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Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial

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Abstract

Background

Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH−) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH− was combined with temozolomide and radiotherapy. As P-AscH− relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH− therapy in glioblastoma participants.

Methods

Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory.

Results

Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival.

Conclusions

This study analyzes iron-related biomarkers in the context of P-AscH− therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

Highlights

  • Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes.

  • Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response.

  • Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival.

  • Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

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Data availability

No datasets were generated or analysed during the current study.

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Funding

This work was supported by the Gateway for Cancer Research grant G-17-1500 and NIH grants P01 CA217797 and R21 CA270742. Core facilities were supported in part by the Carver College of Medicine and the Holden Comprehensive Cancer Center, NIH P30 CA086862.

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Authors and Affiliations

  1. Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA, USA

    M. S. Petronek, K. L. Bodeker, N. Teferi, J. M. Buatti & B. G. Allen

  2. Department of Radiology, University of Iowa, Iowa City, IA, USA

    C. Y. Lee & V. A. Magnotta

  3. Department of Pathology, University of Iowa, Iowa City, IA, USA

    K. L. Eschbacher

  4. Department of Pathology, Division of Neuropathology, Duke University, Durham, NC, USA

    K. A. Jones

  5. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

    B. T. Loeffler

  6. Department of Biostatistics, University of Iowa, Iowa City, IA, USA

    B. J. Smith

Authors
  1. M. S. Petronek
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  2. K. L. Bodeker
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  3. C. Y. Lee
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  4. N. Teferi
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  5. K. L. Eschbacher
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  6. K. A. Jones
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  7. B. T. Loeffler
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  8. B. J. Smith
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  9. J. M. Buatti
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  10. V. A. Magnotta
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  11. B. G. Allen
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Contributions

Conception and design: MSP, KLB, KAJ, JMB, VAM, BGA. Data collection and analysis: MSP, KLB, BGA, CYL, NT, KLE, BTL, BJS. Data curation and preparation: MSP, CYL, KLE, BTL. All authors edited and approved the final version of this manuscript prior to submission.

Corresponding author

Correspondence to M. S. Petronek.

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The authors declare no competing interests.

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Petronek, M.S., Bodeker, K.L., Lee, C.Y. et al. Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial. J Neurooncol 166, 493–501 (2024). https://doi.org/10.1007/s11060-024-04571-z

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  • DOI: https://doi.org/10.1007/s11060-024-04571-z

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