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Scientists Believe They Have Found Cancer’s ‘Achilles Heel’

Philadelphia team works with GSK to develop cure

A trio of scientists has started working with researchers at GlaxoSmithKline (GSK) on a potential cure for cancer. In fact, they believe they’ve found the disease’s “Achilles heel.”

Last month, GSK selected a project submitted by the Wistar Institute and the University of Pennsylvania, both in Philadelphia, for its 2014 Discovery Fast Track Challenge program, which was created to accelerate the development of new medicines.

The project was submitted by Dr. Maureen Murphy, a Wistar professor and program leader of the institute’s molecular and cellular oncogenesis program; Dr. Donna George, a Penn associate professor of genetics; and Dr. Julie Leu, an assistant professor of genetics at Penn. It was the only research project involving Philadelphia-area scientists selected for GSK’s 2-year-old Discovery Fast Track Challenge. GSK chose 14 research project proposals for the program from 428 entries from researchers in 26 countries.

The Wistar/Penn scientists are looking to develop a drug that targets heat shock protein 70 (HSP70), a stress-induced protein that is over-expressed in most tumor cells.

“Normal cells don’t need HSP70 to survive, but cancer cells do,” Murphy said. “It's the Achilles heel of cancer.”

The protein, Murphy explained, is linked to autophagy –– the process through which the body in times of stress promotes survival by self-digestion. Cancer cells use the same process to survive.

“If you limit autophagy, normal cells will live for a time,” Murphy said. “Cancer cells will die immediately.”

Murphy, George, and Leu discovered a series of HSP70 inhibitors that have been effective against lymphoma and melanoma in mice.

They identified the new drug candidates while studying a tumor-suppressor protein, p53. During that process, they determined that a small molecule called 2-phenylethynesulfonamide (2-PES) modified the activity of the p53 protein. They didn’t know, however, what the molecule targeted to cause the modification.

To find out, George said, they had to reverse the normal drug-discovery process. Instead of identifying a target linked to a disease and developing a drug that could modify that target, the Wistar/Penn team started with a drug candidate and needed to find the target. Their efforts eventually led them to HSP70.

The researchers are now working with scientists at GSK in screening their target against the company’s vast collection of compounds. George said the program combines the expertise Murphy, Leu, and she have with the protein and how to target it, with the skills GSK has to rapidly test tens of thousands of compounds for a certain desired activity.

“Those are things we can’t afford to do,” George said. “They are not the kind of things you can do in a small lab.”

Murphy said that while scientists may do assays in a small number of test tubes in their laboratories, a large pharmaceutical company like GSK can do many thousands of assays at a time in a “high throughput” manner with the technology that they have.

Source: Philadelphia Business Journal; January 15, 2014.


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