title: Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma.
abstract: Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the combination of cediranib with a proteasome inhibitor substantially increases the anti-angiogenic efficacy produced from either agent alone, and synergistically slows glioma tumor growth and extends survival, suggesting a promising treatment which warrants further investigation.
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.|Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Merryl R
authors.initials: MR
authors.lastname: Lobo
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kukino
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Huong
authors.initials: H
authors.lastname: Tran
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Schabel
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Springer
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Advanced Imaging Research Center, Oregon Health and Science University, Portland, Oregon, United States of America.|Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Pike
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005910:Glioma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage; D012664:Semicarbazones / Q000008:administration & dosage; D007211:Indoles
chemical_list: D011799:Quinazolines; D012664:Semicarbazones; C545869:SC 68896; C500926:cediranib; D007211:Indoles