Brain metastases as preventive and therapeutic targets

Abstract

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 multi-disciplinary, marrying advanced chemistry, blood-brain barrier pharmacokinetics, neurocognitive testing and radiation biology with metastasis biology, to develop and implement new clinical trial designs. Advances in the chemoprevention of brain metastases, the validation of tumour radiation sensitizers and the amelioration of cognitive deficits caused by whole-brain radiation therapy are discussed.

Figure 1|. Steps in the development of brain metastases in an animal model.

Brain metastatic cancer cells traverse the vascular system and use the outside of vessels as a site of adhesion and migration^,. Later, the tumour cells use the inflamed brain microenvironment as a niche. Tumour cells interact with activated microglia (macrophage-like cells, shown in yellow) and astrocytes (shown in orange), which provide support for neuronal function. As the metastasis expands, neuronal damage ensues. The brain microenvironment also contains damaged axons, oedema (white halo) and vascular changes (such as the disruption of the blood-brain barrier, indicated by dashed black lines). Both vessel co-option and angiogenesis have been reported in brain metastasis. Dormant solitary tumour cells can also reside in the brain, constituting a potential source for the development of additional metastases.

Figure 2|. The blood–brain barrier (BBB) and its role in drug uptake.

a | The BBB protects the normal brain by permitting access to only select substances. Endothelial cells are surrounded by pericytes, a basement membrane and the feet of astrocytes, all of which function as a barrier. Endothelial cells in the normal brain are tightly connected by continuous tight junctions and express multiple efflux pumps to push unwanted substances back into the bloodstream. b | The results in mice harbouring brain metastases that were given an intravenous injection of radiolabelled drug (paclitaxel or doxorubicin) are illustrated. Drug uptake into normal brain and brain metastases was quantified by autoradiography of tissue sections. Although most brain metastases accumulated a higher concentration of the drug than cells in the normal brain, heterogeneous levels of drug uptake were observed and the highest concentration was only observed in ~10% of the lesions. c | Vorinostat, a histone deacetylase inhibitor, was administered to mice with brain metastases (as described in part b). Drug uptake throughout the brain is evident, as well as heterogeneous increased uptake in metastases.

Figure 3|. Pathways mediating radiation sensitization.

Within irradiated turn our cells the most lethal DNA damage is that which results in DNA double-strand breaks (DNA DSBs). Unrepaired DNA DSBs lead to cell cycle arrest, which if prolonged can lead to cell death. Numerous putative radiation sensitizers affect multiple aspects of this cascade, including DNA repair enzymes, cell cycle checkpoints and cellular proliferation. The inhibition of targets within the tumour stroma can also sensitize tumour cells to radiation. For example, the inhibition of growth factor receptors on blood vessels can increase radiation sensitivity in tumour cells. BUDR, bromodeoxyuridine; HDAC, histone deacetylase; IUDR, 5-iodo-2’deoxyuridine; TK, tyrosine kinase; UCN-01, 7-hydroxystaurosporine.