Throwing the Tyrosine Kinase Kitchen Sink Against Glioblastoma

BOSTON, Sept. 13 -- Combinations of targeted drugs may overcome the agents' often tepid or transitory individual actions against brain tumors, researchers here said.

In laboratory analyses of cell lines from glioblastoma multiforme tumors, three or more receptor tyrosine kinases were usually overactive, according to Ronald DePinho, M.D., of the Dana-Farber Cancer Institute and colleagues.

Dosing the tumor cells with a single targeted drug - such as Gleevec (imatinib), which inhibits, among other things platelet-derived growth factor -- did little to block their growth, Dr. DePinho and colleagues reported online in Science.

But using three such drugs almost entirely blocked the growth of the cancer cells, the researchers reported.

They said the finding provides "a rational explanation for the feeble clinical responses" of many solid tumors to single-inhibitor therapy and points the way forward to new clinical trials and treatment patterns.

"This is a transformative finding that will motivate clinicians and our pharmaceutical colleagues to design clinical trials with regimens using several inhibitors," Dr. DePinho said.

The researchers tested glioblastoma cell lines to see what receptor tyrosine kinases - essentially cell-growth switches - were activated. In 19 of 20 cell lines, they found, three or more of the receptor tyrosine kinases were active.

Many of the receptor tyrosine kinases they found feed into the phosphatidylinositol 3-kinase (PI3K) signaling pathway, whose aberrant activation "appears to be universal in human cancer," including glioblastoma multiforme, Dr. DePinho and colleagues said.

The implication of the finding was that blocking a single receptor tyrosine kinase was unlikely to have much effect on the aberrant functioning of the PI3K pathway, Dr. DePinho said.

"Typically one elicits a positive initial response, but rarely durable cures," Dr. DePinho said. "Overall, the record of receptor tyrosine kinases inhibitors in these brain tumors has been somewhat disappointing."

To test the idea, the researchers subjected glioblastoma multiforme cell lines to treatment with erlotinib (Tarceva), erlotinib plus the MET receptor tyrosine kinase inhibitor SU11274, or both plus imatinib.

"Consistently, PI3K signaling was reduced or completely abrogated" with the use of multiple inhibitors, the researchers said, compared to one or even two drugs.

The reduction in PI3K signaling corresponded to a drop in cell viability and growth, they said.

In another set of experiments, the researcher assayed tumor tissue taken from newly diagnosed and untreated patients, where they also found that multiple receptor tyrosine kinases were active.

The combination of the in vitro and in vivo data is enough to show that multiple receptor tyrosine kinases are active in tumor tissue and could potentially be targeted in combination, the researchers said.

Also, they said, "this study provides proof-of-concept for the eventual implementation of a 'personalized' therapeutic paradigm in human cancer."

Dr. DePinho and colleagues noted that several receptor tyrosine kinases are currently approved and others are in the pipeline, so "this treatment paradigm could be readily implemented for cancers that are currently highly refractory to existing therapies."