title: Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer.
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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX. United States.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Venishetty
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV. United States.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV. United States.
authors.forename: Tori B
authors.initials: TB
authors.lastname: Terell-Hall
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV. United States.
authors.forename: Jessica I G
authors.initials: JIG
authors.lastname: Griffith
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH. United States.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Sondag
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH. United States.
authors.forename: Fayez F
authors.initials: FF
authors.lastname: Safadi
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV. United States.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice
chemical_list: D000970:Antineoplastic Agents
keywords: ADME; CNS; Drug resistance; brain cancer; chemotherapy; distribution; drug discovery