Brain metastases as preventive and therapeutic targets

Key Points Brain metastases are most common in patients with lung cancers, breast cancers or melanoma. Treatment includes surgery and radiation therapy. Whole-brain radiation therapy (WBRT) has been shown to prevent lung cancer brain metastases, but causes cognitive decline. In animal models of brain metastasis, tumour cells crawl outside the blood vessels and interact with an inflamed neural microenvironment to colonize the brain. Alterations in the expression of several genes, including ERBB2 , ST6GALNAC5 , TCF , transforming growth factor-β ( TGFB ), vascular endothelial growth factor ( VEGF ), Serpine1 and Timp1 , have modulated brain metastasis. Chemotherapeutic efficacy for brain metastases remains disappointing. In experimental models, brain metastases opened the blood–brain barrier (BBB) several-fold over the normal brain, but only 10% of lesions exhibited sufficient drug permeability to mount an apoptotic response to chemotherapy. BBB-permeable drugs are needed to improve chemotherapeutic efficacy. Prevention of brain metastasis formation in mice has been observed in response to lapatinib, vorinostat, pazopanib, signal transducer and activator of transcription 3 (STAT3) inhibitors and VEGF receptor (VEGFR) inhibitors. New trial designs could test drugs for the prevention of brain metastases. Secondary prevention trials would determine the time to the development of a new brain metastasis in patients with either one or several existing lesions. Radiosensitizers may improve the efficacy of radiation therapy while sparing normal tissue. Inhibition of the neuroinflammatory response is hypothesized to protect the brain from WBRT-induced cognitive decline. The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. As discussed in this Review, translational research that aims to improve the outcome for patients with brain metastases needs to be multi-disciplinary, marrying advanced chemistry, blood–brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology. The incidence of metastasis to the brain is apparently rising in cancer patients and threatens to limit the gains that have been made by new systemic treatments. The brain is considered a 'sanctuary site' as the blood–tumour barrier limits the ability of drugs to enter and kill tumour cells. Translational research examining metastasis to the brain needs to be