RESUMEN
PURPOSE: Treatment paradigms for isocitrate dehydrogenase (IDH)-mutant gliomas are rapidly evolving. Although typically indolent and responsive to initial treatment, these tumors invariably recur at a higher grade and require salvage treatment. Homozygous deletion of the tumor suppressor gene CDKN2A/B frequently emerges at recurrence in these tumors, driving poor patient outcomes. We investigated the effect of CDK-Rb pathway blockade on IDH-mutant glioma growth in vitro and in vivo using CDK4/6 inhibitors (CDKi). EXPERIMENTAL DESIGN: Cell viability, proliferation assays, and flow cytometry were used to examine the pharmacologic effect of two distinct CDKi, palbociclib and abemaciclib, in multiple patient-derived IDH-mutant glioma lines. Isogenic models were used to directly investigate the influence of CDKN2A/B status on CDKi sensitivity. Orthotopic xenograft tumor models were used to examine the efficacy and tolerability of CDKi in vivo. RESULTS: CDKi treatment leads to decreased cell viability and proliferative capacity in patient-derived IDH-mutant glioma lines, coupled with enrichment of cells in the G1 phase. CDKN2A inactivation sensitizes IDH-mutant glioma to CDKi in both endogenous and isogenic models with engineered CDKN2A deletion. CDK4/6 inhibitor administration improves survival in orthotopically implanted IDH-mutant glioma models. CONCLUSIONS: IDH-mutant gliomas with deletion of CDKN2A/B are sensitized to CDK4/6 inhibitors. These results support the investigation of the use of these agents in a clinical setting.
Asunto(s)
Aminopiridinas , Bencimidazoles , Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Inhibidor p15 de las Quinasas Dependientes de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Glioma , Isocitrato Deshidrogenasa , Mutación , Piperazinas , Inhibidores de Proteínas Quinasas , Piridinas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Glioma/genética , Glioma/tratamiento farmacológico , Glioma/patología , Ratones , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Bencimidazoles/farmacología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Piridinas/farmacología , Piridinas/uso terapéutico , Línea Celular Tumoral , Eliminación de Gen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , HomocigotoRESUMEN
An unusual 180 m3 storage room in the basement of a two-story laboratory building is unventilated, and separated from occupiable rooms by double steel doors. The space completely borders on soil through the concrete floor and two of its concrete walls. The room also contains a separate inner chamber with 1 m thick concrete walls designed to damp vibrations in the room above it. The space boasts a relatively high radon level, 1083 Bq m-3, which varies with local outdoor environmental conditions. Measurements were made of radon concentrations at various locations and heights within the facility. More than a year of continuous radon concentration data corresponding to a single location are also available, along with measurements of indoor and outdoor pressure, temperature, and humidity. Data were also collected with as many as five fans placed in different locations and cycled on for variable time periods. First order linear kinetic models were created to explain the observed approaches to steady state due to changing conditions and wash-out resulting from intentional ventilation. Results demonstrate a good fit between changes in the radon concentration level and the developed compartmental models. However, no significant differences were observed between radon concentration at different locations or heights in the chamber.