title: AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.
abstract: Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Sith
authors.initials: S
authors.lastname: Sathornsumetee
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: David
authors.initials: D
authors.lastname: Batt
authors.forename: Timothy
authors.initials: T
authors.lastname: Ramsey
authors.forename: Naeem
authors.initials: N
authors.lastname: Yusuff
authors.forename: B K Ahmed
authors.initials: BK
authors.lastname: Rasheed
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Andrea
authors.initials: A
authors.lastname: Laforme
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001011:Aorta; D001706:Biopsy; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C514876:AAL 881; D000970:Antineoplastic Agents; D007546:Isoquinolines; D040262:Receptors, Vascular Endothelial Growth Factor; D048490:raf Kinases