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!
23.03.2017 | Technische Universität München
How prenatal maternal infections may affect genetic factors in Autism spectrum disorder
22.03.2017 | University of California - San Diego
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
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...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
23.03.2017 | Life Sciences
23.03.2017 | Power and Electrical Engineering
23.03.2017 | Earth Sciences