Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Sarkaria, Jann N.; Hu, Leland; Parney, Ian F.; Pafundi, Deanna H.; Brinkmann, Debra H.; Laack, Nadia N.; Giannini, Caterina; Burns, Terence; Kizilbash, Sani H.; Laramy, Janice K.; Swanson, Kristin R.; Kaufmann, Timothy J.; Brown, Paul D.; Agar, Nathalie Y.R.; Galanis, Evanthia; Buckner, Jan C.; Elmquist, William F.

doi:10.1093/neuonc/nox175

Cited by 502 publications

(401 citation statements)

References 92 publications

Supporting

Mentioning

394

Contrasting

Unclassified

Order By: Relevance

“…They could hence be used to test the efficiency of new drugs, combined treatments or sensitising agents (e.g., radiotherapy, chemotherapy, inhibitors). For this purpose, these models could be transplanted orthotopically, to account for the blood-brain barrier, which despite being disrupted in gliomas, might limit efficiency of therapeutic molecules (reviewed in [44,45]). For radiotherapy experiments, it would be interesting to evaluate their response to ionising radiation by performing tumour control dose 50 experiments [46,47].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Meneceur

Linge

Meinhardt

et al. 2020

Cancers

View full text Add to dashboard Cite

Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the MGMT promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2 + cells (r = 0.49, p = 0.016) and nestin + cells (r = 0.55, p = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.

show abstract

Section: Discussionmentioning

confidence: 99%

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Meneceur

Linge

Meinhardt

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…One important factor to consider in examining reasons for the limited efficacy of these drugs in the CNS is that the delivery of many early EGFR inhibitors has shown to be insufficient to elicit a response at the target site in the CNS. Moreover, many of the early-generation inhibitors are substrates of the major efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), that may lead to limited brain penetration at the blood-brain barrier (BBB), especially in intratumoral regions that have an intact BBB in metastases (Lockman et al, 2010) and primary tumor (Sarkaria et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Kim¹,

Laramy²,

Mohammad³

et al. 2019

Drug Metab Dispos

View full text Add to dashboard Cite

Tyrosine kinase inhibitors that target the epidermal growth factor receptor (EGFR) have had success in treating EGFR-positive tumors, including non-small-cell lung cancer (NSCLC). However, developing EGFR inhibitors that can be delivered to the brain remains a challenge. To identify optimal compounds for brain delivery, eight EGFR inhibitors [afatinib, 6-[4-[(4-ethylpiperazin-and vandetanib] were evaluated for distributional kinetics using cassette dosing with the ultimate goal of understanding the brain penetrability of compounds that share the same molecular target in an important oncogenic signaling pathway for both primary brain tumors (glioblastoma) and brain metastases (e.g., NSCLC). Cassette dosing was validated by comparing the brain-to-plasma ratios obtained from cassette-dosing to discrete-dosing studies. The brain-to-blood partition coefficients (K p,brain ) were calculated following cassette dosing of the eight EGFR inhibitors. The comparison of K p,brain in wild-type and transporter-deficient mice confirmed that two major efflux transporters at the blood-brain barrier (BBB), P-glycoprotein and breast cancer resistance protein, play a crucial role in the brain distribution of seven out of eight EGFR inhibitors. Results show that the prediction of brain distribution based on physicochemical properties of a drug can be misleading, especially for compounds subject to extensive efflux transport. Moreover, this study informs the choice of EGFR inhibitors, i.e., determining BBB permeability combined with a known target potency, that may be effective in future clinical trials for brain tumors.

show abstract

“…The integrity of the BBB in glioblastoma is disrupted to different degrees, ranging from completely compromised in bulky tumor areas and slightly “leaky” in invasive peripheral regions to complete intact in infiltrative tumor regions . In spite of enhanced drug penetration into bulky tumor areas, insufficient penetration of potentially effective therapeutic agents into invasive, infiltrative tumor regions with an intact BBB represents a significant barrier to long‐term, efficacious treatments …”

mentioning

confidence: 99%

Protein Expression and Functional Relevance of Efflux and Uptake Drug Transporters at the Blood–Brain Barrier of Human Brain and Glioblastoma

Bao

Xie

et al. 2019

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The knowledge of transporter protein expression and function at the human blood–brain barrier (BBB) is critical to prediction of drug BBB penetration and design of strategies for improving drug delivery to the brain or brain tumor. This study determined absolute transporter protein abundances in isolated microvessels of human normal brain (N = 30), glioblastoma (N = 47), rat (N = 10) and mouse brain (N = 10), and cell membranes of MDCKII cell lines, using targeted proteomics. In glioblastoma microvessels, efflux transporters (ABCB1 and ABCG2), monocarboxylate transporter 1 (MCT1), glucose transporter 1 (GLUT1), sodium–potassium pump (Na/K ATPase), and Claudin‐5 protein levels were significantly reduced, while large neutral amino acid transporter 1 (LAT1) was increased and GLU3 remained the same, as compared with human normal brain microvessels. ABCC4, OATP1A2, OATP2B1, and OAT3 were undetectable in microvessels of both human brain and glioblastoma. Species difference in BBB transporter abundances was noted. Cellular permeability experiments and modeling simulations suggested that not a single apical uptake transporter but a vectorial transport system consisting of an apical uptake transporter and basolateral efflux mechanism was required for efficient delivery of poor transmembrane permeability drugs from the blood to brain.

show abstract

Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

Cited by 502 publications

References 92 publications

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma

Brain Distribution of a Panel of Epidermal Growth Factor Receptor Inhibitors Using Cassette Dosing in Wild-Type and Abcb1/Abcg2-Deficient Mice

Protein Expression and Functional Relevance of Efflux and Uptake Drug Transporters at the Blood–Brain Barrier of Human Brain and Glioblastoma

Contact Info

Product

Resources

About