools and one college. MCV Hospitals and the
health sciences schools of Virginia Commonwealth
University compose the VCU Medical Center, one
of the nation's leading academic medical
centers.For more, see
http://www.vcu.edu/.
The VCU Massey Cancer Center:
The VCU Massey Cancer Center is one of 61
National Cancer Institute-designated
institutions that leads and shapes America's
cancer research efforts. Working with all kinds
of cancers, the Center conducts basic,
translational and clinical cancer research,
provides state-of-the-art treatments and
clinical trials, and promotes cancer prevention
and education. Since 1974, Massey has served as
an internationally recognized center of
excellence. It offers more clinical trials than
any other institution in Virginia, serving
patients in Richmond and in four satellite
locations. Its 1,000 researchers, clinicians and
staff members are dedicated to improving the
quality of human life by developing and
delivering effective means to prevent, control
and ultimately to cure cancer. Visit Massey
online at
http://www.massey.vcu.edu/.
Contact: Sathya Achia-Abraham
Virginia Commonwealth University
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