Small molecule may deactivate enemy of cancer-fighting p53
Washington, Dec 8 (ANI): Scientists are conducting a pioneering clinical trial to test the effectiveness in leukemia of a small molecule that shuts down MDM2, a protein that can disable the well-known tumor suppressor p53.
The clinical trial is under way at MD Anderson and five other sites in the United States and United Kingdom.
The first-in-class drug has shown clinical activity in some patients and been well-tolerated, Michael Andreeff, at The University of Texas MD Anderson Cancer Center said.
"P53 can be activated by chemotherapy or radiation, but both of these therapies carry risks of causing secondary tumors," Andreeff said.
"If we can activate this tumor-suppressor with a method that is non-genotoxic and does not cause damage to a patient's DNA, we may be able to help avoid secondary tumors caused by other treatments," he added.
Normally, p53 halts the division of defective cells and forces them to commit suicide or lose the ability to reproduce. However, the tumor suppressor is disabled in many types of cancer, often because of gene mutations or defective signaling.
While mutations of the TP53 gene are rare in cancers of the blood, the p53 protein may be degraded by other factors, including high levels of MDM2, which binds to p53 and orchestrates its degradation.
In preclinical studies, small-molecule MDM2 antagonists called Nutlins were found to be effective in solid tumors, leukemia and lymphoma.
The drug used in this study, RG7112, a novel small molecule being developed by Roche, is a member of the Nutlin family.
Patients with relapsed or refractory acute or chronic leukemia were given RG7112 orally each day for 10 days, followed by 18 days of rest. Forty-seven patients, including 27 with acute myeloid leukemia (AML), have been treated to date.
There has been evidence of clinical activity, and one patient with AML has been leukemia-free for nine months. Reductions in lymph node and spleen size, as well as in circulating leukemia cells, were seen in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
The preliminary results of this ongoing Phase I study were presented at the 52nd Annual Meeting of the American Society of Hematology. (ANI)
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