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Combination of two novel anti-cancer agents may help fight chronic myelogenous leukemia resistant to
Combination of two novel anti-cancer agents may help fight chronic myelogenous leukemia resistant to
http :// www .news.vcu.edu/news.aspx?v=detail&nid=2521
For immediate release:
5/29/2008
Sathya Achia Abraham
VCU Communications and Public Relations
(804) 827-0890
sbachia@vcu.edu
Combination of two novel anti-cancer agents may help fight CML resistant to
current therapy
Virginia Commonwealth University Massey Cancer Center researchers have
identified that a combination of novel anti-cancer compounds is able to kill
chronic myelogenous leukemia cells previously resistant to conventional
forms of therapy.
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, or 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 the disease. However, despite initial success,
patients eventually become resistant to imatinib mesylate, often through the
development of further mutations in the Bcr/Abl protein.
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 prompted the search for newer agents that are active against the
mutated forms of Bcr/Abl. Such agents include MK-0457, a Bcr/Abl kinase
inhibitor that also targets another protein called an aurora kinase. Aurora
kinase plays an important role in mitosis and cell division. In preclinical
studies, MK-0457 is active against the T315I Bcr/Abl mutation, a major cause
of imatinib resistance, and has shown promise in early clinical trials,
Grant said.
In this study, Grant and colleagues examined the effects of combining
MK-0457 with vorinostat, a novel targeted agent that has recently been
approved for the treatment of cutaneous T-cell lymphoma. They found that
this combination leads to a dramatic induction of apoptosis, or programmed
cell death in CML cells, including imatinib-resistant cells bearing the
T315I or other mutations. The article was pre-published as a First Edition
Paper in Blood, the journal of the American Society of Hematology, which
appeared online May 27.
Further, Grant said that the interaction between these agents may occur at
multiple levels, including potentiation of Bcr/Abl inhibition as well as
enhanced disruption of aurora kinase and mitosis. In addition, the group
demonstrated that vorinostat-mediated up-regulation of Bim, a pro-apoptotic
protein, contributed significantly to the effectiveness of this regimen.
"Our findings suggest it may be possible to develop a clinical regimen
combining a third-generation Bcr/Abl kinase and aurora kinase inhibitor,
such as MK-0457, with histone deacetylase inhibitors, such as vorinostat,"
Grant said.
"Theoretically, this combination could improve upon the results of Bcr/Abl
kinase inhibitors administered alone, particularly in the case of
imatinib-resistant disease," he said. Further preclinical studies are
underway to test this hypothesis.
This work was supported by grants from the National Institutes of Health,
the Leukemia and Lymphoma Society of America, the V Foundation, and the
Department of Defense. Merck Pharmaceuticals supplied the agents tested in
the preclinical studies.
Grant, who is a professor of medicine and the Shirley Carter and Sture
Gordon Olsson Professor of oncology, worked with a team that included: Yun
Dai, Ph.D., Shuang Chen, Ph.D., Charis A. Venditti, Xin-Yan Pei, Ph.D., and
Tri K. Nguyen, Ph.D., all in the VCU Department of Medicine; and Paul Dent,
Ph.D., a professor in the VCU Department of Biochemistry.
EDITOR'S NOTE: A copy of the study is available for reporters in PDF format
by email request from the Media Relations Department at the American Society
of Hematology. Please contact: lstark@hematology.org.
http :// www .news.vcu.edu/news.aspx?v=detail&nid=2521
For immediate release:
5/29/2008
Sathya Achia Abraham
VCU Communications and Public Relations
(804) 827-0890
sbachia@vcu.edu
Combination of two novel anti-cancer agents may help fight CML resistant to
current therapy
Virginia Commonwealth University Massey Cancer Center researchers have
identified that a combination of novel anti-cancer compounds is able to kill
chronic myelogenous leukemia cells previously resistant to conventional
forms of therapy.
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, or 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 the disease. However, despite initial success,
patients eventually become resistant to imatinib mesylate, often through the
development of further mutations in the Bcr/Abl protein.
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 prompted the search for newer agents that are active against the
mutated forms of Bcr/Abl. Such agents include MK-0457, a Bcr/Abl kinase
inhibitor that also targets another protein called an aurora kinase. Aurora
kinase plays an important role in mitosis and cell division. In preclinical
studies, MK-0457 is active against the T315I Bcr/Abl mutation, a major cause
of imatinib resistance, and has shown promise in early clinical trials,
Grant said.
In this study, Grant and colleagues examined the effects of combining
MK-0457 with vorinostat, a novel targeted agent that has recently been
approved for the treatment of cutaneous T-cell lymphoma. They found that
this combination leads to a dramatic induction of apoptosis, or programmed
cell death in CML cells, including imatinib-resistant cells bearing the
T315I or other mutations. The article was pre-published as a First Edition
Paper in Blood, the journal of the American Society of Hematology, which
appeared online May 27.
Further, Grant said that the interaction between these agents may occur at
multiple levels, including potentiation of Bcr/Abl inhibition as well as
enhanced disruption of aurora kinase and mitosis. In addition, the group
demonstrated that vorinostat-mediated up-regulation of Bim, a pro-apoptotic
protein, contributed significantly to the effectiveness of this regimen.
"Our findings suggest it may be possible to develop a clinical regimen
combining a third-generation Bcr/Abl kinase and aurora kinase inhibitor,
such as MK-0457, with histone deacetylase inhibitors, such as vorinostat,"
Grant said.
"Theoretically, this combination could improve upon the results of Bcr/Abl
kinase inhibitors administered alone, particularly in the case of
imatinib-resistant disease," he said. Further preclinical studies are
underway to test this hypothesis.
This work was supported by grants from the National Institutes of Health,
the Leukemia and Lymphoma Society of America, the V Foundation, and the
Department of Defense. Merck Pharmaceuticals supplied the agents tested in
the preclinical studies.
Grant, who is a professor of medicine and the Shirley Carter and Sture
Gordon Olsson Professor of oncology, worked with a team that included: Yun
Dai, Ph.D., Shuang Chen, Ph.D., Charis A. Venditti, Xin-Yan Pei, Ph.D., and
Tri K. Nguyen, Ph.D., all in the VCU Department of Medicine; and Paul Dent,
Ph.D., a professor in the VCU Department of Biochemistry.
EDITOR'S NOTE: A copy of the study is available for reporters in PDF format
by email request from the Media Relations Department at the American Society
of Hematology. Please contact: lstark@hematology.org.
