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Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine

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Abstract

The treatment of metastatic lesions in the brain represents a serious unmet medical need in the field of neuro-oncology. Even though many effective compounds have demonstrated success in treating peripheral (non-CNS) tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. Many factors can influence the brain delivery of these agents, but one key barrier is a heterogeneously “leaky” BBB that expresses efflux transporters that limit the BBB permeability for many targeted agents. Future success in therapeutics for brain metastases must take into account the adequate delivery of “active, free drug” to the target, and may include combinations of targeted drugs that are appropriate to address each individual patient’s tumor type. This review discusses some issues that are pertinent to precision medicine for brain metastases, using specific examples of tumor types that have a high incidence of brain metastases.

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References

  1. Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–51.

    Article  PubMed  CAS  Google Scholar 

  2. Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, et al. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012;30(4):419–25.

    Article  PubMed  Google Scholar 

  3. Bruzzone MG, D'Incerti L, Farina LL, Cuccarini V, Finocchiaro G. CT and MRI of brain tumors. Q J Nucl Med Mol Imaging. 2012;56(2):112–37.

    PubMed  CAS  Google Scholar 

  4. Brown PD, Buckner JC, Uhm JH, Shaw EG. The neurocognitive effects of radiation in adult low-grade glioma patients. Neuro-Oncology. 2003;5(3):161–7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15(10):1429–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Reungwetwattana T, Weroha SJ, Molina JR. Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC). Clin Lung Cancer. 2012;13(4):252–66.

    Article  PubMed  CAS  Google Scholar 

  7. Bayraktar S, Gluck S. Molecularly targeted therapies for metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2013;138(1):21–35.

    Article  PubMed  CAS  Google Scholar 

  8. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell. 2002;1(1):31–6.

    Article  PubMed  CAS  Google Scholar 

  9. Becker JC, Kirkwood JM, Agarwala SS, Dummer R, Schrama D, Hauschild A. Molecularly targeted therapy for melanoma: current reality and future options. Cancer. 2006;107(10):2317–27.

    Article  PubMed  CAS  Google Scholar 

  10. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012;12(4):278–87.

    Article  PubMed  CAS  Google Scholar 

  11. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16(23):5664–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437–49.

    Article  PubMed  CAS  Google Scholar 

  13. Agarwal S, Sane R, Oberoi R, Ohlfest JR, Elmquist WF. Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med. 2011;13:e17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Gampa G, Vaidhyanathan S, Sarkaria JN, Elmquist WF. Drug delivery to melanoma brain metastases: can current challenges lead to new opportunities? Pharmacol Res. 2017;123:10–25.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 2015;5(11):1164–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol. 1988;45(7):741–4.

    Article  PubMed  CAS  Google Scholar 

  17. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit Cancer surveillance system. J Clin Oncol. 2004;22(14):2865–72.

    Article  PubMed  Google Scholar 

  18. Schouten LJ, Rutten J, Huveneers HAM, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94(10):2698–705.

    Article  PubMed  Google Scholar 

  19. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  20. Kromer C, Xu J, Ostrom QT, Gittleman H, Kruchko C, Sawaya R, et al. Estimating the annual frequency of synchronous brain metastasis in the United States 2010-2013: a population-based study. J Neuro-Oncol. 2017;134(1):55–64.

    Article  Google Scholar 

  21. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14(1):48–54.

    Article  PubMed  Google Scholar 

  22. Newman SJ, Hansen HH. Proceedings: frequency, diagnosis, and treatment of brain metastases in 247 consecutive patients with bronchogenic carcinoma. Cancer. 1974;33(2):492–6.

    Article  PubMed  CAS  Google Scholar 

  23. Chamberlain MC, Baik CS, Gadi VK, Bhatia S, Chow LQ. Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma. Neuro-Oncology. 2017;19(1):i1–i24.

    Article  PubMed  Google Scholar 

  24. Auperin A, Arriagada R, Pignon JP, Le Pechoux C, Gregor A, Stephens RJ, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation overview collaborative group. N Engl J Med. 1999;341(7):476–84.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang W, Jiang W, Luan L, Wang L, Zheng X, Wang G. Prophylactic cranial irradiation for patients with small-cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer. 2014;14:793.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. Am J Pathol. 2005;167(4):913–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004;22(17):3608–17.

    Article  PubMed  Google Scholar 

  28. Rostami R, Mittal S, Rostami P, Tavassoli F, Jabbari B. Brain metastasis in breast cancer: a comprehensive literature review. J Neuro-Oncol. 2016;127(3):407–14.

    Article  CAS  Google Scholar 

  29. Sampson JH, Carter JH Jr, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg. 1998;88(1):11–20.

    Article  PubMed  CAS  Google Scholar 

  30. Zakrzewski J, Geraghty LN, Rose AE, Christos PJ, Mazumdar M, Polsky D, et al. Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival. Cancer. 2011;117(8):1711–20.

    Article  PubMed  Google Scholar 

  31. McWilliams RR, Brown PD, Buckner JC, Link MJ, Markovic SN. Treatment of brain metastases from melanoma. Mayo Clin Proc. 2003;78(12):1529–36.

    Article  PubMed  Google Scholar 

  32. Gorantla V, Kirkwood JM, Tawbi HA. Melanoma brain metastases: an unmet challenge in the era of active therapy. Curr Oncol Rep. 2013;15(5):483–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Davis FG, Dolecek TA, McCarthy BJ, Villano JL. Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data. Neuro-Oncology. 2012;14(9):1171–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Essig M, Weber MA, von Tengg-Kobligk H, Knopp MV, Yuh WT, Giesel FL. Contrast-enhanced magnetic resonance imaging of central nervous system tumors: agents, mechanisms, and applications. Top Magn Reson Imaging. 2006;17(2):89–106.

    Article  PubMed  Google Scholar 

  35. Osswald M, Blaes J, Liao Y, Solecki G, Gommel M, Berghoff AS, et al. Impact of blood-brain barrier integrity on tumor growth and therapy response in brain metastases. Clin Cancer Res. 2016;22(24):6078–87.

    Article  PubMed  CAS  Google Scholar 

  36. Yap KY, Chui WK, Chan A. Drug interactions between chemotherapeutic regimens and antiepileptics. Clin Ther. 2008;30(8):1385–407.

    Article  PubMed  CAS  Google Scholar 

  37. Cheung YT, Yap KY, Chui WK, Chan A. Drug-drug interactions between oral antiepileptics and oral anticancer drugs: implications to clinicians. Eur Neurol. 2010;64(2):88–94.

    Article  PubMed  CAS  Google Scholar 

  38. Shi S, Li Y. Interplay of drug-metabolizing enzymes and transporters in drug absorption and disposition. Curr Drug Metab. 2014;15(10):915–41.

    Article  PubMed  CAS  Google Scholar 

  39. Pang KS, Maeng HJ, Fan J. Interplay of transporters and enzymes in drug and metabolite processing. Mol Pharm. 2009;6(6):1734–55.

    Article  PubMed  CAS  Google Scholar 

  40. Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494–500.

    Article  PubMed  CAS  Google Scholar 

  41. Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–41.

    Article  PubMed  Google Scholar 

  42. Franciosi V, Cocconi G, Michiara M, Di Costanzo F, Fosser V, Tonato M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85(7):1599–605.

    Article  PubMed  CAS  Google Scholar 

  43. Bailon O, Chouahnia K, Augier A, Bouillet T, Billot S, Coman I, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro-Oncology. 2012;14(4):491–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bachelot T, Romieu G, Campone M, Dieras V, Cropet C, Dalenc F, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol. 2013;14(1):64–71.

    Article  PubMed  CAS  Google Scholar 

  45. Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–95.

    Article  PubMed  CAS  Google Scholar 

  46. Dummer R, Goldinger SM, Turtschi CP, Eggmann NB, Michielin O, Mitchell L, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer. 2014;50(3):611–21.

    Article  PubMed  CAS  Google Scholar 

  47. Fidler IJ, Yano S, Zhang RD, Fujimaki T, Bucana CD. The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol. 2002;3(1):53–7.

    Article  PubMed  CAS  Google Scholar 

  48. Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med. 2010;16(1):116–22.

    Article  PubMed  CAS  Google Scholar 

  49. On NH, Mitchell R, Savant SD, Bachmeier CJ, Hatch GM, Miller DW. Examination of blood-brain barrier (BBB) integrity in a mouse brain tumor model. J Neuro-Oncol. 2013;111(2):133–43.

    Article  Google Scholar 

  50. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275(3):772–82.

    Article  PubMed  Google Scholar 

  51. McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Paolini MA, Murray DL, et al. Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without intracranial abnormalities. Radiology. 2017;285(2):546–54.

    Article  PubMed  Google Scholar 

  52. Preusser M, Capper D, Ilhan-Mutlu A, Berghoff AS, Birner P, Bartsch R, et al. Brain metastases: pathobiology and emerging targeted therapies. Acta Neuropathol. 2012;123(2):205–22.

    Article  PubMed  CAS  Google Scholar 

  53. McCoach CE, Berge EM, Lu X, Baron AE, Camidge DR. A brief report of the status of central nervous system metastasis enrollment criteria for advanced non-small cell lung Cancer clinical trials: a review of the ClinicalTrials.gov trial registry. J Thorac Oncol. 2016;11(3):407–13.

    Article  PubMed  Google Scholar 

  54. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 2015;16(6):e270–8.

    Article  PubMed  Google Scholar 

  55. Pafundi DH, Laack NN, Youland RS, Parney IF, Lowe VJ, Giannini C, et al. Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study. Neuro-Oncology. 2013;15(8):1058–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Taskar KS, Rudraraju V, Mittapalli RK, Samala R, Thorsheim HR, Lockman J, et al. Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res. 2012;29(3):770–81.

    Article  PubMed  CAS  Google Scholar 

  57. de Lange EC, Danhof M. Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clin Pharmacokinet. 2002;41(10):691–703.

    Article  PubMed  Google Scholar 

  58. Shen DD, Artru AA, Adkison KK. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev. 2004;56(12):1825–57.

    Article  PubMed  CAS  Google Scholar 

  59. Liu X, Van Natta K, Yeo H, Vilenski O, Weller PE, Worboys PD, et al. Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. Drug Metab Dispos. 2009;37(4):787–93.

    Article  PubMed  CAS  Google Scholar 

  60. de Lange EC. Utility of CSF in translational neuroscience. J Pharmacokinet Pharmacodyn. 2013;40(3):315–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Kodaira H, Kusuhara H, Fujita T, Ushiki J, Fuse E, Sugiyama Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a surrogate. J Pharmacol Exp Ther. 2011;339(3):935–44.

    Article  PubMed  CAS  Google Scholar 

  62. Zhuang Y, Fraga CH, Hubbard KE, Hagedorn N, Panetta JC, Waters CM, et al. Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res. 2006;66(23):11305–13.

    Article  PubMed  CAS  Google Scholar 

  63. de Lange EC. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS. 2013;10(1):12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Hillered L, Persson L, Nilsson P, Ronne-Engstrom E, Enblad P. Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis. Curr Opin Crit Care. 2006;12(2):112–8.

    Article  PubMed  Google Scholar 

  65. Ederoth P, Tunblad K, Bouw R, Lundberg CJ, Ungerstedt U, Nordstrom CH, et al. Blood-brain barrier transport of morphine in patients with severe brain trauma. Br J Clin Pharmacol. 2004;57(4):427–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Friden M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos. 2007;35(9):1711–9.

    Article  PubMed  CAS  Google Scholar 

  67. Kalvass JC, Phipps C, Jenkins GJ, Stuart P, Zhang X, Heinle L, et al. Mathematical and experimental validation of flux Dialysis method: an improved approach to measure unbound fraction for compounds with high protein binding and other challenging properties. Drug Metab Dispos. 2018;46(4):458–69.

    Article  PubMed  CAS  Google Scholar 

  68. Laramy JK, Kim M, Gupta SK, Parrish KE, Zhang S, Bakken KK, et al. Heterogeneous binding and central nervous system distribution of the multitargeted kinase inhibitor Ponatinib restrict Orthotopic efficacy in a patient-derived xenograft model of glioblastoma. J Pharmacol Exp Ther. 2017;363(2):136–47.

    Article  PubMed  CAS  Google Scholar 

  69. Liu X, Chen C, Smith BJ. Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther. 2008;325(2):349–56.

    Article  PubMed  CAS  Google Scholar 

  70. Mittapalli RK, Vaidhyanathan S, Dudek AZ, Elmquist WF. Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther. 2013;344(3):655–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Vaidhyanathan S, Mittapalli RK, Sarkaria JN, Elmquist WF. Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases. Drug Metab Dispos. 2014;42(8):1292–300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Heffron TP. Small molecule kinase inhibitors for the treatment of brain Cancer. J Med Chem. 2016;59(22):10030–66.

    Article  PubMed  CAS  Google Scholar 

  73. Heffron TP. Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels. Neuro-Oncology. 2018;20(3):307–12.

    Article  PubMed  Google Scholar 

  74. Maurer TS, Debartolo DB, Tess DA, Scott DO. Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab Dispos. 2005;33(1):175–81.

    Article  PubMed  CAS  Google Scholar 

  75. Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19(6):771–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13–25.

    Article  PubMed  CAS  Google Scholar 

  77. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.

    Article  PubMed  CAS  Google Scholar 

  78. Haseloff RF, Blasig IE, Bauer HC, Bauer H. In search of the astrocytic factor(s) modulating blood-brain barrier functions in brain capillary endothelial cells in vitro. Cell Mol Neurobiol. 2005;25(1):25–39.

    Article  PubMed  CAS  Google Scholar 

  79. Tietz S, Engelhardt B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J Cell Biol. 2015;209(4):493–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Agarwal S, Hartz AM, Elmquist WF, Bauer B. Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. Curr Pharm Des. 2011;17(26):2793–802.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333–45.

    Article  PubMed  CAS  Google Scholar 

  82. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491–502.

    Article  PubMed  CAS  Google Scholar 

  83. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996;97(11):2517–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Begley DJ. ABC transporters and the blood-brain barrier. Curr Pharm Des. 2004;10(12):1295–312.

    Article  PubMed  CAS  Google Scholar 

  85. Steeg PS, Camphausen KA, Smith QR. Brain metastases as preventive and therapeutic targets. Nat Rev Cancer. 2011;11(5):352–63.

    Article  PubMed  CAS  Google Scholar 

  86. Kis O, Robillard K, Chan GN, Bendayan R. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci. 2010;31(1):22–35.

    Article  PubMed  CAS  Google Scholar 

  87. Miller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Fricker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol. 2000;58(6):1357–67.

    Article  PubMed  CAS  Google Scholar 

  88. Cisternino S, Mercier C, Bourasset F, Roux F, Scherrmann JM. Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood-brain barrier. Cancer Res. 2004;64(9):3296–301.

    Article  PubMed  CAS  Google Scholar 

  89. de Lange EC. Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv Drug Deliv Rev. 2004;56(12):1793–809.

    Article  PubMed  CAS  Google Scholar 

  90. Eilers M, Roy U, Mondal D. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood). 2008;233(9):1149–60.

    Article  CAS  Google Scholar 

  91. Lingineni K, Belekar V, Tangadpalliwar SR, Garg P. The role of multidrug resistance protein (MRP-1) as an active efflux transporter on blood-brain barrier (BBB) permeability. Mol Divers. 2017;

  92. de Vries NA, Zhao J, Kroon E, Buckle T, Beijnen JH, van Tellingen O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res. 2007;13(21):6440–9.

    Article  PubMed  CAS  Google Scholar 

  93. de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O. Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Investig New Drugs. 2012;30(2):443–9.

    Article  CAS  Google Scholar 

  94. Elmeliegy MA, Carcaboso AM, Tagen M, Bai F, Stewart CF. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation. Clin Cancer Res. 2011;17(1):89–99.

    Article  PubMed  CAS  Google Scholar 

  95. Lin F, de Gooijer MC, Roig EM, Buil LC, Christner SM, Beumer JH, et al. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res. 2014;20(10):2703–13.

    Article  PubMed  CAS  Google Scholar 

  96. Oberoi RK, Mittapalli RK, Elmquist WF. Pharmacokinetic assessment of efflux transport in sunitinib distribution to the brain. J Pharmacol Exp Ther. 2013;347(3):755–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Parrish KE, Cen L, Murray J, Calligaris D, Kizilbash S, Mittapalli RK, et al. Efficacy of PARP inhibitor Rucaparib in Orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. Mol Cancer Ther. 2015;14(12):2735–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Parrish KE, Pokorny J, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. Efflux transporters at the blood-brain barrier limit delivery and efficacy of cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) in an orthotopic brain tumor model. J Pharmacol Exp Ther. 2015;355(2):264–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Polli JW, Humphreys JE, Harmon KA, Castellino S, O'Mara MJ, Olson KL, et al. The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos 2008;36(4):695–701.

  100. Tang SC, Nguyen LN, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014;134(6):1484–94.

    Article  PubMed  CAS  Google Scholar 

  101. Westerhout J, Smeets J, Danhof M, de Lange EC. The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid. J Pharmacokinet Pharmacodyn. 2013;40(3):327–42.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mittapalli RK, Chung AH, Parrish KE, Crabtree D, Halvorson KG, Hu G, et al. ABCG2 and ABCB1 limit the efficacy of Dasatinib in a PDGF-B-driven brainstem glioma model. Mol Cancer Ther. 2016;15(5):819–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Becker CM, Oberoi RK, McFarren SJ, Muldoon DM, Pafundi DH, Pokorny JL, et al. Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. Neuro-Oncology. 2015;17(9):1210–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  104. Broccatelli F, Larregieu CA, Cruciani G, Oprea TI, Benet LZ. Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012;64(1):95–109.

    Article  PubMed  CAS  Google Scholar 

  105. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693–703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Doroshow JH. Targeting EGFR in non-small-cell lung cancer. N Engl J Med. 2005;353(2):200–2.

    Article  PubMed  CAS  Google Scholar 

  107. Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108–11.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Togashi Y, Masago K, Fukudo M, Terada T, Fujita S, Irisa K, et al. Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer. J Thorac Oncol. 2010;5(7):950–5.

    Article  PubMed  Google Scholar 

  109. Chen Y, Wang M, Zhong W, Zhao J. Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis. Lung Cancer. 2013;82(2):313–8.

    Article  PubMed  Google Scholar 

  110. Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010;334(1):147–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos. 2013;41(1):33–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Heon S, Yeap BY, Lindeman NI, Joshi VA, Butaney M, Britt GJ, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 2012;18(16):4406–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343(2):342–50.

    Article  PubMed  CAS  Google Scholar 

  114. Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M, et al. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015;10(1):156–63.

    Article  PubMed  CAS  Google Scholar 

  115. Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of Osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40.

    Article  PubMed  CAS  Google Scholar 

  116. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-Pemetrexed in EGFR T790M-positive lung Cancer. N Engl J Med. 2017;376(7):629–40.

    Article  PubMed  CAS  Google Scholar 

  117. Zeng Q, Wang J, Cheng Z, Chen K, Johnstrom P, Varnas K, et al. Discovery and evaluation of clinical candidate AZD3759, a potent, oral active, central nervous system-penetrant, epidermal growth factor receptor tyrosine kinase inhibitor. J Med Chem. 2015;58(20):8200–15.

    Article  PubMed  CAS  Google Scholar 

  118. Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z, et al. AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci Transl Med. 2016;8(368):368ra172.

    Article  PubMed  CAS  Google Scholar 

  119. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14(13):4275–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115(8):1723–33.

    Article  PubMed  CAS  Google Scholar 

  121. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15(16):5216–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011;29(15):e443–5.

    Article  PubMed  Google Scholar 

  123. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with Crizotinib in patients with advanced ALK-rearranged non-small-cell lung Cancer and brain metastases. J Clin Oncol. 2015;33(17):1881–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  PubMed  CAS  Google Scholar 

  125. A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014) [Internet]. 2014.

  126. Kodama T, Tsukaguchi T, Satoh Y, Yoshida M, Watanabe Y, Kondoh O, et al. Alectinib shows potent antitumor activity against RET-rearranged non-small cell lung cancer. Mol Cancer Ther. 2014;13(12):2910–8.

    Article  PubMed  CAS  Google Scholar 

  127. Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol. 2014;15(10):1119–28.

    Article  PubMed  CAS  Google Scholar 

  128. Metro G, Lunardi G, Bennati C, Chiarini P, Sperduti I, Ricciuti B, et al. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series. J Neuro-Oncol. 2016;129(2):355–61.

    Article  CAS  Google Scholar 

  129. Kodama T, Hasegawa M, Takanashi K, Sakurai Y, Kondoh O, Sakamoto H. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. Cancer Chemother Pharmacol. 2014;74(5):1023–8.

    Article  PubMed  CAS  Google Scholar 

  130. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Corporation NP. Zykadia. Product insert.

  132. Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57(11):4720–44.

    Article  PubMed  CAS  Google Scholar 

  134. Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, et al. Discovery of Entrectinib: a new 3-Aminoindazole as a potent anaplastic lymphoma kinase (ALK), c-ROS oncogene 1 kinase (ROS1), and pan-tropomyosin receptor kinases (pan-TRKs) inhibitor. J Med Chem. 2016;59(7):3392–408.

    Article  PubMed  CAS  Google Scholar 

  135. Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neuro-Oncol. 2005;75(1):5–14.

    Article  Google Scholar 

  136. Sloan AE, Nock CJ, Einstein DB. Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Control. 2009;16(3):248–55.

    Article  PubMed  Google Scholar 

  137. Damsky WE, Theodosakis N, Bosenberg M. Melanoma metastasis: new concepts and evolving paradigms. Oncogene. 2014;33(19):2413–22.

    Article  PubMed  CAS  Google Scholar 

  138. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  PubMed  CAS  Google Scholar 

  139. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Capper D, Berghoff AS, Magerle M, Ilhan A, Wohrer A, Hackl M, et al. Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol. 2012;123(2):223–33.

    Article  PubMed  CAS  Google Scholar 

  141. Durmus S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-GLYCOprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Mol Pharm. 2012;9(11):3236–45.

    Article  PubMed  CAS  Google Scholar 

  142. Kim A, Cohen MS. The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma. Expert Opin Drug Discov. 2016;11(9):907–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Luke JJ, Hodi FS. Vemurafenib and BRAF inhibition: a new class of treatment for metastatic melanoma. Clin Cancer Res. 2012;18(1):9–14.

    Article  PubMed  CAS  Google Scholar 

  144. Mittapalli RK, Vaidhyanathan S, Sane R, Elmquist WF. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther. 2012;342(1):33–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306–12.

    Article  PubMed  Google Scholar 

  146. Narayana A, Mathew M, Tam M, Kannan R, Madden KM, Golfinos JG, et al. Vemurafenib and radiation therapy in melanoma brain metastases. J Neuro-Oncol. 2013;113(3):411–6.

    Article  CAS  Google Scholar 

  147. Rochet NM, Kottschade LA, Markovic SN. Vemurafenib for melanoma metastases to the brain. N Engl J Med. 2011;365(25):2439–41.

    Article  PubMed  CAS  Google Scholar 

  148. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet. 2012;379(9829):1893–901.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Azer MW, Menzies AM, Haydu LE, Kefford RF, Long GV. Patterns of response and progression in patients with BRAF-mutant melanoma metastatic to the brain who were treated with dabrafenib. Cancer. 2014;120(4):530–6.

    Article  PubMed  CAS  Google Scholar 

  150. Jiang CC, Chen LH, Gillespie S, Wang YF, Kiejda KA, Zhang XD, et al. Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res. 2007;67(20):9750–61.

    Article  PubMed  CAS  Google Scholar 

  151. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.

    Article  PubMed  CAS  Google Scholar 

  153. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.

    Article  PubMed  CAS  Google Scholar 

  154. Choo EF, Ly J, Chan J, Shahidi-Latham SK, Messick K, Plise E, et al. Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib. Mol Pharm. 2014;11(11):4199–207.

    Article  PubMed  CAS  Google Scholar 

  155. Patel BG, Ahmed KA, Johnstone PA, Yu HH, Etame AB. Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases. Melanoma Res. 2016;26(4):382–6.

    Article  PubMed  CAS  Google Scholar 

  156. Planchard D, Besse B, Groen HJ, Souquet PJ, Quoix E, Baik CS, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving Dabrafenib combined with Trametinib. J Clin Oncol. 2016;34(8):871–8.

    Article  PubMed  CAS  Google Scholar 

  158. Engelhardt B, Coisne C. Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids and Barriers of the CNS. 2011;8(1):4.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Di Giacomo AM, Margolin K. Immune checkpoint blockade in patients with melanoma metastatic to the brain. Semin Oncol. 2015;42(3):459–65.

    Article  PubMed  CAS  Google Scholar 

  160. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–65.

    Article  PubMed  CAS  Google Scholar 

  161. Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neuro-Oncol. 2014;118(1):109–16.

    CAS  Google Scholar 

  162. Aversa C, Rossi V, Geuna E, Martinello R, Milani A, Redana S, et al. Metastatic breast cancer subtypes and central nervous system metastases. Breast. 2014;23(5):623–8.

    Article  PubMed  CAS  Google Scholar 

  163. Kodack DP, Askoxylakis V, Ferraro GB, Fukumura D, Jain RK. Emerging strategies for treating brain metastases from breast cancer. Cancer Cell. 2015;27(2):163–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Clayton AJ, Danson S, Jolly S, Ryder WD, Burt PA, Stewart AL, et al. Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer. 2004;91(4):639–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Leyland-Jones B. Human epidermal growth factor receptor 2-positive breast cancer and central nervous system metastases. J Clin Oncol. 2009;27(31):5278–86.

    Article  PubMed  Google Scholar 

  166. Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer. 2003;97(12):2972–7.

    Article  PubMed  Google Scholar 

  167. Gori S, Lunardi G, Inno A, Foglietta J, Cardinali B, Del Mastro L, et al. Lapatinib concentration in cerebrospinal fluid in two patients with HER2-positive metastatic breast cancer and brain metastases. Ann Oncol. 2014;25(4):912–3.

    Article  PubMed  CAS  Google Scholar 

  168. Morikawa A, Peereboom DM, Thorsheim HR, Samala R, Balyan R, Murphy CG, et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro-Oncology. 2015;17(2):289–95.

    Article  PubMed  CAS  Google Scholar 

  169. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008;112(3):533–43.

    Article  PubMed  CAS  Google Scholar 

  170. Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2008;26(12):1993–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009;15(4):1452–9.

    Article  PubMed  CAS  Google Scholar 

  172. Dawood S, Broglio K, Esteva FJ, Yang W, Kau SW, Islam R, et al. Survival among women with triple receptor-negative breast cancer and brain metastases. Ann Oncol. 2009;20(4):621–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Mikule K, Wilcoxen K, editors. The PARP inhibitor, niraparib, crosses the blood brain barrier in rodents and is efficacious in a BRCA2-mutant intracranial tumor model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015; Philadelphia (PA).

  174. Mehta MP, Wang D, Wang F, Kleinberg L, Brade A, Robins HI, et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neuro-Oncol. 2015;122(2):409–17.

    Article  CAS  Google Scholar 

  175. Palmieri D, Lockman PR, Thomas FC, Hua E, Herring J, Hargrave E, et al. Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res. 2009;15(19):6148–57.

    Article  PubMed  CAS  Google Scholar 

  176. Hanson JE, La H, Plise E, Chen YH, Ding X, Hanania T, et al. SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition. PLoS One. 2013;8(7):e69964.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Fitzgerald DP, Emerson DL, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, et al. TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther. 2012;11(9):1959–67.

    Article  PubMed  CAS  Google Scholar 

  178. Freedman RA, Gelman RS, Melisko ME, Anders CK, Moy B, Blackwell KL, et al. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). J Clin Oncol. 2017;35(15_suppl):1005.

    Article  Google Scholar 

  179. Anders CK, Deal AM, Miller CR, Khorram C, Meng H, Burrows E, et al. The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases. Cancer. 2011;117(8):1602–11.

    Article  PubMed  Google Scholar 

  180. Bianchi M, Sun M, Jeldres C, Shariat SF, Trinh QD, Briganti A, et al. Distribution of metastatic sites in renal cell carcinoma: a population-based analysis. Ann Oncol. 2012;23(4):973–80.

    Article  PubMed  CAS  Google Scholar 

  181. Bennani O, Derrey S, Langlois O, Castel H, Laquerriere A, Freger P, et al. Brain metastasis from renal cell carcinoma. Neurochirurgie. 2014;60(1–2):12–6.

    Article  PubMed  CAS  Google Scholar 

  182. Gore ME, Hariharan S, Porta C, Bracarda S, Hawkins R, Bjarnason GA, et al. Sunitinib in metastatic renal cell carcinoma patients with brain metastases. Cancer. 2011;117(3):501–9.

    Article  PubMed  CAS  Google Scholar 

  183. Dudek AZ, Raza A, Chi M, Singhal M, Oberoi R, Mittapalli RK, et al. Brain metastases from renal cell carcinoma in the era of tyrosine kinase inhibitors. Clin Genitourin Cancer. 2013;11(2):155–60.

    Article  PubMed  Google Scholar 

  184. Roberto M, Bassanelli M, Iannicelli E, Giacinti S, D'Antonio C, Aschelter AM, et al. Clinical outcome of third-line Pazopanib in a patient with metastatic renal cell carcinoma. Case Rep Oncol Med. 2015;629046:2015.

    Google Scholar 

  185. Anders CK, Adamo B, Karginova O, Deal AM, Rawal S, Darr D, et al. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. PLoS One. 2013;8(5):e61359.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Kreuter J. Drug delivery to the central nervous system by polymeric nanoparticles: what do we know? Adv Drug Deliv Rev. 2014;71:2–14.

    Article  PubMed  CAS  Google Scholar 

  187. Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. 2007;7(4):447–59.

    Article  PubMed  CAS  Google Scholar 

  188. Sandler A, Gordon M, De Alwis DP, Pouliquen I, Green L, Marder P, et al. A phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy. Clin Cancer Res. 2004;10(10):3265–72.

    Article  PubMed  CAS  Google Scholar 

  189. Morschhauser F, Zinzani PL, Burgess M, Sloots L, Bouafia F, Dumontet C. Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma. Leuk Lymphoma. 2007;48(4):708–15.

    Article  PubMed  CAS  Google Scholar 

  190. Salphati L, Shahidi-Latham S, Quiason C, Barck K, Nishimura M, Alicke B, et al. Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging. Drug Metab Dispos. 2014;42(7):1110–6.

    Article  PubMed  CAS  Google Scholar 

  191. Heffron TP, Salphati L, Alicke B, Cheong J, Dotson J, Edgar K, et al. The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase alpha. J Med Chem. 2012;55(18):8007–20.

    Article  PubMed  CAS  Google Scholar 

  192. Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crino L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15(7):1042–7.

    Article  PubMed  CAS  Google Scholar 

  193. Porta R, Sanchez-Torres JM, Paz-Ares L, Massuti B, Reguart N, Mayo C, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2011;37(3):624–31.

    Article  PubMed  CAS  Google Scholar 

  194. Wind S, Giessmann T, Jungnik A, Brand T, Marzin K, Bertulis J, et al. Pharmacokinetic drug interactions of afatinib with rifampicin and ritonavir. Clin Drug Investig. 2014;34(3):173–82.

    Article  PubMed  CAS  Google Scholar 

  195. Katayama R, Sakashita T, Yanagitani N, Ninomiya H, Horiike A, Friboulet L, et al. P-glycoprotein mediates Ceritinib resistance in anaplastic lymphoma kinase-rearranged non-small cell lung Cancer. EBioMedicine. 2016;3:54–66.

    Article  PubMed  Google Scholar 

  196. Crino L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter phase II study of whole-body and intracranial activity with Ceritinib in patients with ALK-rearranged non-small-cell lung Cancer previously treated with chemotherapy and Crizotinib: results from ASCEND-2. J Clin Oncol. 2016;34(24):2866–73.

    Article  PubMed  CAS  Google Scholar 

  197. Rosell R, Gettinger SN, Bazhenova LA, Langer CJ, Salgia R, Shaw AT, et al. 1330: Brigatinib efficacy and safety in patients (pts) with anaplastic lymphoma kinase (ALK)-positive (ALK+) non-small cell lung cancer (NSCLC) in a phase 1/2 trial. J Thorac Oncol. 2016;11(4 Suppl):S114.

    Article  PubMed  Google Scholar 

  198. Ardini E, Menichincheri M, Banfi P, Bosotti R, De Ponti C, Pulci R, et al. Entrectinib, a pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined Cancer indications. Mol Cancer Ther. 2016;15(4):628–39.

    Article  PubMed  CAS  Google Scholar 

  199. Sakji-Dupre L, Le Rhun E, Templier C, Desmedt E, Blanchet B, Mortier L. Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma. Melanoma Res. 2015;25(4):302–5.

    Article  PubMed  CAS  Google Scholar 

  200. Gampa G, Kim M, Cook-Rostie N, Laramy JK, Sarkaria JN, Paradiso L, et al. Brain distribution of a novel MEK inhibitor E6201: implications in the treatment of melanoma brain metastases. Drug Metab Dispos. 2018;46(5):658–66.

    Article  PubMed  CAS  Google Scholar 

  201. Stemmler HJ, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anti-Cancer Drugs. 2007;18(1):23–8.

    Article  PubMed  CAS  Google Scholar 

  202. Lawlor D, Martin P, Busschots S, Thery J, O'Leary JJ, Hennessy BT, et al. PARP inhibitors as P-glyoprotein substrates. J Pharm Sci. 2014;103(6):1913–20.

    Article  PubMed  CAS  Google Scholar 

  203. Kizilbash SH, Gupta SK, Chang K, Kawashima R, Parrish KE, Carlson BL, et al. Restricted delivery of Talazoparib across the blood-brain barrier limits the sensitizing effects of PARP inhibition on Temozolomide therapy in glioblastoma. Mol Cancer Ther. 2017;16(12):2735–46.

    Article  PubMed  CAS  Google Scholar 

  204. Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther. 2011;336(1):223–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  205. Poller B, Iusuf D, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Differential impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on axitinib brain accumulation and oral plasma pharmacokinetics. Drug Metab Dispos. 2011;39(5):729–35.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. University of Minnesota, Minneapolis, Minnesota, USA

    Minjee Kim, Janice K. Laramy, Gautham Gampa, Karen E. Parrish & William F. Elmquist

  2. Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA

    Sani H. Kizilbash & Jann N. Sarkaria

Authors
  1. Minjee Kim
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  2. Sani H. Kizilbash
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  3. Janice K. Laramy
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  4. Gautham Gampa
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  5. Karen E. Parrish
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  6. Jann N. Sarkaria
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  7. William F. Elmquist
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Correspondence to William F. Elmquist.

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Kim, M., Kizilbash, S.H., Laramy, J.K. et al. Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine. Pharm Res 35, 177 (2018). https://doi.org/10.1007/s11095-018-2455-9

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  • DOI: https://doi.org/10.1007/s11095-018-2455-9

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