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Updated: Mar 7, 2026
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
Window of opportunity study measuring defactinib and avutometinib delivery in glioblastomas
Miguel Mayol Del Valle1, Emely Morales Colon2, Kavitha Kettimuthu3
1Department of Neurosurgery, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, USA.
Purpose:
Glioblastoma (GBM) is the most common malignant brain tumor in adults, and durable control or cure with current standard or investigational therapies is rare. Therefore, novel approaches are needed. This exploratory study evaluated whether defactinib and avutometinib, inhibitors of FAK/Pyk2 and RAF/MEK signaling respectively, penetrate GBM and produce measurable effects on their molecular targets.
Methods:
Defactinib or avutometinib was administered to six subjects each, in two escalating dose levels: avutometinib at 3.2 mg and 4 mg, and defactinib at 200 mg and 400 mg (three patients per dose level). Administration occurred immediately prior to craniotomy for tumor resection. Tumor tissue, peritumoral brain tissue, and blood were collected during surgery. Drug concentrations were measured by liquid chromatography-mass spectrometry, and effects on the intended molecular targets were assessed by western blot analysis.
Results:
Even after a single preoperative dose, both defactinib and, to a lesser extent, avutometinib were detectable in tumor tissue 3-4 h after administration. Peritumoral brain tissue contained lower concentrations of each agent. Exploratory pharmacodynamic analyses suggested target engagement: avutometinib (3.2 mg) reduced Erk1/2 phosphorylation approximately 28-fold, while defactinib (400 mg) reduced Pyk2 phosphorylation by 5.7-fold within tumor tissue. Effects in peritumoral tissue were minimal.
Conclusion:
These exploratory findings demonstrate that defactinib and avutometinib can penetrate GBM tissue and produce measurable modulation of their intended molecular targets after a single dose, with limited impact on surrounding brain. While the small sample size and inherent tissue heterogeneity limit definitive conclusions, this study supports the feasibility of presurgical pharmacokinetic and pharmacodynamic evaluation in GBM and provides a rationale for further clinical studies to optimize dosing, target inhibition, and therapeutic efficacy.
Trial Registration Number:
ClinicalTrials.gov NCT05798507. Date of Registration March 3, 2023.
Insights
Defactinib and avutometinib penetrate glioblastoma tissue, modulating molecular targets like FAK/Pyk2 and RAF/MEK signaling. This study supports further clinical trials for glioblastoma treatment optimization.
Area of Science:
- Neuro-oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma (GBM) is a common adult brain malignancy with limited treatment options.
- Novel therapeutic strategies are essential for improving patient outcomes.
- This study investigates targeted therapies for GBM.
Purpose of the Study:
- To evaluate the penetration of defactinib and avutometinib into GBM tissue.
- To assess the molecular effects of these drugs on their targets within the tumor.
- To determine the feasibility of presurgical pharmacokinetic and pharmacodynamic evaluation in GBM patients.
Main Methods:
- Defactinib and avutometinib were administered to GBM patients prior to surgery.
- Drug concentrations were measured in tumor, peritumoral brain, and blood.
- Western blot analysis assessed target engagement (e.g., phosphorylation levels).
Main Results:
- Both drugs were detectable in GBM tissue 3-4 hours post-administration.
- Avutometinib reduced Erk1/2 phosphorylation; defactinib reduced Pyk2 phosphorylation.
- Drug effects were primarily observed within tumor tissue, with minimal impact on surrounding brain.
Conclusions:
- Defactinib and avutometinib can penetrate GBM and modulate their molecular targets.
- The findings support presurgical drug evaluation in GBM.
- Further clinical studies are warranted to optimize dosing and therapeutic efficacy.
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