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Nat Commun. 2017 Nov 28;8(1):1816. doi: 10.1038/s41467-017-01968-5.

Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer.

Author information

1
Department of Genitourinary Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
2
Department of Integrated Mathematical Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
3
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
4
Department of Integrated Mathematical Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA. Robert.Gatenby@moffitt.org.
5
Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA. Robert.Gatenby@moffitt.org.

Abstract

Abiraterone treats metastatic castrate-resistant prostate cancer by inhibiting CYP17A, an enzyme for testosterone auto-production. With standard dosing, evolution of resistance with treatment failure (radiographic progression) occurs at a median of ~16.5 months. We hypothesize time to progression (TTP) could be increased by integrating evolutionary dynamics into therapy. We developed an evolutionary game theory model using Lotka-Volterra equations with three competing cancer "species": androgen dependent, androgen producing, and androgen independent. Simulations with standard abiraterone dosing demonstrate strong selection for androgen-independent cells and rapid treatment failure. Adaptive therapy, using patient-specific tumor dynamics to inform on/off treatment cycles, suppresses proliferation of androgen-independent cells and lowers cumulative drug dose. In a pilot clinical trial, 10 of 11 patients maintained stable oscillations of tumor burdens; median TTP is at least 27 months with reduced cumulative drug use of 47% of standard dosing. The outcomes show significant improvement over published studies and a contemporaneous population.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02415621.

PMID:
29180633
PMCID:
PMC5703947
DOI:
10.1038/s41467-017-01968-5
[Indexed for MEDLINE]
Free PMC Article

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