Use multiple ‘targeted’ drugs on tumors, say researchers

The switches are formed by molecules called receptor tyrosine kinases (RTKs) that often are mutated and hyperactive in cancer cells. Since a number of kinase-blocking drugs are already available – Novartis’s Gleevec and OSI Pharmaceuticals’s Tarceva are two of the best-known – the researchers said clinical trials of combinations of the compounds should be planned quickly.

Director of the Center for Applied Cancer Science at the Dana-Farber, Ronald DePinho, who led the team, said: “This is a transformative finding that will motivate clinicians and our pharmaceutical colleagues to design clinical trials with regimens using several inhibitors.” He noted that in the laboratory study using cancer cell lines and fresh specimens of brain tumors, three or more kinase inhibitors were needed to quell the abnormal cell-growth signals.

The study focused on glioblastoma multiforme, an aggressive brain tumor that is nearly always fatal. The scientists also found similar patterns of multiply activated RTKs in other common cancers of the pancreas and lung.

The researchers tested 20 glioblastoma cell lines using an antibody array technique that measured the activation of 45 different RTKs at one time. In 19 of the 20 cell lines, three or more RTKs were activated at the same time, sending abnormal growth signals in triplicate to the nucleus. Moving from cell lines to fresh cells, the researchers saw the same multiple-RTK activity when they studied tumor samples from newly diagnosed patients.

The kinase inhibitor Gleevec (imatinib) had little effect on the errant signaling pathways when applied to the brain tumor cells. But when imatinib was given in combination with two other kinase inhibitors, Tarceva (erlotinib) and SU11274, traffic in the PI3K signaling pathway was eliminated, and the cancer cells died.

“This study provides proof of concept for the eventual implementation of a ‘personalized’ therapeutic paradigm in human cancer,” the researchers concluded.