ArticleMolecular cancer therapeutics2012
Active efflux of Dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly targeted agents.
Article in Molecular cancer therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 92 citations in OpenAlex.
- Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627).Neuro-oncology · 2015Trial
- Current review on inducible nitric oxide synthase and Src tyrosine kinase inhibitors as disease-modifiers in preclinical models of epilepsy.Histology and histopathology · 2026Review
- The Emerging Role of Senolytics as a Next-Generation Strategy Against Glioma Recurrence: A Narrative Review.Cancers · 2026Review
- Extracellular matrix stiffness conditions glioblastoma cells for long-term migration: Mechanical memory as a driver of invasion and recurrence in glioblastoma.Neuro-oncology · 2026Review
- Revisiting an old therapy for new, promising combinations: Biology and perspectives of lomustine in glioma treatment.Neuro-oncology · 2025Review
- Beyond the Walls of Troy: A Scoping Review on Pharmacological Strategies to Enhance Drug Delivery Across the Blood-Brain Barrier and Blood-Tumor Barrier.International journal of molecular sciences · 2025Article
- Polypept(o)ide-Based Core-Shell Bottlebrush Polymers: A Versatile Platform for Drug Encapsulation.Macromolecular bioscience · 2025Article
- Olaparib: A Chemosensitizer for the Treatment of Glioblastoma.Mini reviews in medicinal chemistry · 2025Review
- The Glioblastoma Landscape: Hallmarks of Disease, Therapeutic Resistance, and Treatment Opportunities.Medical research archives · 2023Article
- Clinical Trials in the Brain Tumour Population: Challenges and Strategies for the Future.Current oncology reports · 2023Review
- Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours.Nature reviews. Clinical oncology · 2023Review
- Case report: Stem cell-based suicide gene therapy mediated by the herpes simplex virus thymidine kinase gene reduces tumor progression in multifocal glioblastoma.Frontiers in neurology · 2023Article
- Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood-Brain Tumour Barrier.Pharmaceutics · 2022Review
- Anti-Survival Effect of SI306 and Its Derivatives on Human Glioblastoma Cells.Pharmaceutics · 2022Article
- Promising Chemotherapy for Malignant Pediatric Brain Tumor in Recent Biological Insights.Molecules (Basel, Switzerland) · 2022Review
- Review
- A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.Neuro-oncology · 2022Article
- Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development.Frontiers in pharmacology · 2022Review
- Identification of imidazo[4,5-c]pyridin-2-one derivatives as novel Src family kinase inhibitors against glioblastoma.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Optical tissue clearing and machine learning can precisely characterize extravasation and blood vessel architecture in brain tumors.Communications biology · 2021Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
The importance of the blood-brain barrier in preventing effective pharmacotherapy of glioblastoma has been controversial. The controversy stems from the fact that vascular endothelial cell tight junctions are disrupted in the tumor, allowing some systemic drug delivery. P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) efflux drugs from brain capillary endothelial cells into the blood. We tested the hypothesis that although the tight junctions are "leaky" in the core of glioblastomas, active efflux limits drug delivery to tumor-infiltrated normal brain and consequently, treatment efficacy. Malignant gliomas were induced by oncogene transfer into wild-type (WT) mice or mice deficient for Pgp and BCRP (knockout, KO). Glioma-bearing mice were orally dosed with dasatinib, a kinase inhibitor and dual BCRP/PgP substrate that is being currently tested in clinical trials. KO mice treated with dasatinib survived for twice as long as WT mice. Microdissection of the tumor core, invasive rim, and normal brain revealed 2- to 3-fold enhancement in dasatinib brain concentrations in KO mice relative to WT. Analysis of signaling showed that poor drug delivery correlated with the lack of inhibition of a dasatinib target, especially in normal brain. A majority of human glioma xenograft lines tested expressed BCRP or PgP and were sensitized to dasatinib by a dual BCRP/Pgp inhibitor, illustrating a second barrier to drug delivery intrinsic to the tumor itself. These data show that active efflux is a relevant obstacle to treating glioblastoma and provide a plausible mechanistic basis for the clinical failure of numerous drugs that are BCRP/Pgp substrates.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.