Steven Belinsky, Ph.D.
Institutional Affiliation
Senior Scientist
Director, Lung Cancer Program
Lovelace Respiratory Research Institute
http://www.lrri.org/ScientistInfo.aspx?S=13
Education
University of North Carolina at Chapel Hill, B.S.
University of North Carolina at Chapel Hill, Ph.D.
Research
Novel Therapies Targeting Epigenetic Silencing of Tumor Suppressors
Impact
These studies could lead to the development of epigenetic therapy as a standard-of-care for treatment of lung and other devastating cancers. This study will evaluate the ability of the epigenetic therapy to both cure cancer and to block the growth of advanced (large tumors) cancer. The success of these animal studies could lead to clinical trials of this epigenetic therapy in many human cancers, including lung and lead to a more effective treatment option for these debilitating diseases.
Summary of Research
Lung cancer is the leading cause of cancer-related death in the U.S. and is projected to reach epidemic levels in the world during the 21st century. Chemotherapy has been largely ineffective in producing complete responses or cures in advanced disease so that over 85% of patients with lung cancer eventually succumb to the disease. This has prompted a renewed focus on targeted therapy based on pathways and/or genes that are altered during the development of lung cancer. Unfortunately, even pre-selecting patients based on alteration in a targeted pathway has not proven to yield sustained effects on inhibiting tumor growth due to the alteration of many other pathways that limit the response. Rather than targeting alterations in single genes, epigenetic therapy (described below) can effect multiple genes in multiple pathways and block growth or even kill tumor cells.
The major epigenetic change involves a process called DNA methylation that leads to the "silencing" of a large number of genes in all types of human cancer. The process of DNA methylation involves changes in the sequence of the base cytosine to 5-methylcytosine and the way a gene's DNA is packaged. This packaging involves proteins called histones that wrap around the base sequences including the 5-methylcytosine that together block access to factors that allow the gene to be expressed in the cell.
We have made many important contributions to the basic science of epigenetics. These include the identification of many genes that are silenced in cancer and the demonstration that these changes occur very early in cancer development. This knowledge suggests that if a therapy could be developed to awaken these genes, it could have a profound effect on the cancer cell. Drugs have been identified that reverse abnormal 5-methylcytosine to cytosine (5-azacytidine) and reverse abnormal histone changes (MS275). Combinations of these drugs are being used in the clinic with extremely promising results in leukemia. Investigators on our team have discovered drugs that target specific proteins that affect the histones unique to the histones being affected by MS275. These drugs target proteins called SIRT1 and LSD1. The major question addressed this project is whether a cocktail of drugs at low doses that includes 5-azacytidine, MS275, and inhibitors of SIRT1 and LSD1 can effectively cause high levels of gene re-expression that in turn leads to a marked reduction in growth of lung tumors.
We will use human lung tumor cells that can be injected into the lungs of a nude rat and grow in the lungs of the rat as tumors. This model is very close to mimicking actual lung cancer in man. A step-wise approach is being taken in which first the ability of 5-azacytidine and MS275 to cause re-expression of methylated genes in the growing lung tumors is assessed at different low doses of these agents. Second, dose response studies with inhibitors of SIRT1 and LSD1 added to 5-azacytidine and MS275 will assess whether further increases in expression of these genes can occur. Ultimately a cocktail of these drugs at doses which cause very few side effects, but result in high re-expression of the many genes silenced in the lung tumor cells will be administered chronically to nude rats with lung tumors. This study will evaluate the ability of the epigenetic therapy to both cure cancer and to block the growth of advanced (large tumors) cancer. The success of these animal studies could lead to clinical trials of this epigenetic therapy in many human cancers, including lung and lead to a more effective treatment option for these debilitating diseases. |
