Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma.

Unlabelled: We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact.

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma.

Background: Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes.

Methods: An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma.

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Background: Distinct genetic alterations determine glioma aggressiveness, however, the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of the disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability.

Methods: A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n = 1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n = 206).

Glioma genetic profiles associated with electrophysiologic hyperexcitability.

Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures is uncertain. In a large cohort of patients with sequenced gliomas (n=1716), we used discriminant analysis models to identify somatic mutation variants associated with electrographic hyperexcitability in a subset with continuous EEG recording (n=206). Overall tumor mutational burdens were similar between patients with and without hyperexcitability.

CaMKII binds both substrates and activators at the active site.

Ca/calmodulin-dependent protein kinase II (CaMKII) is a signaling protein required for long-term memory. When activated by Ca/CaM, it sustains activity even after the Ca dissipates. In addition to the well-known autophosphorylation-mediated mechanism, interaction with specific binding partners also persistently activates CaMKII.

Early EEG hyperexcitability is associated with decreased survival in newly diagnosed IDH-wildtype glioma.

Purpose: The relationship between peritumoral neuronal activity, early onset clinical seizures, and glioma survival outcomes remains poorly understood. Hyperexcitability on continuous EEG in the peri-operative period was studied as a prognostic biomarker in patients with newly diagnosed IDH-wildtype diffuse glioma.

Methods: A retrospective observational cohort study was performed including adults with newly diagnosed diffuse glioma, absence of IDH1/2 mutations, and continuous EEG monitoring prior to chemoradiation and within 1 month of initial resection.

Effect of PIK3CA variants on glioma-related epilepsy and response to treatment.

Upregulation of the PI3K/AKT/mTOR pathway has been implicated in glioma-related epileptogenesis. In this retrospective analysis, epilepsy characteristics and response to treatment were evaluated in patients with gliomas harboring somatic mutation variants in PIK3CA. A cohort of 134 patients with 150 PIK3CA variants was extracted from previously validated databases.

Characterization of CaMKIIα holoenzyme stability.

Ca /calmodulin-dependent protein kinase II (CaMKII) is a Ser/Thr kinase necessary for long-term memory formation and other Ca -dependent signaling cascades such as fertilization. Here, we investigated the stability of CaMKIIα using a combination of differential scanning calorimetry (DSC), X-ray crystallography, and mass photometry (MP). The kinase domain has a low thermal stability (apparent T = 36°C), which is slightly stabilized by ATP/MgCl binding (apparent T = 40°C) and significantly stabilized by regulatory segment binding (apparent T = 60°C).