- Lancet Neurol. 2008 Dec;7(12):1152-60.
Novel anti-angiogenic therapies for malignant gliomas.
Norden AD, Drappatz J, Wen PY.
Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Despite optimum treatment with surgery, radiation therapy, and
chemotherapy, most patients with malignant glioma have a poor
prognosis. Malignant gliomas are vascular tumours that produce vascular
endothelial growth factor (VEGF), which is an important mediator of
angiogenesis. Preclinical data indicate that angiogenesis is essential
for the proliferation and survival of malignant glioma cells, which
suggests that inhibition of angiogenesis might be an effective
therapeutic strategy. Anti-angiogenic therapies that target VEGF and
the VEGF receptor (VEGFR) are effective adjuncts to the treatment of
solid tumours. Normalisation of dilated and leaky tumour vasculature
might also enable anti-angiogenic therapy to increase the efficacy of
radiation therapy and cytotoxic chemotherapy.
Several studies have investigated the use of bevacizumab--a humanised
monoclonal antibody against VEGF--for patients with recurrent malignant
glioma. Treatment with bevacizumab is commonly combined with cytotoxic
chemotherapy and results in dramatic responses seen on radiographs,
prolongation of progression-free survival, and less need for
corticosteroids. Similar results have been shown with small-molecule
inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is
generally well tolerated but common adverse effects include
hypertension and proteinuria, whereas the potentially more serious
adverse effects, such as thromboembolic disease and haemorrhage, occur
infrequently. At least half of patients fail to respond to
anti-angiogenic treatment and the response duration is variable.
Resistance to anti-angiogenic therapy might implicate alternative
pro-angiogenic factors, such as basic fibroblast growth factor,
stromal-derived factor-1alpha, the angiopoietin receptor Tie2, and
placental growth factor. Anti-angiogenic therapy might also lead to
mobilisation of circulating endothelial cells towards the tumour, which
supports angiogenesis. Another possible mechanism of resistance of
malignant glioma cells might be upregulation of pro-invasive molecules,
which would result in increased infiltrative tumour growth along the
WHERE NEXT?: Although anti-angiogenic therapies are
promising, the duration of response with available regimens is modest.
Continuing investigations will determine whether these drugs are best
used for newly diagnosed or recurrent tumours and will establish the
optimum combinations with radiation, cytotoxic chemotherapy, and other
targeted molecular compounds. As yet, there are no effective treatments
for patients on anti-angiogenic therapies whose tumours progress.
Further understanding of the mechanisms of resistance to
anti-angiogenic therapies and better selection of patients will be
crucial to improve outcomes for patients with malignant glioma.