Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15900
Título
On optimal temozolomide scheduling for slowly growing glioblastomas
Autor(es)
Segura-Collar, Berta ISCIII | Jiménez-Sánchez, Juan | Gargini, Ricardo ISCIII | Dragoj, Miodrag | Sepúlveda-Sánchez, Juan M | Pešić, Milica | Ramírez-González, María A ISCIII | Ayala-Hernández, Luis E | Sánchez-Gómez, Pilar ISCIII | Pérez-García, Víctor M
Fecha de publicación
2022-09
Cita
Neurooncol Adv. 2022 Sep 27;4(1):vdac155.
Idioma
Inglés
Tipo de documento
journal article
Resumen
Background: Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes. Methods: Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study. Results: Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico. In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients. Conclusions: In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs.
Palabras clave
In-silico trials | Mathematical oncology | Optimal drug scheduling | Temozolomide resistance | Tumor phenotype
Versión en línea
DOI
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