Wednesday, Jan. 17, 2007
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.
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.
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
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.
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.
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
About VCU and VCU Medical Center
Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 226 degree and certificate programs in the arts, sciences and humanities. Sixty-seven of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University comprise VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.
About the VCU Massey Cancer Center
VCU Massey Cancer Center is one of only 68 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, Massey 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 the most cancer clinical trials in Virginia and serves patients at 10 locations. Its 1,000-plus 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 cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.