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A Repurposed Drug Selection Pipeline to Identify CNS-Penetrant Drug Candidates for Glioblastoma
Ioannis Ntafoulis1, Stijn L W Koolen2,3, Olaf van Tellingen4
1Department of Neurosurgery, Brain Tumor Center, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Background:
Glioblastoma is an aggressive and incurable type of brain cancer. Little progress has been made in the development of effective new therapies in the past decades. The blood-brain barrier (BBB) and drug efflux pumps, which together hamper drug delivery to these tumors, play a pivotal role in the gap between promising preclinical findings and failure in clinical trials. Therefore, selecting drugs that can reach the tumor region in pharmacologically effective concentrations is of major importance.
Methods:
In the current study, we utilized a drug selection platform to identify candidate drugs by combining in vitro oncological drug screening data and pharmacokinetic (PK) profiles for central nervous system (CNS) penetration using the multiparameter optimization (MPO) score. Furthermore, we developed intracranial patient-derived xenograft (PDX) models that recapitulated the in situ characteristics of glioblastoma and characterized them in terms of vascular integrity, BBB permeability and expression of ATP-binding cassette (ABC) transporters. Omacetaxine mepesuccinate (OMA) was selected as a proof-of-concept drug candidate to validate our drug selection pipeline.
Results:
We assessed OMA's PK profile in three different orthotopic mouse PDX models and found that OMA reaches the brain tumor tissue at concentrations ranging from 2- to 11-fold higher than in vitro IC50 values on patient-derived glioblastoma cell cultures.
Conclusions:
This study demonstrates that OMA, a drug selected for its in vitro anti-glioma activity and CNS- MPO score, achieves brain tumor tissue concentrations exceeding its in vitro IC50 values in patient-derived glioblastoma cell cultures, as shown in three orthotopic mouse PDX models. We emphasize the importance of such approaches at the preclinical level, highlighting both their significance and limitations in identifying compounds with potential clinical implementation in glioblastoma.
Insights
Omacetaxine mepesuccinate (OMA) effectively targets glioblastoma by crossing the blood-brain barrier. This drug candidate achieves therapeutic concentrations in brain tumors, offering new hope for treating this aggressive cancer.
Area of Science:
- Neuro-oncology
- Pharmacology
- Drug Discovery
Background:
- Glioblastoma is an aggressive brain cancer with limited treatment options.
- The blood-brain barrier (BBB) and drug efflux pumps impede effective drug delivery to brain tumors.
- Bridging the gap between preclinical success and clinical failure requires drugs that reach tumors at effective concentrations.
Purpose of the Study:
- To develop and validate a drug selection platform for identifying glioblastoma therapies with CNS penetration.
- To assess the efficacy of omacetaxine mepesuccinate (OMA) as a potential glioblastoma drug candidate.
Main Methods:
- Utilized a drug selection platform combining in vitro screening and pharmacokinetic (PK) data with a multiparameter optimization (MPO) score for CNS penetration.
- Developed and characterized intracranial patient-derived xenograft (PDX) models of glioblastoma, assessing vascular integrity, BBB permeability, and ABC transporter expression.
- Selected OMA as a proof-of-concept drug to validate the drug selection pipeline.
Main Results:
- OMA demonstrated a favorable PK profile in three orthotopic mouse PDX models.
- OMA achieved brain tumor tissue concentrations 2- to 11-fold higher than in vitro IC50 values in patient-derived glioblastoma cell cultures.
Conclusions:
- OMA, selected for its anti-glioma activity and CNS MPO score, achieves concentrations exceeding its IC50 in patient-derived glioblastoma models.
- This study highlights the importance of preclinical drug selection strategies for identifying potential glioblastoma treatments.
- The findings underscore the significance and limitations of such approaches for clinical implementation.
