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

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

Venishetty Vinay K; Geldenhuys Werner J; Terell-Hall Tori B; Griffith Jessica I G; Sondag Gregory R; Safadi Fayez F; Lockman Paul R

Current cancer drug targets

2017

1905-7

BACKGROUND: 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. METHOD: 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. RESULTS: 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). CONCLUSION: 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.

Female; Humans; Animals; Mice; Apoptosis; Cell Line; ADME; Antineoplastic Agents/*therapeutic use; brain cancer; Brain Neoplasms/*drug therapy/pathology/*secondary; Breast Neoplasms/*pathology; chemotherapy; CNS; distribution; drug discovery; Drug resistance; Tumor

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479–485

5

17