posted on 2024-09-16, 09:57authored byJill Gallaher, Maximilian Strobl, Jeffrey West, Robert Gatenby, Jingsong Zhang, Mark Robertson-Tessi, Alexander R.A. Anderson
Movies corresponding to simulation examples in Figure 4, comparing metastases simulations with different drug resistance and turnover.
History
ARTICLE ABSTRACT
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 PSA levels in sixteen metastatic castration resistant prostate cancer patients 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 inter-metastasis heterogeneity responded better to continuous therapy and correlated with dynamics from patients with high or low Gleason scores. Conversely, systems with higher intra-metastasis heterogeneity responded better to adaptive therapy and correlated with dynamics from patients with intermediate Gleason scores.