Preclinical experiments led by a team of researchers at VCU Massey Cancer Center have shown that blocking the production of a protein known as chromodomain helicase DNA-binding protein 4 (CHD4) may help increase the effectiveness of first-line treatments for acute myeloid leukemia (AML), a particularly lethal blood cancer that is increasing in incidence among older adults.
Recently published in the journal Blood, the novel findings demonstrate that depletion of the CHD4 protein makes AML cells more susceptible to standard chemotherapy agents by reducing their ability to repair DNA damage. Importantly, blocking CHD4 did not increase the sensitivity of healthy bone marrow cells to the chemotherapy agent or affect their growth. Additionally, the scientists found that depletion of CHD4 decreased the ability of AML cells to form colonies in preclinical laboratory and animal models. These tumor-forming properties are thought to be a major cause of AML relapse in patients who respond to first-line chemotherapy regimens.
"We are very encouraged by these findings," says the study's lead author Gordon Ginder, M.D., who is director of Massey Cancer Center, Lipman Chair in Oncology, a member of Massey's Cancer Molecular Genetics research program and a professor of internal medicine in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine. "Targeting the CHD4 protein could allow us to reduce chemotherapy doses, which could potentially mean more effective first- and second-line treatments with fewer serious side effects."
CHD4 is an enzyme that is involved in silencing tumor suppressor genes in cancer cells. Recently, it has been shown to play a role in repairing DNA damage, which is a major mechanism through which chemotherapy kills cancer cells. In preclinical experiments, the researchers observed that CHD4 depletion severely restricted the ability of AML cells to develop colonies in soft agar models as well as established tumors in mouse models (both types of models provide methods for confirming a hallmark of tumor-initiating cells). In addition, blocking the production of CHD4 rendered AML cells more sensitive to daunorubicin and cytarabine, two chemotherapy agents that are the basis for standard initial AML treatment.
"This study builds on our team's efforts to understand the molecular processes through which epigenetic regulators impact gene expression," says Ginder. "Future studies will attempt to uncover the detailed mechanism through which CHD4 decreases the ability of AML cells to initiate leukemia and will look for potential ways to target this important protein. The fact that it functions as an enzyme suggests it may be druggable."
Ginder and M.D./Ph.D. student Justin Sperlazza collaborated on this research with Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research, co-leader and member of the Developmental Therapeutics research program and member of the Cancer Cell Signaling research program at Massey as well as professor in the VCU Division of Hematology, Oncology and Palliative Care; Kellie Archer, Ph.D., member of the Cancer Molecular Genetics research program and director of the Biostatistics Shared Resource Core at Massey as well as associate professor in the VCU Department of Biostatistics ; Catherine Dumur, Ph.D., member of the Cancer Molecular Genetics research program and co-director of the Tissue and Data Acquisition and Analysis Core at Massey as well as associate professor in the VCU Department of Pathology; and Mohamed Rahmani, research assistant professor in the VCU Department of Internal Medicine as well as Jason Beckta, Mandy Aust, Elisa Hawkins, Shou Zhen Wang, Sheng Zu Zhu, and Shreya Podder, all researchers at Massey.
This study was supported by Leukemia and Lymphoma Society of America grant #6472-15, National Institutes of Health (NIH) grants R01 CA 67708, R01 DK 29902, P30 NS047463 and ULITR000058, and, in part, by Massey's National Institutes of Health-National Cancer Institute Cancer Center Support Grant P30 CA016059.
The full manuscript of this study is available online at: http://www.
About VCU Massey Cancer Center
VCU Massey Cancer Center is among the top 4 percent of cancer centers in the country to be designated by the National Cancer Institute to lead and shape America's cancer research efforts. Working with all kinds of cancers, Massey conducts every form of cancer research, including basic science, translational, clinical social, behavioral and population sciences research; provides state-of-the-art cancer treatments and cutting-edge clinical trials; serves as a vital resource for oncology education, teaching and training; and promotes cancer prevention. Since 1974, Massey has been an internationally recognized center of excellence. Massey provides award-winning cancer care at multiple sites throughout Virginia by leading cancer sub-specialists and offers one of the largest cancer clinical trial menus as well as a statewide network that brings trials to communities across the Commonwealth. Its 1,000-plus researchers, clinicians and staff members are dedicated to improving the quality of human life by discovering, developing, delivering and teaching effective means to prevent, detect, treat and ultimately cure cancer. Visit Massey online at http://www.