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Targeted agent blocked growth of deadly brain cancer in preclinical studies
Date:3/30/2010

es, cyclin-dependent kinases 4 and 6 (cdk4/6), that drive cell division. "In normal cells, these kinases are kept under exquisite control by a gene known as p16," says Waldman. "But in glioblastoma, and other cancers, p16 is frequently deleted, and these two kinases are uncontrollably activated, which drives the cell to divide and form cancer."

The agent, however, does not work if the cancer is missing expression of a tumor suppressor protein known as retinoblastoma (Rb) because Rb is needed to control growth in these cells even if cdk4/6 are inhibited. A test to determine if RB is present is already being used to screen patients for use of PD-0332991 in the ongoing clinical trials.

A research team at Georgetown led by Waldman, conducted laboratory studies on 21 different cell lines derived from the tumors of patients with glioblastoma. They tested PD-0332991 at various concentrations to see if it could stop growth of the cancer cells, and found it to be effective in all 16 cell lines with a functioning Rb gene, but it did not work in 5 cell lines missing Rb. "The agent was very potent in stopping cancer growth, but it was also quite clean in that it only seemed to inhibit the two molecules it targeted, and no other," says Waldman. "Most drugs are dirtier than that they hit multiple unintended targets."

What intrigues Waldman, he says, is that no one has discovered what the "normal" function for cdk4/6 is. "Mice lacking either cdk4 or cdk6 grow up to be relatively healthy, so it may be that these kinases are really only important for cancer growth," Waldman says. "That would be an exciting development, if true, but no one knows yet."

James led a team of scientists at UCSF that implanted three different kinds of human glioblastoma directly into the brains of mice, and then they treated them with PD-0332991. They discovered first that the agent effectively reached intracranial tumors "and it wasn't known beforehand that it would, so this was v
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Contact: Karen Mallet
km463@georgetown.edu
215-514-9751
Georgetown University Medical Center
Source:Eurekalert

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