New approach to starving cancers

Salk, Sanford Burnham Prebys scientists collaborate to stop autophagy

By Bradley J. Fikes The San Diego Union-Tribune 9 A.M.JUNE 25, 2015 VIEW ORIGINAL

Fast-growing cancers are notoriously hungry. Their ravenous cells commander all the glucose and other nutrients they can get. They'll will even stimulate new blood vessels to grow into the tumor to better feed them.

When all else fails, cancer cells feed on their own components, breaking down nonessential substances and recycling them to stay alive, a process called autophagy.

A new cancer strategy to stop autophagy and render cancers more vulnerable has been devised by a team of scientists from the Salk Institute and the newly renamed Sanford Burnham Prebys Medical Discovery Institute.

The potential therapy is discussed in a study released Thursday in the journal Molecular Cell. (Click here to get the study).

The small molecule now being tested has been demonstrated in the lab to block the start of autophagy. Now it must confirm effectiveness in animal trials, which are under way. The results will be discussed in an upcoming paper once the findings are in.

Reuben Shaw, who led the study, said the goal is to develop a drug cancer patients can take along with other therapies, to reduce the options cancers use to survive. Hitting a cancer with an angiogenesis/autophagy combo, for example, will reduce blood vessel growth to the tumor and impede it from turning to autophagy to compensate.

The work is a collaboration between his lab and that of Nicholas Cosford, a Sanford Burnham Prebys professor, Shaw said.

"They're the chemists who actually designed the molecules," Shaw said. "We fully partnered with them -- postdocs in my lab and their lab -- we've had meetings every month for the past couple of years to get this accomplished. Either one by ourselves could never have done it."

Cosford's lab was already interested in making anti-autophagy molecules before the collaboration began, Shaw said. "What no one in the world knew how to do was test for its function in cells."

Meanwhile, Shaw's lab had been developing such tools to study the autophagy process, in particular an enzyme called ULK1 that starts the process.

"We'd working on it for more than a year, and we had developed a number of new ways to study this enzyme inside cells," Shaw said. "So we had something no one else in the world had -- we had a way to actually test its function inside cells.

"You can make drugs that work perfectly inside a tube, like a purified enzyme. But when you put them into cells, there are all these complicating things. They don't get into the cell well, or there's off-target effects. There's all these complicating things once you leave the test tube and go into the cell."

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