Defining and Altering the Natural Trajectories of Glioma: Seizures and Brainstem Infiltration

Drumm, Michael Raymond

doi:https://doi.org/10.21985/n2-23kn-nb93

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Defining and Altering the Natural Trajectories of Glioma: Seizures and Brainstem Infiltration

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Multiple facets of the natural trajectory of glioma remain poorly understood, which results in a universally poor prognosis for patients with glioma. Many patients with glioma experience tumor-associated epilepsy (TAE) throughout their disease course, but the mechanism by which TAE occurs, who is at continued risk for TAE, and whether TAE management can be improved with new therapies is unknown. Ultimately, patients rapidly pass away from their glioma, and progress in extending their survival has been slow over the last two decades, suggesting that the true pattern of disease is not yet understood. To better define the natural trajectory of glioma, we undertook detailed in vitro and in vivo modeling as well as clinical analyses of TAE, and performed gross and microscopic analyses as well as multi-modal profiling of postmortem glioma across time and space. We found that postoperative seizure risk in adult-type diffuse glioma varies in large part by molecular subtype, and that postoperative seizures are often associated with tumor recurrence. The metabolic product of mutated IDH protein (IDHmut), D-2-hydroxyglutarate, rapidly synchronizes neuronal spike firing in a seizure-like manner, but only when nonneoplastic glial cells are present. In vitro and in vivo models can recapitulate TAE, and IDHmut enzyme inhibitors can inhibit seizures in these models. We also found that on postmortem examination of a modern cohort of patients with glioblastoma, two-thirds of these patients had extensive glioblastoma infiltration into their brainstem with accompanying destruction of the pons and white matter tracts, whereas mass effect was far less common. Multi-modal profiling of this brainstem tumor compared to matched pretherapy tumor and postmortem tumor that remained at the original tumor location revealed that while methylation patterns and somatic mutations were largely similar across tumor samples, protein expression greatly varied. In contrast to postmortem tumor that remained at the original tumor location, the tumor that extensively infiltrated the brainstem was CD44-low with elevated proliferative Ki-67+ cells in a normoxic HIF1a-low environment. Together, these studies more precisely define the natural trajectories of tumor-associated epilepsy and brainstem infiltration in patients with glioma, and suggest manners in which to alter these patterns of disease.

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