How New Insights in the Biology of Brain Metastases May Lead to the Identification of New Effective Medical Therapies

ABSTRACT Brain metastases are a devastating event in the progression of cancer and are expected to increase in incidence as chemotherapies improve and lead to better systemic disease control. The brain offers unique environment as it is protected by the blood–brain barrier, which strongly limits the penetration of drugs. Using a quantitative model system for experimental breast cancer brain metastasis, vascular permeability was heterogeneous in brain metastases, with only 10% of lesions exhibiting sufficient permeability to mount an apoptotic response to taxol, suggesting that inadequate chemotherapeutic drug distribution accounts for a lack of efficacy. We have tested 18 compounds, both traditional chemotherapeutics and small molecule inhibitors, for efficacy in an experimental brain metastasis model. Prevention of the development of brain metastases was observed using vorinostat, lapatinib, pazopanib, TPI-287, gemcitabine and irinotecan. No drug effectively shrunk already established metastases. Our work strongly suggests that preventive approaches for the development of brain metastases constitutes a feasible clinical goal. We advocate the use of “secondary brain metastasis prevention” trials, in which patients with limited, treated brain metastases (without whole brain radiotherapy) are randomized to a preventive or placebo, with time to the development of a new metastasis as an endpoint. Close collaboration between researchers and medical oncologists will be needed to address these challenges brought on by this growing and incurable disease. Disclosure B. Gril: Dr. Patricia Steeg received research founding from Glaxo Smith Kline (for lapatinib, pazopanib and PLK inhibitor) and from Millennium Pharmaceuticals (for TAK-285).