Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging.

Abstract	Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes and hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation and survival in vitro and VEGF-induced angiogenesis in vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both in normal tissue and in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Similarly, tumor interstitial fluid pressure, a phenomenon that is also dependent of tumor permeability, was significantly reduced by NVP-BEZ235 in a dose-dependent manner on p.o. administration. Because RAD001, a specific mTOR allosteric inhibitor, was ineffective in the preceding experiments, we concluded that the effects observed for NVP-BEZ235 are in part driven by PI3K target modulation. Hence, tumor vasculature reduction was correlated with full blockade of endothelial nitric oxide (NO) synthase, a PI3K/Akt-dependent but mTORC1-independent effector involved in tumor permeability through NO production. In the BN472 tumor model, early reduction of permeability, as detected by K(trans) quantification using the dynamic contrast-enhanced magnetic resonance imaging contrasting agent P792 (Vistarem), was found to be a predictive marker for late-stage antitumor activity by NVP-BEZ235.
Authors	Christian R Schnell, Frédéric Stauffer, Peter R Allegrini, Terence O'Reilly, Paul M J McSheehy, Celine Dartois, Michael Stumm, Robert Cozens, Amanda Littlewood-Evans, Carlos García-Echeverría, Sauveur-Michel Maira
Journal	Cancer research (Cancer Res) Vol. 68 Issue 16 Pg. 6598-607 (Aug 15 2008) ISSN: 1538-7445 [Electronic] United States
PMID	18701483 (Publication Type: Journal Article)
Chemical References	Angiogenesis Inhibitors Imidazoles Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors Quinolines VEGFA protein, human Vascular Endothelial Growth Factor A vascular endothelial growth factor A, mouse Protein Kinases MTOR protein, human mTOR protein, mouse AKT1 protein, human Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases dactolisib
Topics	Angiogenesis Inhibitors (pharmacology) Animals Cell Proliferation Endothelium, Vascular (cytology, drug effects, metabolism) Female Humans Imidazoles (pharmacology) Immunoblotting Immunoenzyme Techniques Magnetic Resonance Imaging Mammary Neoplasms, Experimental (blood supply, drug therapy, pathology) Mice Neovascularization, Pathologic (drug therapy) Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors (pharmacology) Protein Kinases (chemistry, metabolism) Proto-Oncogene Proteins c-akt (metabolism) Quinolines (pharmacology) Rats Rats, Inbred BN TOR Serine-Threonine Kinases Umbilical Veins (cytology, drug effects, metabolism) Vascular Endothelial Growth Factor A (metabolism) Xenograft Model Antitumor Assays

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