Dissertation
Redox-based, quantitative MRI as a method of evaluating and enhancing glioblastoma treatment responses
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2022
DOI: 10.25820/etd.006765
Abstract
Glioblastoma is the most common primary central nervous system malignancy with an incidence rate of approximately 14,000 new diagnoses per year in the United States. Currently, the standard of care treatment of glioblastoma is maximal safe surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide. Despite this aggressive treatment protocol, treatment outcomes remain poor with historical median progression-free survival of approximately 6 months and overall survival of 14.6 months. Thus, a dire need exists for new therapeutic approaches to improve patient responses. A new treatment strategy has emerged with clinical promise is pharmacological ascorbate (high dose vitamin C delivered intravenously reaching plasma concentrations ≥ 20 mM) as a phase 1 clinical trial evaluated 11 subjects showed a median overall survival of 18 months.
Mechanistically, pharmacological ascorbate is an iron-dependent therapy that chemically reduces intracellular iron, releasing it from iron containing enzymes, to generate freely chelatable iron (i.e., labile iron). This redox active iron can catalyze the formation of damaging reactive oxygen species through reactions with O2 and H2O2. Despite its damaging potential, iron is a critical, elemental nutrient that is utilized in a wide variety of cellular processes (e.g., DNA replication and protein translation) to promote cellular proliferation. Based on this relationship, it has been observed that cancer cells frequently contain significantly higher levels of iron than their normal tissue counterparts and thus, may represent a critical vulnerability in cancer cells that can be exploited by pharmacological ascorbate. Therefore, it can be hypothesized that non-invasively visualizing manipulations of intratumoral iron content can provide a novel approach to evaluate pharmacological ascorbate sensitivity and therapeutic responses.
To evaluate tumor iron content and its relationship to pharmacological ascorbate sensitivity a quantitative MRI approach, T2* mapping, has been utlized. T2* mapping is a technique that monitors alterations of proton relaxation in the transverse plane (i.e., xy-plane; T2 relaxation) resulting from magnetic field inhomogeneities. These magnetic field inhomogeneities result from intrinsic variations of the applied external magnetic field from the MRI scanner or the deposition of paramagnetic materials (e.g., iron) within the region of interest. To this extent, T2* mapping has been applied clinically to assess iron overload of the heart and liver. Moreover, it has been suggested that T2* mapping can detect changes in iron oxidation state (Fe3+↔ Fe2+) in glioblastoma subjects treated with pharmacological ascorbate. However, this fundamental mechanism has been poorly characterized from a physical perspective and its ability to evaluate sensitivity to pharmacological ascorbate remains unclear.
In this dissertation, the physical mechanism of T2* oxidation state specificity is tested along with its utility as a clinical biomarker in glioblastoma subjects receiving pharmacological ascorbate with standard chemoradiation. Using a variety of model systems including basic physiochemical, in vitro, and in vivo systems, it can be seen that T2* mapping exhibits iron oxidation state specificity and is a useful biomarker for the evaluation of pharmacological ascorbate treatment responses. In physiochemical models, T2* mapping can detect transition metals with varying numbers of unpaired electrons, suggesting that T2* relaxation can be vii influenced by electron-proton dipole-dipole interactions which gives rise to its associated oxidation state specificity. In glioblastoma cells and in orthotopic glioblastoma tumors, T2* mapping can detect the reduction of iron by pharmacological ascorbate, further suggesting the biological relevance of this technique. However, this effect is tumor-specific and appears to be linked to the endogenous iron content. Importantly, glioblastoma subjects with low T2* relaxation times (indicative of high iron content) show increased survival outcomes (progression free survival and overall survival) when receiving pharmacological ascorbate in combination with standard chemoradiation. Based on this observation, it can be hypothesized that providing an iron reserve would enhance pharmacological ascorbate therapy. Furthermore, magnetite (Fe3O4) nanoparticles have unique physiochemical properties that are favorable for use as an iron supplement to overcoming pharmacological ascorbate resistance in glioblastoma. Overall, this dissertation provides considerable evidence that T2* mapping is a highly informative, noninvasive biomarker in glioblastoma that can be leveraged to personalize therapy.
Details
- Title: Subtitle
- Redox-based, quantitative MRI as a method of evaluating and enhancing glioblastoma treatment responses
- Creators
- Michael Stephen Petronek
- Contributors
- Bryan G. Allen (Advisor)Douglas R. Spitz (Committee Member)Vincent A. Magnotta (Committee Member)Joel J. St-Aubin (Committee Member)Garry R. Buettner (Committee Member)Karra A. Jones (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Free Radical and Radiation Biology
- Date degree season
- Autumn 2022
- DOI
- 10.25820/etd.006765
- Publisher
- University of Iowa
- Number of pages
- xiv, 101 pages
- Copyright
- Copyright 2022 Michael Stephen Petronek
- Language
- English
- Description illustrations
- Illustrations, charts, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 86-101).
- Public Abstract (ETD)
Brain cancer is one of the deadliest forms of primary cancers with very poor overall survival (14.6 months). High dose vitamin C (pharmacological ascorbate) has recently been shown to have the potential to enhance brain cancer therapy. Brain tumors frequently contain significantly higher levels of iron to facilitate rapid cell growth and pharmacological ascorbate can kill these tumor cells by chemically disrupting these mechanisms. T2*-based MRI is readily used to detect iron in tissues, but its ability to detect chemical disruptions like those accomplished by pharmacological ascorbate remain unclear. In this dissertation, the physical mechanisms driving T2*-based MRI are shown to allow for the detection of pharmacological ascorbate-iron chemistry. These results appear to be clinically relevant as patients with low MRI signals (indicative of high levels of tumor iron) have been observed to have increased treatment responses when receiving pharmacological ascorbate therapy. Consistent with these observations, iron-oxide nanoparticles can enhance pharmacological ascorbate therapy in tumors that are resistant to treatment.
- Academic Unit
- Free Radical and Radiation Biology Program
- Record Identifier
- 9984362458102771
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