title: Unsanctifying the sanctuary: challenges and opportunities with brain metastases.
abstract: While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Shannon
authors.initials: S
authors.lastname: Puhalla
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: William
authors.initials: W
authors.lastname: Elmquist
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: David
authors.initials: D
authors.lastname: Freyer
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kleinberg
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Chris
authors.initials: C
authors.lastname: Adkins
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Paul
authors.initials: P
authors.lastname: Lockman
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: John
authors.initials: J
authors.lastname: McGregor
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Leslie
authors.initials: L
authors.lastname: Muldoon
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Gary
authors.initials: G
authors.lastname: Nesbit
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: David
authors.initials: D
authors.lastname: Peereboom
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Quentin
authors.initials: Q
authors.lastname: Smith
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Sara
authors.initials: S
authors.lastname: Walker
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania (S.P.); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (W.E.); Department of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (D.F.); Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (L.K.); Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (C.A.); Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University and the Mary Babb Randolph Cancer Center, Morgantown, West Virginia (P.L.); Department of Neurological Surgery, The Ohio State University Medical Center, Columbus, Ohio (J.M.); Blood Brain-Barrier Program, Oregon Health & Science University, Portland, Oregon (L.M., E.N.); Dotter Radiology/Neuroradiology, Oregon Health & Science University, Portland, Oregon (G.N.); Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio (D.P.); School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas (Q.S.); Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (S.W.); Portland Veterans Affairs Medical Center, Portland, Oregon (E.N.).
authors.forename: Edward
authors.initials: E
authors.lastname: Neuwelt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000517:prevention & control / Q000556:secondary* / Q000628:therapy*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents
keywords: CNS sanctuary; brain metastases; imaging; prevention; therapy
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