Antagonism of platelet-derived growth factor receptor in non small cell lung cancer: rationale and investigations.
Molecules that target growth and survival pathways in cancer cells have revolutionized the treatment of cancer. Imatinib mesylate is one such agent inhibiting the tyrosine kinase that results from the Bcr-Abl translocation. Imatinib is also a potent inhibitor of the platelet-derived growth factor receptor. The platelet-derived growth factor receptor is crucial in the regulation of interstitial fluid pressure, as well as in the function of pericytes. Increased interstitial fluid pressure is a common feature of solid tumors and is thought to impede transcapillary transport of chemotherapy. Preclinical data show that platelet-derived growth factor receptor antagonism decreases interstitial fluid pressure, augments intratumoral concentration of chemotherapy, and impairs tumor growth. Pericytes are important cells in the vascular support structure of tumors regulating endothelial cell survival and directing capillary growth. Preclinical data suggest that dual targeting of pericytes and endothelial cells is a more effective antiangiogenic strategy than antiendothelial monotherapy. Two phase II studies in advanced non-small cell lung cancer are currently under way with imatinib. The first trial evaluates the use of intermittent imatinib and weekly paclitaxel in elderly patients. The second trial evaluates a novel maintenance strategy of imatinib and the antivascular endothelial growth factor antibody bevacizumab after first-line chemotherapy with bevacizumab. These trials should indicate whether encouraging preclinical data can be translated into clinical benefit in non-small cell lung cancer.