27 Apr New Drug Class Targeting RAS Oncogenes Being Tested For Myelodysplastic Syndrome
MedicalResearch.com Interview with:
E. Premkumar Reddy, Ph.D.
Professor, Department of Oncological Sciences
and Department of Structural and Chemical Biology
Director, Experimental Cancer Therapeutics
Mount Sinai School of Medicine
New York, NY 10029
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Reddy: It is now well established that cancer cells harbor mutations in their genome which are responsible for uncontrolled proliferation. Nearly 30 years ago, we as well as two other groups discovered that RAS genes are often mutated in human cancers. Later studies showed that nearly 25-30% of human cancers contain this mutation and these mutations can be caused by chemical carcinogens such as tobacco smoke. Since then there has been an intense effort to understand the biological functions of RAS and to develop drugs that block the activity of these mutant RAS genes. Although molecular oncologists have made significant headway in understanding these mutations and their impact on cellular signaling, little progress has been made towards developing drugs that systematically target the RAS oncogenes. This lack of progress has led many in the field to label RAS as “undruggable”. However, basic research conducted by scientists in this field has revealed that RAS proteins function as ON-OFF switches to signal cells to grow or not to grow because of their ability to bind to a large number of cellular proteins and transmit this signal to their binding partners. These findings also revealed that mutations in RAS genes leaves them in a permanent “ON” position which continues to transmit growth signals permanently. Since most efforts to develop drugs that bind to RAS proteins and reverse their activity failed, we took a different approach to block these signals. Since transmission of growth signals by RAS genes requires their interaction with cellular proteins, all of which contain a domain called “RAS-Binding Domain (RBD)” we created a drug named “Rigosertib” that binds to these RBDs and block their binding to RAS, thereby interrupting RAS signals. When Rigosertib was tested in animals, it could readily inhibit the growth of human tumors that contain RAS mutations. Our studies also show that Rigosertib is a very safe drug with minimal side-effects.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Reddy: Rigosertib is currently in Phase III clinical trials for the treatment of Myelodysplastic Syndrome (MDS) and it will soon be tested in other cancers that harbor RAS mutations.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Reddy: The rigosertib mechanism of action represents a new paradigm for attacking the intractable RAS oncogenes. Our current focus is to use the information from our studies with rigosertib to design the next generation of small molecule RAS-targeting therapies, and we are excited to have recently identified several compounds which we think improve on the qualities of rigosertib.
MedicalResearch.com: Is there anything else you would like to add?
Dr. Reddy: The human genome encodes a large number of RAS-related proteins, several of which are members of the heterotrimeric G protein gene family. Like RAS, these proteins mediate their effects by binding to cellular proteins via their RBD-like domains. The strategy used to inactivate RAS signals by blocking its interaction with RBDs may be similarly applied to the large family of G proteins, which could pave the way for a new class of drugs for the treatment of G-protein mediated diseases.
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Premkumar Reddy et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.Cell, April 2016 DOI: 10.1016/j.cell.2016.03.045
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