UC San Diego researchers have discovered an effective, alternative method for killing fast-growing cancer cells without causing some of the negative effects of current therapies.he scientists, led by David A. Cheresh, PhD, professor of pathology and associate director for translational research at the Moores Cancer Centre, used an innovative chemical and biological approach to design a new class of new drugs that arrests division in virtually all tumour cells by binding to and altering the structure of an enzyme called RAF.

RAF has been long-studied, but its role in cell division - critical to cell proliferation and tumour growth - was a surprise.

"By designing a new class of drugs that changes the shape of RAF, we were able to reveal this previously undiscovered role for RAF in a wide range of highly proliferative tumours," Cheresh said.

Current cancer drugs that target enzymes like RAF are generally designed to interact with the active site of the enzyme. Unfortunately, these drugs often lack specificity, Cheresh said.

"They hit many different targets, meaning they can produce undesired side effects and induce dose-limiting toxicity," he noted.

Cheresh and colleagues pursued development of a new class of RAF inhibitors that do not bind to the active site of the enzyme and so avoid the limitations of current drugs.

Instead, this new class, called allosteric inhibitors, changes the shape of the target enzyme and in doing so, renders it inactive.

The specific drug tested, known as KG5, singles out RAF in proliferating cells, but ignores normal or resting cells.

In affected tumour cells, RAF is unable to associate with the mitotic apparatus to direct cell division, resulting in cell cycle arrest leading to apoptosis or programmed cell death. KG5 in a similar manner effectively interferes with proliferating blood vessels, a process called angiogenesis.

"It's an unusual discovery, one that really challenges current dogma," said Cheresh.

KG5 produced similar results in tests on cancer cell lines, in animal models and in tissue biopsies from human cancer patients.

The research team has since developed variants of KG5 that are 100-fold more powerful than the original drug. They hope one of these more powerful compounds will soon enter clinical trials at Moores Cancer Center.

The study was published in the Nov. 13 online issue of the journal Nature. (ANI)