title: Comparison of dynamic contrast-enhanced MR, ultrasound and optical imaging modalities to evaluate the antiangiogenic effect of PF-03084014 and sunitinib.
abstract: Noninvasive imaging has been widely applied for monitoring antiangiogenesis therapy in cancer drug discovery. In this report, we used different imaging modalities including high-frequency ultrasound (HFUS), dynamic contrast enhanced-MR (DCE-MR), and fluorescence molecular tomography (FMT) imaging systems to monitor the changes in the tumor vascular properties after treatment with γ-secretase inhibitor PF-03084014. Sunitinib was tested in parallel for comparison. In the MDA-MB-231Luc model, we demonstrated that antiangiogenesis was one of the contributing mechanisms for the therapeutic effect of PF-03084014. By immunohistochemistry and FITC-lectin perfusion assays, we showed that the vascular defects upon treatment with PF-03084014 were associated with Notch pathway modulation, evidenced by a decrease in the HES1 protein and by the changes in VEGFR2 and HIF1α levels, which indicates down-stream effects. Using a 3D power Doppler scanning method, ultrasound imaging showed that the% vascularity in the MDA-MB-231Luc tumor decreased significantly at 4 and 7 days after the treatment with PF-03084014. A decrease in the tumor vessel function was also observed through contrast-enhanced ultrasound imaging with microbubble injection. These findings were consistent with the PF-03084014-induced functional vessel changes measured by suppressing the K(trans) values using DCE-MRI. In contrast, the FMT imaging with the AngioSence 680EX failed to detect any treatment-associated tumor vascular changes. Sunitinib demonstrated an outcome similar to PF-03084014 in the tested imaging modalities. In summary, ultrasound and DCE-MR imaging successfully provided longitudinal measurement of the phenotypic and functional changes in tumor vasculature after treatment with PF-03084014 and sunitinib.
authors.affiliation: Oncology Research Unit, Pfizer Global Research and Development, La Jolla, California.
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Zhang
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Yan
authors.forename: Anand
authors.initials: A
authors.lastname: Giddabasappa
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Lappin
authors.forename: Cory L
authors.initials: CL
authors.lastname: Painter
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Goodman
authors.forename: Brett
authors.initials: B
authors.lastname: Simmons
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pascual
authors.forename: Joseph
authors.initials: J
authors.lastname: Lee
authors.forename: Ted
authors.initials: T
authors.lastname: Levkoff
authors.forename: Tim
authors.initials: T
authors.lastname: Nichols
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008279:Magnetic Resonance Imaging; D057054:Molecular Imaging; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D011859:Radiography; D000077210:Sunitinib; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D014463:Ultrasonography; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D007211:Indoles; D011758:Pyrroles; D013764:Tetrahydronaphthalenes; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat; D000077210:Sunitinib
keywords: Antiangiogenesis; PF-03084014; imaging; sunitinib; γ-secretase inhibitor