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.
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