Platelet-derived growth factor receptor (PDGF-R) inhibitor, imatinib, substantially improves response to the chemotherapeutic agent paclitaxel in paclitaxel sensitive, as well as in multi drug resistant, tumor models. Using immunostaining methods, it was demonstrated that the improved response results from targeting of tumor-associated endothelial cells. This method however, cannot inform on vascular functionality and cannot be used routinely in-vivo to monitor response to therapy. Thus, the purpose of this study was to use dynamic contrast enhanced (DCE)- magnetic resonance imaging (MRI) to monitor changes in vascular function associated with response to anti-PDGF-R therapy in advanced prostate cancer bone metastases.
Human prostate cancer bone metastasis model was initiated by intratibial injection of 1x105 PC-3MM2 cells in male CD-1 nude mice. Mice were imaged periodically by macromolecular DCE-MRI using albumin-GdDTPA as contrast material. Drug therapy was initiated approximately one week after tumor exits the bone, and combined imatinib (50 mg/kg; ip, daily; Novartis Pharma, Basel, Switzerland) and paclitaxel (8 mg/kg; ip, once, on the first day; Bristol-Myers Squibb, Princeton, NJ).
In early stages, tumor that was replacing the bone marrow was detected as high intensity in the pre-contrast T2 weighted images and as low enhancement relative to normal bone marrow in DCE-MRI. Over time, the tumor progressed throughout the bone marrow and finally exited the bone. One week after the tumor was first observed outside the bone (typically at 4-5 weeks), the intratibial tumor developed fibrotic and necrotic regions characterized by late enhancement and prolonged retention of the macromolecular contrast material. At the same time, the tumor portion growing outside the bone showed marked early contrast enhancement and accumulation of contrast material, reflecting high blood volume (microvascular density) and vascular permeability. Short term (2 days) combined imatinib and paclitaxel treatment resulted in the elimination of this rapid extravasation and accumulation of contrast material. Parametric analysis indicated a slight decrease in blood volume and a dramatic decrease in vascular permeability following treatment.
These results provide the first in-vivo demonstration of the anti-vascular effect induced by the combined imatinib and paclitaxel therapy in an advanced-stage prostate cancer bone metastases model. Moreover, the extent of the reduction in vascular function detected by macromolecular DCE-MRI is very dramatic and comparable to that previously observed upon withdrawal of vascular endothelial growth factor in a tetracycline regulated system. Next we propose to monitor anti-PDGF-R therapy in the early stages of bone infiltration where changes in DCE-MRI are expected to reflect tumor regression or a decrease in interstitial fluid pressure.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA