Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. In this study we used a novel screening method to i...

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Bibliographic Details
Published inCurrent cancer drug targets Vol. 17; no. 5; p. 479
Main Authors Venishetty, Vinay K, Geldenhuys, Werner J, Terell-Hall, Tori B, Griffith, Jessica I G, Sondag, Gregory R, Safadi, Fayez F, Lockman, Paul R
Format Journal Article
LanguageEnglish
Published Netherlands 01.01.2017
Subjects
drug discovery
ADME
CNS
brain cancer
Drug resistance
distribution
chemotherapy
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Summary:Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.
ISSN:1873-5576
DOI:10.2174/1568009617666161121123948