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  • Review Article
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Brain metastases as preventive and therapeutic targets

Nature Reviews Cancer volume 11, pages 352–363 (2011)Cite this article

Subjects

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.

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.

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Figure 1: Steps in the development of brain metastases in an animal model.
Figure 2: The blood–brain barrier (BBB) and its role in drug uptake.
Figure 3: Pathways mediating radiation sensitization.

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Acknowledgements

This work was supported by the Intramural Program, Center for Cancer Research, US National Cancer Institute, and from the Center of Excellence grant W81XWH-062-0033 from the US Department of Defense Breast Cancer Research Program. The authors regret that space restrictions did not permit all citations to be included.

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Patricia S. Steeg

  2. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Kevin A. Camphausen

  3. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, 79106, Texas, USA

    Quentin R. Smith

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Correspondence to Patricia S. Steeg.

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Research support was provided by GlaxoSmithKline and Millennium Pharmaceuticals.

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Glossary

Parenchymal metastases

Secondary tumour growth in the essential and distinctive tissue of the brain.

Leptomeningeal metastases

Secondary tumour growth in the linings of the brain.

Cranial neuropathies

Abnormal function (either sensory or motor) of one of the 12 cranial nerves.

Stereotactic radiosurgery

Radiation therapy in which multiple convergent beams of high energy X-rays, γ-rays or protons are delivered to a discrete lesion in the brain.

Astrocytes

Brain cells that form a physical and metabolic support system for nerves while releasing communicative transmitters. When activated, astrocytes produce glial fibrillary acid protein intermediate filaments and shield neurons from damage.

Iron oxide particles

In magnetic resonance imaging, these supramagnetic particles generate a region emitting no radiofrequency signal, known as a signal void.

Temozolomide

A brain-permeable chemotherapeutic with alkylating activity.

Partial response

At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Stable disease

Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

Disease progression

At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Facilitated diffusion

The spontaneous passage of molecules or ions across a biological membrane passing through specific transmembrane integral proteins.

Epothilones

A new class of microtubule-active drugs.

Nomogram

A form of line chart showing scales for the variables involved in a particular formula so that corresponding values for each variable lie in a straight line intersecting all the scales.

Performance status

A measure of a patient's well-being defined as the amount of normal activity that the patient can maintain.

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Steeg, P., Camphausen, K. & Smith, Q. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer 11, 352–363 (2011). https://doi.org/10.1038/nrc3053

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