Abstract
Glioblastoma multiforme is a malignant brain tumor with poor prognosis and high morbidity due to its invasiveness. Hypoxia-driven motility and concentration-driven motility are two mechanisms of glioblastoma multiforme invasion in the brain. The use of anti-angiogenic drugs has uncovered new progression patterns of glioblastoma multiforme associated with significant differences in overall survival. Here, we apply a mathematical model of glioblastoma multiforme growth and invasion in humans and design computational trials using agents that target angiogenesis, tumor replication rates, or motility. The findings link highly-dispersive, moderately-dispersive, and hypoxia-driven tumors to the patterns observed in glioblastoma multiforme treated by anti-angiogenesis, consisting of progression by Expanding FLAIR, Expanding FLAIR + Necrosis, and Expanding Necrosis, respectively. Furthermore, replication rate-reducing strategies (e.g. Tumor Treating Fields) appear to be effective in highly-dispersive and moderately-dispersive tumors but not in hypoxia-driven tumors. The latter may respond to motility-reducing agents. In a population computational trial, with all three phenotypes, a correlation was observed between the efficacy of the rate-reducing agent and the prolongation of overall survival times. This research highlights the potential applications of computational trials and supports new hypotheses on glioblastoma multiforme phenotypes and treatment options.
Highlights
Glioblastoma multiforme is associated with a poor prognosis
To validate the pattern of glioblastoma multiforme progression suggested by these simulations, we reviewed the magnetic resonance imaging of 69 patients diagnosed with glioblastoma multiforme and one patient with gliosarcoma, were treated with bevacizumab at first recurrence. 23/70 patients met the criterion of at least one stable magnetic resonance imaging following the maximal effects of bevacizumab
The findings reveal that variations in the motility phenotypes/mechanisms determine tumor response to anti-angiogenesis therapy
Summary
Glioblastoma multiforme is associated with a poor prognosis. Clinical trials of bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, showed no significant. Summary of the tumor motility phenotypes, the associated nomenclature in the literature and in this paper for the progression patterns of glioblastoma multiforme under anti-angiogenesis treatment, and the types of motility (hypoxia-driven, HypD, versus concentration-driven, CoD) that produce these phenotypes. Invasive cells are dispersed throughout healthy brain tissue in the concentration-driven motility model (see double-sided blue arrow labeled FLAIR) whereas they accumulate sharply at the edge of hypoxia and healthy brain tissue in the hypoxia-driven motility model (see double-sided red arrow labeled FLAIR) These different motility types largely affect the behavior of the tumor in our simulations and may offer explanations for the different progression patterns described in the sections above. Does the mathematical model replicate the three progression patterns, but the titrations of hypoxia-driven and concentration-driven motility reveal novel insights into the behavior of glioblastoma multiforme treated by anti-angiogenesis therapy. Tumors with moderate and high concentration-driven motility may respond to rate-reducing agents like Tumor Treating Fields, while patients with hypoxia-driven glioblastoma multiforme may benefit from motility-reducing agents
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