Re-examination of common diabetes drug may lead to new cancer treatment
Dr. Anand Selvaraj
Great scientific discoveries are sometimes the result of lucky “accidents” made by very observant scientists.
Penicillin was discovered when blue-green algae accidently contaminated a Petri dish being used to grow bacteria. Microwave ovens were created after a researcher noticed that a magnetron tube melted a candy bar in his pocket. Viagra® failed in its original tests to treat angina (heart pain) but is now solely used for men’s health.
When Dr. Anand Selvaraj joined a team from the U.S. Air Force Research Laboratory through the Postgraduate Research Participation Program (PRPP) managed by the Oak Ridge Institute for Science and Education, he had some idea that a common diabetes drug might work differently than originally thought. Little did he know that the team’s work may have added a new, inexpensive weapon to the war on cancer.
“When we first started looking at metformin, it was known to function by disabling the mTOR complex, or mammalian target of rapamycin—a protein that helps regulate protein synthesis, cell growth and proliferation,” said Selvaraj, who holds a Ph.D. in molecular biology and specializes in the study of signal transduction in cells.
When used for treatment of diabetes, metformin blocks the production of glucose (sugar) and increases the body’s sensitivity to insulin—a hormone that assists with the conversion of sugar to energy. Affecting millions of people worldwide, diabetes occurs when the body is unable to use insulin properly and can lead to vision loss, kidney damage and heart failure if left untreated.
“Prior to our research, it was believed metformin blocked an enzyme called AMPK to activate the tuberous sclerosis complex [TSC], which then acts to inhibit the mTOR complex from becoming active,” said Selvaraj, who worked under the expert guidance of Dr. George Thomas at the University of Cincinnati. “We now know that neither of these first two elements is necessary. Metformin affects a completely different enzyme, known as RAG GTPase, to modulate the mTOR complex.”
The fact that the drug does not act through the TSC may open the door for its use in treating cancer and diseases linked to a TSC deficiency, such as tuberous sclerosis and lymphangioleiomyomatosis. Plus, since it is already available in generic form, it could prove to be a low-cost treatment, unlike many other cancer medications.
Could there be other drugs out there with similar hidden potential benefits? “We’ve only had the tools to explore these questions for a few years, so it’s certainly possible,” Selvaraj said. “For example, preliminary studies with 2-deoxy glucose have shown that it might also work like metformin.”
Selvaraj highlights the collaborative nature of PRPP as a key to success in this type of research. “Bringing people together from diverse fields to do this type of work is significant. Personally, it allowed me to look at questions from a different perspective to find potential answers.”
In addition to further study on metformin to better understand exactly how it uses RAG GTPase, Selvaraj is continuing his work on the mTORC1 signaling pathway, which may lead to new treatments to strengthen and preserve nerve synapse and memory.