Delobel, Thibault; Ayala-Hernández, Luis E; Bosque, Jesús J; Pérez-Beteta, Julián; Chulián, Salvador; García-Ferrer, Manuel; Piñero, Pilar; Schucht, Philippe; Murek, Michael; Pérez-García, Víctor M (2023). Overcoming chemotherapy resistance in low-grade gliomas: A computational approach. PLoS computational biology, 19(11), e1011208. Public Library of Science 10.1371/journal.pcbi.1011208
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Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurosurgery |
UniBE Contributor: |
Schucht, Philippe, Murek, Michael Konrad |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1553-734X |
Publisher: |
Public Library of Science |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
21 Nov 2023 09:20 |
Last Modified: |
06 Dec 2023 00:18 |
Publisher DOI: |
10.1371/journal.pcbi.1011208 |
PubMed ID: |
37983271 |
BORIS DOI: |
10.48350/189213 |
URI: |
https://boris.unibe.ch/id/eprint/189213 |
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