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

[ Vol. 17 , Issue. 5 ]

Author(s):

Vinay K. Venishetty, Werner J. Geldenhuys, Tori B. Terell-Hall, Jessica I.G. Griffith, Gregory R. Sondag, Fayez F. Safadi and Paul R. LockmanPages 479-485 (7)

Abstract:


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.

Keywords:

Drug resistance, CNS, distribution, brain cancer, drug discovery, chemotherapy, ADME.

Affiliation:

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV

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