Abstract
The effective treatment of brain tumors is a considerable challenge in part due to the presence of the blood-brain barrier (BBB) that limits drug delivery. Multiple hurdles pose challenges in identifying drugs that may be effective in treating brain tumors, including limited central nervous system (CNS) distribution of therapeutics, heterogeneous disruption of the blood-brain barrier in the regions of the tumor that lead to heterogenous drug distribution within the tumor, and genetic heterogeneity of tumor drivers. This chapter discusses the current standard of care and its limitations, as well as complex challenges in the treatment of primary and metastatic brain tumors. We review a variety of prospective delivery solutions of therapeutics to the brain and CNS for the treatment of brain tumors that will in the future lead to opening new doors for more effective treatments.
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References
Abe T et al (1998) Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. J Neurooncol. https://doi.org/10.1023/A:1005954406809
Achrol AS et al (2019) Brain metastases. Nat Rev Dis Primers. https://doi.org/10.1038/s41572-018-0055-y
Agarwal S et al (2012) Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. Curr Pharm Des. https://doi.org/10.2174/138161211797440186
Akimoto J (2016) Photodynamic therapy for malignant brain tumors. Neurol Med Chir. https://doi.org/10.2176/nmc.ra.2015-0296
Aldape K et al (2019) Challenges to curing primary brain tumours. Nat Rev Clin Oncol. https://doi.org/10.1038/s41571-019-0177-5
Alifieris C, Trafalis DT (2015) Glioblastoma multiforme: pathogenesis and treatment. Pharmacol Therapeutic. https://doi.org/10.1016/j.pharmthera.2015.05.005
Allison RR, Sibata CH (2010) Oncologic photodynamic therapy photosensitizers: a clinical review. Photodiagnosis Photodyn Ther. https://doi.org/10.1016/j.pdpdt.2010.02.001
Amelio D, Amichetti MA (2012) Radiation therapy for the treatment of recurrent glioblastoma: an overview. Cancer. https://doi.org/10.3390/cancers4010257
Amsbaugh, M. J. and Kim, C. S. (2019) Cancer, brain metastasis, StatPearls.
Aronica E et al (2005) Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain. Epilepsia 46(6):849–857
Arvanitis CD et al (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.1807105115
Barani IJ, Larson DA (2015) Radiation therapy of glioblastoma. Cancer Treat Res. https://doi.org/10.1007/978-3-319-12048-5_4
Bartsch R et al (2015) Activity of T-DM1 in Her2-positive breast cancer brain metastases. Clin Exp Metastasis. https://doi.org/10.1007/s10585-015-9740-3
Basit S et al (2017) European journal of medicinal chemistry first macrocyclic 3rd-generation ALK inhibitor for treatment of ALK / ROS1 cancer: clinical and designing strategy update of lorlatinib. Eur J Med Chem 134:348–356. https://doi.org/10.1016/j.ejmech.2017.04.032. Elsevier Masson SAS
Bastien JIL, McNeill KA, Fine HA (2015) Molecular characterizations of glioblastoma, targeted therapy, and clinical results to date. Cancer. https://doi.org/10.1002/cncr.28968
Bauer TM et al (2020) Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer. Target Oncol. https://doi.org/10.1007/s11523-020-00702-4
Baumert C, Hilgeroth A (2012) Recent advances in the development of P-gp inhibitors. Anticancer Agents Med Chem. https://doi.org/10.2174/1871520610909040415
Bellavance MA, Blanchette M, Fortin D (2008) Recent advances in blood-brain barrier disruption as a CNS delivery strategy. AAPS J. https://doi.org/10.1208/s12248-008-9018-7
Bhagavathi S, Wilson JD (2008) Primary central nervous system lymphoma. Arch Pathol Lab Med. https://doi.org/10.1043/1543-2165-132.11.1830
Bhardwaj RK et al (2006) The functional evaluation of human peptide/histidine transporter 1 (hPHT1) in transiently transfected COS-7 cells. Eur J Pharm Sci. https://doi.org/10.1016/j.ejps.2005.09.014
Bhatia P et al (2012) Breast cancer resistance protein (BCRP/ABCG2) localises to the nucleus in glioblastoma multiforme cells. Xenobiotica. 2012/03/10 42(8):748–755. https://doi.org/10.3109/00498254.2012.662724
Bi WL, Beroukhim R (2014) Beating the odds: extreme long-term survival with glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/nou166
Blakeley J (2008) Drug delivery to brain tumors. Curr Neurol Neurosci Rep. https://doi.org/10.1007/s11910-008-0036-8
Blakeley JO et al (2009) Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study. J Neurooncol. https://doi.org/10.1007/s11060-008-9678-2
Bleau AM et al (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4(3):226–235. https://doi.org/10.1016/j.stem.2009.01.007
Boado RJ et al (2010) IgG-single chain Fv fusion protein therapeutic for Alzheimer’s disease: expression in CHO cells and pharmacokinetics and brain delivery in the Rhesus monkey. Biotechnol Bioeng. https://doi.org/10.1002/bit.22576
Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell. 2013/10/15 155(2):462–477. https://doi.org/10.1016/j.cell.2013.09.034
Bruzzone MG et al (2012) CT and MRI of brain tumors. Q J Nucl Med Mol Imaging
Bui K et al (2016) The effect of quinidine, a strong P-glycoprotein inhibitor, on the pharmacokinetics and central nervous system distribution of naloxegol. J Clin Pharmacol. https://doi.org/10.1002/jcph.613
Bunevicius A, McDannold NJ, Golby AJ (2020) Focused ultrasound strategies for brain tumor therapy. Oper Neurosurg. https://doi.org/10.1093/ons/opz374
Calias P et al (2014) Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. Pharmacol Therapeutic. https://doi.org/10.1016/j.pharmthera.2014.05.009
Cardoso FL, Brites D, Brito MA (2010) Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. Elsevier B.V 64(2):328–363. https://doi.org/10.1016/j.brainresrev.2010.05.003
Castedo M et al (2004) Cell death by mitotic catastrophe: a molecular definition. Oncogene. https://doi.org/10.1038/sj.onc.1207528
Castro M et al (2001) High-affinity sodium-vitamin C co-transporters (SVCT) expression in embryonic mouse neurons. J Neurochem. https://doi.org/10.1046/j.1471-4159.2001.00461.x
Chamberlain MC et al (2014) A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the brain tumor investigational consortium (BTIC). J Neurooncol. https://doi.org/10.1007/s11060-014-1437-y
Chen JS et al (2006) EGFR regulates the side population in head and neck squamous cell carcinoma. Laryngoscope. 2006/03/17 116(3):401–406. https://doi.org/10.1097/01.mlg.0000195075.14093.fb
Cho HS et al (2016) Localized down-regulation of P-glycoprotein by focused ultrasound and microbubbles induced blood-brain barrier disruption in rat brain. Sci Rep. Nature Publishing Group 6(May):1–10. https://doi.org/10.1038/srep31201
Chowdhary S, Chamberlain M (2013) Bevacizumab for the treatment of glioblastoma. Expert Rev Neurother. https://doi.org/10.1586/14737175.2013.827414
Cloughesy TF, Cavenee WK, Mischel PS (2014) Glioblastoma: from molecular pathology to targeted treatment. https://doi.org/10.1146/annurev-pathol-011110-130324
Cooray HC et al (2002) Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport. https://doi.org/10.1097/00001756-200211150-00014
Cordon-Cardo C et al (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci 86:695–698. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC286540/pdf/pnas00242-0297.pdf
Cramer SW, Chen CC (2020) Photodynamic therapy for the treatment of glioblastoma. Front Surg. https://doi.org/10.3389/fsurg.2019.00081
Davis ME (2016) HHS public access. 20(5):1–14. https://doi.org/10.1188/16.CJON.S1.2-8.Glioblastoma
de Trizio I et al (2020) Expression of P-gp in glioblastoma: what we can learn from brain development. Curr Pharm Des. https://doi.org/10.2174/1381612826666200318130625
Debinski W, Tatter SB (2009) Convection-enhanced delivery for the treatment of brain tumors. Expert Rev Neurother. https://doi.org/10.1586/ern.09.99
Delattre JY et al (1988) Distribution of brain metastases. Arch Neurol. https://doi.org/10.1001/archneur.1988.00520310047016
Demeule M et al (2001) Expression of multidrug-resistance p-glycoprotein (MDR1) in human brain tumors. Int J Cancer 93:62–66
Dempke WCM et al (2015) Brain metastases in NSCLC-are TKIs changing the treatment strategy? Anticancer Res
Deng Z, Sheng Z, Yan F (2019) Ultrasound-induced blood-brain-barrier opening enhances anticancer efficacy in the treatment of glioblastoma: current status and future prospects. J Oncol. https://doi.org/10.1155/2019/2345203
Drappatz J et al (2013) Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res 19(6):1567–1576. Available at: http://clincancerres.aacrjournals.org/content/19/6/1567.abstract
Dubey RK et al (1989) Plasma binding and transport of diazepam across the blood-brain barrier. No evidence for in vivo enhanced dissociation. J Clin Investig. https://doi.org/10.1172/JCI114279
Durant ST et al (2018) The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. https://doi.org/10.1126/sciadv.aat1719
Eisenblaetter T, Galla H-J (2002) A new multidrug resistance protein at the blood–brain barrier. Biochem Biophys Res Commun 293:1273–1278
El-Osta A et al (2002) Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol Cell Biol 22(6):1844–1857. https://doi.org/10.1128/mcb.22.6.1844-1857.2002
Emery IF et al (2017) Expression and function of ABCG2 and XIAP in glioblastomas. J Neurooncol. 2017/04/23 133(1):47–57. https://doi.org/10.1007/s11060-017-2422-z
Eskilsson E et al (2018) EGFR heterogeneity and implications for therapeutic intervention in glioblastoma. Neuro Oncol. 2017/10/19 20(6):743–752. https://doi.org/10.1093/neuonc/nox191
Ewend MG et al (2007) Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-06-2095
Fokas E, Steinbach JP, Rödel C (2013) Biology of brain metastases and novel targeted therapies: time to translate the research. Biochim Biophys Acta Rev Cancer. https://doi.org/10.1016/j.bbcan.2012.10.005
Fox E, Bates SE (2007) Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. https://doi.org/10.1586/14737140.7.4.447
Fridén M et al (2009) Development of a high-throughput brain slice method for studying drug distribution in the central nervous system. Drug Metab Dispos. https://doi.org/10.1124/dmd.108.026377
Fridén M et al (2011) Measurement of unbound drug exposure in brain: modeling of pH partitioning explains diverging results between the brain slice and brain homogenate methods. Drug Metab Dispos. https://doi.org/10.1124/dmd.110.035998
Gadgeel S et al (2018) Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALKþ) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. https://doi.org/10.1093/annonc/mdy405
Gaillard PJ et al (2014) Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101). PLoS One. https://doi.org/10.1371/journal.pone.0082331
Gampa G et al (2020) Influence of transporters in treating cancers in the CNS. In: Drug efflux pumps in cancer resistance pathways: from molecular recognition and characterization to possible inhibition strategies in chemotherapy. https://doi.org/10.1016/b978-0-12-816434-1.00009-7
Gil ES et al (2009) Quaternary ammonium β-cyclodextrin nanoparticles for enhancing doxorubicin permeability across the in vitro blood-brain barrier. Biomacromolecules. https://doi.org/10.1021/bm801026k
Ginguene C et al (2010) P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) localize in the microvessels forming the blood-tumor barrier in ependymomas. Brain Pathol. 2010/04/22 20(5):926–935. https://doi.org/10.1111/j.1750-3639.2010.00389.x
Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med. https://doi.org/10.1146/annurev.med.53.082901.103929
Grossman R et al (2013) Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model. Cancer Chemother Pharmacol. https://doi.org/10.1007/s00280-013-2172-3
Hammarlund-Udenaes M et al (2008) On the rate and extent of drug delivery to the brain. Pharm Res. https://doi.org/10.1007/s11095-007-9502-2
Han SR et al (2015) Effect and mechanism of peroxisome proliferator-activated receptor-gamma on the drug resistance of the U-87 MG/CDDP human malignant glioma cell line. Molecular Mol Med Rep 12(2):2239–2246. https://doi.org/10.3892/mmr.2015.3625
Harmsen S et al (2013) PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors. Eur J Pharm Sci 48(4–5):644–649. https://doi.org/10.1016/j.ejps.2012.12.019
Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell. https://doi.org/10.1016/j.molcel.2007.11.015
Hartz AMS, Mahringer A et al (2010a) 17-beta-Estradiol: a powerful modulator of blood-brain barrier BCRP activity. J Cereb Blood Flow Metab 30(10):1742–1755. https://doi.org/10.1038/jcbfm.2010.36
Hartz AMS, Madole EK et al (2010b) Estrogen receptor beta signaling through phosphatase and tensin homolog/phosphoinositide 3-kinase/Akt/glycogen synthase kinase 3 down-regulates blood-brain barrier breast cancer resistance protein. J Pharmacol Exp Ther 334(2):467–476. https://doi.org/10.1124/jpet.110.168930
Hawkins BT et al (2010) The blood-brain barrier / neurovascular unit in health and disease. Neurobiol Dis. Elsevier B.V 64(1):13–25. https://doi.org/10.1016/j.brainresrev.2010.05.003
Heffron TP (2016) Small molecule kinase inhibitors for the treatment of brain cancer. J Med Chem:10030–10066. https://doi.org/10.1021/acs.jmedchem.6b00618
Heffron TP et al (2016) Discovery of clinical development candidate GDC-0084, a brain penetrant inhibitor of PI3K and mTOR. ACS Med Chem Lett. https://doi.org/10.1021/acsmedchemlett.6b00005
Hellmann-Regen J et al (2012) Retinoic acid as target for local pharmacokinetic interaction with modafinil in neural cells. Eur Arch Psychiatry Clin Neurosci 262(8):697–704. https://doi.org/10.1007/s00406-012-0309-8
Hoeijmakers JHJ (2009) DNA damage, aging, and cancer. N Engl J Med. https://doi.org/10.1056/NEJMra0804615
Huang FF et al (2013) Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia. Cancer Lett. 2013/04/23 336(1):96–105. https://doi.org/10.1016/j.canlet.2013.04.006
Huang J et al (2014) Regenerating gene family member 4 promotes growth and migration of gastric cancer through protein kinase B pathway. Int J Clin Exp Med 7(9):3037–3044
Huisman MT et al (2003) Assessing safety and efficacy of directed P-glycoprotein inhibition to improve the pharmacokinetic properties of saquinavir coadministered with ritonavir. J Pharmacol Experiment Therapeutic. https://doi.org/10.1124/jpet.102.044388
Hunt Bobo R et al (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.91.6.2076
J.G., P.-L et al (2011) Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: An ANOCEF phase II trial. J Clin Oncol. https://doi.org/10.1200/JCO.2011.34.8086LK. http://onesearch.unifi.it/openurl/39UFI/39UFI_Services?&sid=EMBASE&issn=0732183X&id=doi:10.1200%2FJCO.2011.34.8086&atitle=Temozolomide+in+elderly+patients+with+newly+diagnosed+glioblastoma+and+poor+performance+status%3A+An+ANOCEF+phase+II+trial&stitle=J.+Clin.+Oncol.&title=Journal+of+Clinical+Oncology&volume=29&issue=22&spage=3050&epage=3055&aulast=P%C3%A9rez-Larraya&aufirst=Jaime+G%C3%A1llego&auinit=J.G.&aufull=P%C3%A9rez-Larraya+J.G.&coden=JCOND&isbn=&pages=3050-
Jackson S et al (2016) The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain. J Neurooncol. 2015/12/03 126(3):433–439. https://doi.org/10.1007/s11060-015-1998-4
Jackson S et al (2017) The effect of regadenoson on the integrity of the human blood–brain barrier, a pilot study. J Neurooncol. https://doi.org/10.1007/s11060-017-2404-1
Jackson S et al (2018) The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma. Fluid Barrier CNS. 2018/01/16 15(1):2. https://doi.org/10.1186/s12987-017-0088-8
Johnson RA, Ince TA, Scotto KW (2001) Transcriptional repression by p53 through direct binding to a novel DNA element. J Biol Chem. 2001/05/15 276(29):27716–27720. https://doi.org/10.1074/jbc.C100121200
Karaoglu Hanzatian D et al (2018) Brain uptake of multivalent and multi-specific DVD-Ig proteins after systemic administration. MAbs. https://doi.org/10.1080/19420862.2018.1465159
Keith KC et al (2016) Activity of trastuzumab-emtansine (TDM1) in HER2-positive breast cancer brain metastases: A case series. Cancer Treat Commun. https://doi.org/10.1016/j.ctrc.2016.03.005
Kemper EM et al (2004) Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours? Cancer Treat Rev. https://doi.org/10.1016/j.ctrv.2004.04.001
Kim DG, Bynoe MS (2015) A2A Adenosine Receptor Regulates the Human Blood-Brain Barrier Permeability. Mol Neurobiol. 2014/09/30 52(1):664–678. https://doi.org/10.1007/s12035-014-8879-2
Kim DG, Bynoe MS (2016) A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier. J Clin Invest. 2016/04/05 126(5):1717–1733. https://doi.org/10.1172/JCI76207
Kim M et al (2018) Barriers to effective drug treatment for brain metastases: a multifactorial problem in the delivery of precision medicine. Pharm Res. https://doi.org/10.1007/s11095-018-2455-9
Kim M et al (2019a) Brain distribution of a panel of epidermal growth factor receptor inhibitors using cassette dosing in wild-type and ABCB1/ABCG2-deficient mice. Drug Metab Dispos. https://doi.org/10.1124/dmd.118.084210
Kim SS et al (2019b) A tumor-targeting nanomedicine carrying the p53 gene crosses the blood–brain barrier and enhances anti-PD-1 immunotherapy in mouse models of glioblastoma. Int J Cancer. https://doi.org/10.1002/ijc.32531
Kondo S et al (1996) mdm2 gene mediates the expression of mdrl gene and P-glycoprotein in a human glioblastoma cell line. Br J Cancer 74:1263–1268
Korshunov A et al (1999) Prognostic value of immunoexpression of the chemoresistance-related proteins in ependymomas: an analysis of 76 cases. J Neurooncol 45:219–227
Kroll RA et al (1998) Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers. Neurosurgery. United States 43(4):879
Kuang Y et al (2013) T7 peptide-functionalized nanoparticles utilizing RNA interference for glioma dual targeting. Int J Pharm. https://doi.org/10.1016/j.ijpharm.2013.07.019
Kunwar S et al (2010) Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/nop054
Kuppens IELM et al (2007) A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-06-2414
Kurzrock R et al (2012) Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-11-0566
Laack NN, Brown PD (2004) Cognitive sequelae of brain radiation in adults. Semin Oncol. https://doi.org/10.1053/j.seminoncol.2004.07.013
Lambert JM, Chari RVJ (2014) Ado-trastuzumab emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. https://doi.org/10.1021/jm500766w
Laramy JK et al (2017) 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. https://doi.org/10.1124/jpet.117.243477
Lee SY (2016) Temozolomide resistance in glioblastoma multiforme. Genes and Diseases. https://doi.org/10.1016/j.gendis.2016.04.007
Lee J et al (2019) Flexible, sticky, and biodegradable wireless device for drug delivery to brain tumors. Nat Commun. https://doi.org/10.1038/s41467-019-13198-y
Levin AB, Duff TA, Javid MJ (1979) Treatment of increased intracranial pressure: a comparison of different hyperosmotic agents and the use of thiopental. Neurosurgery. https://doi.org/10.1227/00006123-197911000-00005
Li J et al (2017) Quantitative and mechanistic understanding of AZD1775 penetration across human blood-brain barrier in glioblastoma patients using an IVIVE-PBPK modeling approach. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-17-0983
Lim M et al (2019) Innovative therapeutic strategies for effective treatment of brain metastases. Int J Mol Sci. https://doi.org/10.3390/ijms20061280
Lin X, DeAngelis LM (2015) Treatment of brain metastases. J Clin Oncol. https://doi.org/10.1200/JCO.2015.60.9503
Liu HL et al (2014) Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics. https://doi.org/10.7150/thno.8074
Liu Q, Tong X, Wang J (2019) Management of brain metastases: history and the present. Chin Neurosurg J. https://doi.org/10.1186/s41016-018-0149-0
Liu EK et al (2020) Novel therapies for glioblastoma. Curr Neurol Neurosci Rep. https://doi.org/10.1007/s11910-020-01042-6
Lonser RR et al (2015) Convection-enhanced delivery to the central nervous system. J Neurosurg. https://doi.org/10.3171/2014.10.JNS14229
Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature. https://doi.org/10.1038/nature10760
Loryan I, Fridén M, Hammarlund-Udenaes M (2013) The brain slice method for studying drug distribution in the CNS. Fluid Barrier CNS. https://doi.org/10.1186/2045-8118-10-6
Löscher W, Potschka H (2005) Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx: J Am Soc Experiment NeuroTherapeutic 2(1):86–98. https://doi.org/10.1602/neurorx.2.1.86
Lyon JG et al (2017) Engineering challenges for brain tumor immunotherapy. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2017.06.006
Mack F et al (2016) Therapy of leptomeningeal metastasis in solid tumors. Cancer Treat Rev. https://doi.org/10.1016/j.ctrv.2015.12.004
Mahmoudi K et al (2019) 5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas. J Neurooncol. https://doi.org/10.1007/s11060-019-03103-4
Mamelak AN et al (2006) Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol. https://doi.org/10.1200/JCO.2005.05.4569
Mani S et al (2005) Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res 11(17):6359–6369. https://doi.org/10.1158/1078-0432.CCR-05-0252
Mani S, Dou W, Redinbo MR (2013) PXR antagonists and implication in drug metabolism. Drug Metab Rev 45(1):60–72. https://doi.org/10.3109/03602532.2012.746363
Marroni M et al (2003) Relationship between expression of multiple drug resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes. Neuroscience. https://doi.org/10.1016/S0306-4522(03)00515-3
McClelland S et al (2018) Application of tumor treating fields for newly diagnosed glioblastoma: understanding of nationwide practice patterns. J Neurooncol. https://doi.org/10.1007/s11060-018-2945-y
McNeill KA (2016) Epidemiology of brain tumors. Neurol Clin. https://doi.org/10.1016/j.ncl.2016.06.014
Meng Y et al (2018) Low-intensity MR-guided focused ultrasound mediated disruption of the blood-brain barrier for intracranial metastatic diseases. Front Oncol. https://doi.org/10.3389/fonc.2018.00338
Munoz JL et al (2014) Temozolomide induces the production of epidermal growth factor to regulate MDR1 expression in glioblastoma cells. Mol Cancer Ther 13(10):2399–2411. https://doi.org/10.1158/1535-7163.Mct-14-0011
Murthy R et al (2018) Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study. Lancet Oncol. https://doi.org/10.1016/S1470-2045(18)30256-0
Murthy RK et al (2020) Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1914609
Nakanishi T, Ross DD (2012) Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression. Chin J Cancer 31(2):73–99. https://doi.org/10.5732/cjc.011.10320
Nakanishi T, Shiozawa K, Hamburger AW (2006) Bcrp expression is functionally upregulated by epidermal growth factor receptor (EGFR, ERBB1) mediated signaling in human ovarian cancer cell lines, but not in human breast cancer cell lines. AACR Meeti Abstract 146
Nayak L, Lee EQ, Wen PY (2012) Epidemiology of brain metastases. Curr Oncol Rep. https://doi.org/10.1007/s11912-011-0203-y
Neuwelt EA (1980) Reversible osmotic blood-brain barrier disruption in humans: implications for the chemotherapy of malignant brain tumors. Neurosurgery:204. https://doi.org/10.1097/00006123-198008000-00018
Neyns B et al (2009) Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. https://doi.org/10.1093/annonc/mdp032
Niwińska A, Rudnicka H, Murawska M (2015) Breast cancer leptomeningeal metastasis: The results of combined treatment and the comparison of methotrexate and liposomal cytarabine as intra-cerebrospinal fluid chemotherapy. Clin Breast Cancer. https://doi.org/10.1016/j.clbc.2014.07.004
O’Connor MJ (2015) Targeting the DNA damage response in cancer. Mol Cell. https://doi.org/10.1016/j.molcel.2015.10.040
Oberoi RK et al (2016) Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro-Oncology:27–36. https://doi.org/10.1093/neuonc/nov164
Okines A et al (2018) Development and responses of brain metastases during treatment with trastuzumab emtansine (T-DM1) for HER2 positive advanced breast cancer: A single institution experience. Breast J. https://doi.org/10.1111/tbj.12906
Oliveira M et al (2011) Complete response in HER2+ leptomeningeal carcinomatosis from breast cancer with intrathecal trastuzumab. Breast Cancer Res Treat. https://doi.org/10.1007/s10549-011-1417-2
Omidi Y, Barar J (2012) Impacts of blood-brain barrier in drug delivery and targeting of brain tumors. Bioimpacts. https://doi.org/10.5681/bi.2012.002
Ostrom QT et al (2014) The epidemiology of glioma in adults: a state of the science review. Neuro Oncol. https://doi.org/10.1093/neuonc/nou087
Ostrom QT et al (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. https://doi.org/10.1093/neuonc/noz150
Pan-Weisz TM et al (2019) Patient-reported health-related quality of life outcomes in supportive-care interventions for adults with brain tumors: a systematic review. Psychooncology. https://doi.org/10.1002/pon.4906
Pardridge WM (2016) CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. https://doi.org/10.1517/17425247.2016.1171315
Pardridge WM, Eisenberg J, Yang J (1985) Human blood—brain barrier insulin receptor. J Neurochem. https://doi.org/10.1111/j.1471-4159.1985.tb07167.x
Pardridge WM, Eisenberg J, Yang J (1987) Human blood-brain barrier transferrin receptor. Metabolism. https://doi.org/10.1016/0026-0495(87)90099-0
Parrish KE, Sarkaria JN, Elmquist WF (2015) Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clinic Pharmacol Therapeutic:336–346. https://doi.org/10.1002/cpt.71
Pearl LH et al (2015) Therapeutic opportunities within the DNA damage response. Nat Rev Cancer. https://doi.org/10.1038/nrc3891
Perissinotti AJ, Reeves DJ (2010) Role of intrathecal rituximab and trastuzumab in the management of leptomeningeal carcinomatosis. Ann Pharmacother. https://doi.org/10.1345/aph.1P197
Perkins A, Liu G (2016) Primary brain tumors in adults: Diagnosis and treatment. Am Fam Physician
Perria C, Capuzzo T, Cavagnaro G (1980) First attempts at the photodynamic treatment of human gliomas. J Neurosurg Sci
Perus LJM, Walsh LA (2019) Microenvironmental heterogeneity in brain malignancies. Front Immunol. https://doi.org/10.3389/fimmu.2019.02294
Porter KR et al (2010) Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro Oncol. https://doi.org/10.1093/neuonc/nop066
Portnow J et al (2009) The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-09-1349
Puris E et al (2020) L-Type amino acid transporter 1 as a target for drug delivery. Pharm Res. https://doi.org/10.1007/s11095-020-02826-8
Ramalingam SS et al (2020) Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. https://doi.org/10.1056/NEJMoa1913662
Rankovic Z (2015) CNS drug design: balancing physicochemical properties for optimal brain exposure. J Med Chem:2584–2608. https://doi.org/10.1021/jm501535r
Rankovic Z (2017) CNS physicochemical property space shaped by a diverse set of molecules with experimentally determined exposure in the mouse brain. J Med Chem:5943–5954. https://doi.org/10.1021/acs.jmedchem.6b01469
Rapoport SI (2000) Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications. Cell Mol Neurobiol. https://doi.org/10.1023/A:1007049806660
Rapoport SI, Hori M, Klatzo I (1972) Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am J Physiol. https://doi.org/10.1152/ajplegacy.1972.223.2.323
Reungwetwattana T et al (2018) CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer’, Journal of Clinical Oncology. https://doi.org/10.1200/JCO.2018.78.3118
Ricciardi GRR et al (2018) Efficacy of T-DM1 for leptomeningeal and brain metastases in a HER2 positive metastatic breast cancer patient: New directions for systemic therapy - a case report and literature review. BMC Cancer. https://doi.org/10.1186/s12885-018-3994-5
Rick JW et al (2019) Systemic therapy for brain metastases. Crit Rev Oncol Hematol. https://doi.org/10.1016/j.critrevonc.2019.07.012
Riganti C et al (2013) Temozolomide downregulates P-glycoprotein expression in glioblastoma stem cells by interfering with the Wnt3a/glycogen synthase-3 kinase/beta-catenin pathway. Neuro Oncol. 2013/07/31 15(11):1502–1517. https://doi.org/10.1093/neuonc/not104
Sakata S et al (2011) ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells. Oncol Rep 25(2):333–339. https://doi.org/10.3892/or.2010.1102
Salphati L et al (2012) Targeting the PI3K pathway in the brain - efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-12-0720
Sampath J et al (2001) Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 Not MRP1. J Biol Chem. https://doi.org/10.1074/jbc.M103429200
Sandler A et al (2004) 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. https://doi.org/10.1158/1078-0432.CCR-03-0644
Sarkadi B et al (2006) Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev. https://doi.org/10.1152/physrev.00037.2005
Sarkaria JN et al (2018) Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. https://doi.org/10.1093/neuonc/nox175
Shapira-Furman T et al (2019) Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer. J Control Release. https://doi.org/10.1016/j.jconrel.2018.12.048
Sharma J, Lv H, Gallo JM (2012) Analytical approach to characterize the intratumoral pharmacokinetics and pharmacodynamics of gefitinib in a glioblastoma model. J Pharm Sci. https://doi.org/10.1002/jps.23283
Sharma J, Lv H, Gallo JM (2013) Intratumoral modeling of gefitinib pharmacokinetics and pharmacodynamics in an orthotopic mouse model of glioblastoma. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-13-0690
Shaw AT et al (2017) Alectinib versus crizotinib in treatment-naive advanced ALK -positive non-small cell lung cancer (NSCLC): primary results of the global phase III ALEX study. J Clin Oncol. https://doi.org/10.1200/jco.2017.35.18_suppl.lba9008
Shawahna R et al (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. https://doi.org/10.1021/mp200129p
Shen F et al (2008) Quantitation of doxorubicin uptake, efflux, and modulation of multidrug resistance (MDR) in MDR human cancer cells. J Pharmacol Experiment Therapeutic. https://doi.org/10.1124/jpet.107.127704
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin. https://doi.org/10.3322/caac.21551
Soria JC et al (2018) Osimertinib in untreated EGFR-Mutated advanced non-small-cell lung cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1713137
Sperduto PW et al (2012) 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. https://doi.org/10.1200/JCO.2011.38.0527
Spiegl-Kreinecker S et al (2002) Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. J Neurooncol 57:27–36
St-Amour I et al (2013) Brain bioavailability of human intravenous immunoglobulin and its transport through the murine blood-brain barrier. J Cereb Blood Flow Metab. https://doi.org/10.1038/jcbfm.2013.160
Stupp R (2019) Changing paradigms in the treatment of brain metastases. J Oncol Pract. https://doi.org/10.1200/JOP.19.00602
Stupp R et al (2008) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma – a critical review. Clinic Med Oncol. https://doi.org/10.1056/NEJMoa043330
Sugawara M et al (2010) Expressions of cytochrome P450, UDP-glucuronosyltranferase, and transporter genes in monolayer carcinoma cells change in subcutaneous tumors grown as xenografts in immunodeficient nude mice. Drug Metab Dispos 38(3):526–533. https://doi.org/10.1124/dmd.109.030668
Sun M, Chen Y, Hu B (2018) The inhibition of DNA damage response contributes to cancer radiotherapy. 5(1):149–156. https://doi.org/10.17554/j.issn.2313-3406.2018.05.47
Sutherlin DP et al (2010) Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available Pan-PI3-kinase and dual Pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. J Med Chem 53(3):1086–1097. https://doi.org/10.1021/jm901284w
Takada T et al (2005) Regulation of the cell surface expression of human BCRP/ABCG2 by the phosphorylation state of Akt in polarized cells. Drug Metab Dispos. 2005/04/22 33(7):905–909. https://doi.org/10.1124/dmd.104.003228
Tanaka Y et al (1994) Ultrastructural localization of P-glycoprotein on capillary endothelial cells in human gliomas. Virchows Arch 425:133–138
Tews DS et al (2000) Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors. J Neurooncol 50:227–237
Timbie KF, Mead BP, Price RJ (2015) Drug and gene delivery across the blood-brain barrier with focused ultrasound. J Control Release. https://doi.org/10.1016/j.jconrel.2015.08.059
Toms SA et al (2019) Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol. https://doi.org/10.1007/s11060-018-03057-z
Toth K et al (1996) MDR1 P-Glycoprotein Is Expressed by Endothelial Cells of Newly Formed Capillaries in Human Gliomas but Is Not Expressed in the Neovasculature of Other Primary Tumors. Am J Pathol 149:853–858
Tran PN, Klempner SJ (2017) ALK on my mind: Alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements. Ann Trans Med. https://doi.org/10.21037/atm.2017.03.47
Trédan O et al (2007) Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djm135
Uchida Y et al (2011) Blood-Brain Barrier (BBB) pharmacoproteomics: Reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain. J Pharmacol Experiment Therapeutic. https://doi.org/10.1124/jpet.111.184200
Uchida Y et al (2015) Major involvement of Na + -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells. J Neurochem. https://doi.org/10.1111/jnc.13092
Ueno M et al (2010) The expression of LDL receptor in vessels with blood-brain barrier impairment in a stroke-prone hypertensive model. Histochem Cell Biol. https://doi.org/10.1007/s00418-010-0705-y
Valera ET et al (2007) Quantitative PCR analysis of the expression profile of genes related to multiple drug resistance in tumors of the central nervous system. J Neurooncol. 2007/04/13 85(1):1–10. https://doi.org/10.1007/s11060-007-9382-7
Van Den Bent MJ et al (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. https://doi.org/10.1200/JCO.2008.17.5984
Van Den Bent M et al (2020) INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/noz222
Veringa SJ et al (2013) In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma. PLoS One. 2013/05/03 8(4):e61512. https://doi.org/10.1371/journal.pone.0061512
Vogelbaum MA, Aghi MK (2015) Convection-enhanced delivery for the treatment of glioblastoma. Neuro Oncol. https://doi.org/10.1093/neuonc/nou354
Vu CU et al (2014) Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice. Endocrinology. https://doi.org/10.1210/en.2014-1320
Wager TT et al (2010) Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem Nerosci 1(6):435–449. https://doi.org/10.1021/cn100008c
Wager TT et al (2016) Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem Nerosci. https://doi.org/10.1021/acschemneuro.6b00029
Wang S et al (2008) Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-07-2070
Weaver M, Laske DW (2003) Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) therapy of malignant gliomas. J Neurooncol. https://doi.org/10.1023/A:1026246500788
Wei X et al (2014) Brain tumor-targeted drug delivery strategies. Acta Pharm Sin B. https://doi.org/10.1016/j.apsb.2014.03.001
Weller M et al (2015) Glioma. Nat Rev Dis Primers. https://doi.org/10.1038/nrdp.2015.17
Wen PY et al (2020) First-in-human phase i study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-2808
Wolinsky JB, Colson YL, Grinstaff MW (2012) Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J Control Release. https://doi.org/10.1016/j.jconrel.2011.11.031
Wu Y et al (2019) MicroRNA-302c enhances the chemosensitivity of human glioma cells to temozolomide by suppressing P-gp expression. Biosci Rep. 2019/08/15 39(9). https://doi.org/10.1042/BSR20190421
Xu S et al (2013) Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2012.09.041
Yan A et al (2019) CD73 promotes glioblastoma pathogenesis and enhances its chemoresistance via A(2B) adenosine receptor signaling. J Neurosci 39(22):4387–4402. https://doi.org/10.1523/jneurosci.1118-18.2019
Yasuda M et al (2019) The Involvement of Pregnane X Receptor-regulated Pathways in the Antitumor Activity of Cisplatin. Anticancer Res 39(7):3601–3608. https://doi.org/10.21873/anticanres.13507
Zeng Q et al (2015) 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 58(20):8200–8215. https://doi.org/10.1021/acs.jmedchem.5b01073
Zhang Y, Pardridge WM (2001) Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol. https://doi.org/10.1016/S0165-5728(01)00242-9
Zhang W et al (2003) Expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J. https://doi.org/10.1096/fj.02-1131fje
Zhou J et al (2006) Reversal of P-glycoprotein-mediated multidrug resistance in cancer cells by the c-Jun NH2-terminal kinase. Cancer Res 66(1):445–452. https://doi.org/10.1158/0008-5472.CAN-05-1779
Zhou Z, Singh R, Souweidane M (2016) Convection-enhanced delivery for diffuse intrinsic pontine glioma treatment. Curr Neuropharmacol. https://doi.org/10.2174/1570159x14666160614093615
Zong T et al (2014) Enhanced glioma targeting and penetration by dual-targeting liposome co-modified with T7 and TAT. J Pharm Sci. https://doi.org/10.1002/jps.24186
Acknowledgments
This work was supported by the National Institutes of Health [Grants RO1 NS107548, U54 CA210180, U01 CA227954]. The authors would also like to thank the editors of the book for their comments and valuable inputs.
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Talele, S. et al. (2022). Drug Delivery to Primary and Metastatic Brain Tumors: Challenges and Opportunities. In: de Lange, E.C., Hammarlund-Udenaes, M., Thorne, R.G. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-030-88773-5_24
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