Intermetastatic and Intrametastatic Heterogeneity Shapes Adaptive Therapy Cycling Dynamics.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 08 2023
15 08 2023
Historique:
received:
22
08
2022
revised:
11
03
2023
accepted:
17
05
2023
medline:
16
8
2023
pubmed:
19
5
2023
entrez:
19
5
2023
Statut:
ppublish
Résumé
Adaptive therapies that alternate between drug applications and drug-free vacations can exploit competition between sensitive and resistant cells to maximize the time to progression. However, optimal dosing schedules depend on the properties of metastases, which are often not directly measurable in clinical practice. Here, we proposed a framework for estimating features of metastases through tumor response dynamics during the first adaptive therapy treatment cycle. Longitudinal prostate-specific antigen (PSA) levels in 16 patients with metastatic castration-resistant prostate cancer undergoing adaptive androgen deprivation treatment were analyzed to investigate relationships between cycle dynamics and clinical variables such as Gleason score, the change in the number of metastases over a cycle, and the total number of cycles over the course of treatment. The first cycle of adaptive therapy, which consists of a response period (applying therapy until 50% PSA reduction), and a regrowth period (removing treatment until reaching initial PSA levels), delineated several features of the computational metastatic system: larger metastases had longer cycles; a higher proportion of drug-resistant cells slowed the cycles; and a faster cell turnover rate sped up drug response time and slowed regrowth time. The number of metastases did not affect cycle times, as response dynamics were dominated by the largest tumors rather than the aggregate. In addition, systems with higher intermetastasis heterogeneity responded better to continuous therapy and correlated with dynamics from patients with high or low Gleason scores. Conversely, systems with higher intrametastasis heterogeneity responded better to adaptive therapy and correlated with dynamics from patients with intermediate Gleason scores. Multiscale mathematical modeling combined with biomarker dynamics during adaptive therapy helps identify underlying features of metastatic cancer to inform treatment decisions.
Identifiants
pubmed: 37205789
pii: 726541
doi: 10.1158/0008-5472.CAN-22-2558
pmc: PMC10425736
doi:
Substances chimiques
Prostate-Specific Antigen
EC 3.4.21.77
Androgen Antagonists
0
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2775-2789Subventions
Organisme : NCI NIH HHS
ID : U01 CA232382
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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