In the study, published in the journal Cancer Research, researchers combined the drug ABT-737 with another agent BEZ235. ABT-737 targets proteins known as B-cell lymphoma 2 (Bcl-2) and Bcl-xL, which prevent apoptosis, a form of cell suicide, in cancer cells. BEZ235 directly inhibits the PI3K/AKT/mTOR pathway, and as a result, reduces the expression of another anti-apoptotic protein known as Mcl-1, which is not targeted by ABT-737. Among their many functions, signaling pathways regulate biological processes required for cellular survival. The PI3K/AKT/mTOR pathway helps keep apoptosis in check, in part, by controlling the production of Mcl-1.
However, the pathway can become dysregulated in cancer, and in so doing, contribute to uncontrolled tumor growth and resistance to conventional cancer therapies. It is activated in 50 to 80 percent of patients with acute myelogenous leukemia (AML), and in some, but not all cases, is associated with genetic mutations. Significantly, disabling both anti-apoptotic proteins, Bcl-2 and Bcl-xL, in conjunction with Mcl-1, caused profound cell death of leukemia cells in the test tube as well as in animal models of AML.
"This study builds on many years of work in our laboratory investigating the mechanisms that regulate apoptosis in human leukemia cells. To the best of our knowledge, it is the first to raise the possibility that activation of the P13K/AKT/mTOR pathway, rather than genetic mutations within the pathway, may represent the best predictor of leukemia cell responses to these targeted agents," says one of the study's key researchers Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, program co-leader of Developmental Therapeutics and Cancer Cell Signaling research member at VCU Massey Cancer Center. "These findings could lead to a new therapeutic strategy for patients with AML and potentially other diseases by targeting patients whose leukemia cells display activation of a specific survival pathway."
Grant's team made another discovery that helped explain the new therapy's effectiveness. They found that the therapy releases and/or activates the pro-apoptotic proteins Bim, Bak and Bax, which help trigger apoptosis. Thus, in addition to disabling major pro-survival proteins, the combination therapy also helps to unleash several additional proteins that promote apoptosis.
Moving forward, Grant and his team hope to work with pharmaceutical companies and the National Cancer Institute to develop strategies combining inhibitors of the PI3K/AKT/mTOR pathway with Bcl-2 family antagonists for the treatment of patients with AML.
Grant collaborated on this research with lead author Mohamed Rahmani, Ph.D., associate professor of internal medicine at the VCU School of Medicine, who spearheaded this research. Other collaborators included David C. Williams M.D., Ph.D., co-director of the Tissue and Data Acquisition and Analysis Core at VCU Massey Cancer Center, researcher in the Developmental Therapeutics program at Massey and assistant professor in the VCU Department of Pathology; and Andrea Ferreira-Gonzalez, Ph.D., professor in the VCU Department of Pathology.
This research was supported by National Institutes of Health grants CA93738, CA100866-01, CA130805, CA142509, and CA148431; awards from the Leukemia and Lymphoma Society of America and the Multiple Myeloma Research Foundation; and, in part, by funding from VCU Massey Cancer Center's NIH-NCI Cancer Center Support Grant P30 CA016059.
The full manuscript of this study can be found online at: http://cancerres.aacrjournals.org/content/73/4/1340.long.
News directors: Broadcast access to VCU Massey Cancer Center experts is available through VideoLink ReadyCam. ReadyCam transmits video and audio via fiber optics through a system that is routed to your newsroom. To schedule a live or taped interview, contact Alaina Farrish, (804) 628-4578.
About VCU Massey Cancer Center
VCU Massey Cancer Center is one of only 67 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at http://www.massey.vcu.edu or call 877-4-MASSEY for more information.
About VCU and the VCU Medical Center
Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 222 degree and certificate programs in the arts, sciences and humanities. Sixty-six of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see http://www.vcu.edu.
Alaina Farrish | EurekAlert!
Bioinspired nanoscale drug delivery method developed by WSU, PNNL researchers
10.01.2019 | Washington State University
How herpesviruses shape the immune system
09.01.2019 | German Center for Infection Research
Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.
It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:
The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.
One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...
Just in time for Christmas, a Mars-analogue mission in Morocco, coordinated by the Robotics Innovation Center of the German Research Center for Artificial Intelligence (DFKI) as part of the SRC project FACILITATORS, has been successfully completed. SRC, the Strategic Research Cluster on Space Robotics Technologies, is a program of the European Union to support research and development in space technologies. From mid-November to mid-December 2018, a team of more than 30 scientists from 11 countries tested technologies for future exploration of Mars and Moon in the desert of the Maghreb state.
Close to the border with Algeria, the Erfoud region in Morocco – known to tourists for its impressive sand dunes – offered ideal conditions for the four-week...
Research opens doors in photonic quantum information processing, optical signal processing and microwave photonics
Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new integrated photonics platform that can...
A team of experimentalists at the U.S. Department of Energy's Ames Laboratory and theoreticians at University of Alabama Birmingham discovered a remarkably long-lived new state of matter in an iron pnictide superconductor, which reveals a laser-induced formation of collective behaviors that compete with superconductivity.
"Superconductivity is a strange state of matter, in which the pairing of electrons makes them move faster," said Jigang Wang, Ames Laboratory physicist and...
14.01.2019 | Event News
12.12.2018 | Event News
10.12.2018 | Event News
15.01.2019 | Life Sciences
15.01.2019 | Information Technology
15.01.2019 | Materials Sciences