A pioneering clinical trial is testing the effectiveness in leukemia of a small molecule that shuts down MDM2, a protein that can disable the well-known tumor suppressor p53.
Michael Andreeff, M.D., Ph.D., professor of Medicine and chief of Molecular Hematology and Therapy in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, presented preliminary results of this ongoing Phase I study at the 52nd Annual Meeting of the American Society of Hematology. 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, Andreeff said.
Andreeff has been researching the interaction between MDM2 and p53 for five years. He says he believes this study may lead to an effective new way to fight some types of cancer with fewer side effects.
"P53 can be activated by chemotherapy or radiation, but both of these therapies carry risks of causing secondary tumors," he 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."
Too much MDM2 degrades p53
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.
Previous research has suggested that p53 activation by disrupting the binding of MDM2 to p53 may be a novel strategy for cancer therapy. 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.
Clinical effects seen
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).
"RG7112 has been well tolerated, and we've seen some effectiveness," Andreeff said. "So far it has done exactly what we thought it would. This gives us evidence it can be used in patients, is well-tolerated and can be given in dosages that can escalate to a point that shows a higher response rate."
Enrollment in this study is ongoing and will be updated. Future single-agent and combination studies of RG7112 in leukemias are planned.
Co-authors with Andreeff are Kensuke Kojima, M.D., Ph. D., Molecular Hematology & Therapy, MD Anderson Department of Leukemia and Susan O'Brien, M.D., Gautam Borthakur, M.D., and Marina Konopleva, M.D., Ph.D., all of the Department of Leukemia; Felipe Samaniego, M.D. MD Anderson Department of Lymphoma/Myeloma; Swaminathan Padmanabhan, M.D., The University of Texas Health Science Center at San Antonio; Roger Strair, M.D., Cancer Institute of New Jersey, New Brunswick; Mark Kirschbaum, M.D., City of Hope National Medical Center, Duarte, Calif.; Peter Maslak, M.D., Memorial Sloan-Kettering Cancer Center, New York; Peter Hillmen, MBChB, Ph.D., St. James's University Hospital, Leeds, United Kingdom; and Lyubomir Vassilev, Ph.D. and Gwen Nichols, M,D., Roche, Nutley, NJ
The research was funded in part by Roche and by grants from the National Cancer Institute to Andreeff.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For seven of the past nine years, including 2010, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Get MD Anderson News Via RSS Follow MD Anderson News on Twitter
Scott Merville | EurekAlert!
Research team of the HAW Hamburg reanimated ancestral microbe from the depth of the earth
01.03.2017 | Hochschule für Angewandte Wissenschaften Hamburg
Researchers Imitate Molecular Crowding in Cells
01.03.2017 | Universität Basel
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded after a glide flight with an Airbus A320 in ditching on the Hudson River. All 155 people on board were saved.
On January 15, 2009, Chesley B. Sullenberger was celebrated world-wide: after the two engines had failed due to bird strike, he and his flight crew succeeded...
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
01.03.2017 | Health and Medicine
01.03.2017 | Physics and Astronomy
01.03.2017 | Life Sciences