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!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy