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.