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!
Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH
Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
20.01.2017 | Awards Funding
20.01.2017 | Materials Sciences
20.01.2017 | Life Sciences