For many types of brain tumours there is no effective treatment, but promising work by Rosalind A. Segal and colleagues has found that a small molecular antagonist of the chemokine receptor Cxcr4 causes a big headache for brain tumours in mice. As this antagonist already has an encouraging safety profile in humans, they believe it could be considered for immediate evaluation in clinical trials.

Chemokine stromal-cell-derived factor 1α (CXCL12) and its receptor CXCR4 have a crucial role in brain development and are expressed in adult glioblastoma multiforme (GBM), so Segal and colleagues wondered if other types of brain tumours also expressed these proteins. Immunohistochemical staining of human brain tumours identified CXCR4 expression in 9/10 paediatric medulloblastomas and 3/5 anaplastic astrocytomas examined. In addition, published gene-array data from paediatric brain tumours showed that CXCR4 expression was increased in tumours of glial and neuronal origin. CXCL12 expression in the medulloblastomas was similar to that in GBM, indicating that the CXCR4–CXCL12 interaction might contribute to tumour formation.

CXCR4–CXCL12 signalling is known to cause chemotaxis, increase proliferation and decrease apoptosis, and when Daoy medulloblastoma or U87 GBM cells were stimulated with CXCL12, all of these effects were observed. But addition of AMD 3100 — a small molecule inhibitor of CXCR4 — to the cultures reduced chemotaxis and proliferation, and blocked serum-free survival. The next step was to determine whether AMD 3100 produced a similar effect in vivo. First, they established intracranial xenografts of Daoy and U87 cells that were engineered to express luciferase — which allowed non-invasive imaging of the tumours — then osmotic pumps containing AMD 3100 or PBS were implanted into tumour-bearing mice. Tumour burden was substantially diminished in the AMD-3100-treated animals. Twice-daily subcutaneous injection of AMD 3100 to tumour-bearing animals also reduced tumour growth with no evidence of toxicity in the treated animals.

Interestingly, the antitumour effects of AMD 3100 were different for different tumour types. AMD 3100 increased apoptosis in the GBM tumours but had no effect on proliferation, whereas apoptosis was increased and proliferation reduced in medulloblastomas. AMD 3100 decreased phosphorylation of Erk1/Erk2 and Akt, downstream effectors of CXCL12, in tumour cells from both animal models, confirming that CXCR4 signalling is impaired.

These are promising results, as the safety of AMD 3100 has already been established in human clinical trials and trials to evaluate its effect on malignant brain tumours could be rapidly established. If successful, CXCR4 antagonists might be useful for treating other types of malignancies that express CXCR4.