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Purpose <p>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.</p> Methods <p>Defactinib or avutometinib was administered to six subjects each, in two escalating dose levels: avutometinib at 3.2&#xa0;mg and 4&#xa0;mg, and defactinib at 200&#xa0;mg and 400&#xa0;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.</p> Results <p>Even after a single preoperative dose, both defactinib and, to a lesser extent, avutometinib were detectable in tumor tissue 3–4&#xa0;h after administration. Peritumoral brain tissue contained lower concentrations of each agent. Exploratory pharmacodynamic analyses suggested target engagement: avutometinib (3.2&#xa0;mg) reduced Erk1/2 phosphorylation approximately 28-fold, while defactinib (400&#xa0;mg) reduced Pyk2 phosphorylation by 5.7-fold within tumor tissue. Effects in peritumoral tissue were minimal.</p> Conclusion <p>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.</p> Trial Registration Number <p>ClinicalTrials.gov NCT05798507. Date of Registration March 3, 2023.</p>

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Window of opportunity study measuring defactinib and avutometinib delivery in glioblastomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Miguel Mayol Del Valle,
  • Emely Morales Colon,
  • Kavitha Kettimuthu,
  • Kristal Maner-Smith,
  • Jeffrey J. Olson,
  • Lilia Y. Kucheryavykh

摘要

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.