Adaptive Therapy Exploits Fitness Deficits in Chemotherapy-Resistant Ovarian Cancer to Achieve Long-Term Tumor Control
Journal article, 2025
Drug resistance results in poor outcomes for patients with cancer. Adaptive therapy is a potential strategy to address drug resistance that exploits competitive interactions between sensitive and resistant subclones. In this study, we showed that adapting carboplatin dose according to tumor response (adaptive therapy) significantly prolonged survival of murine ovarian cancer models compared with standard carboplatin dosing, without increasing mean daily drug dose or toxicity. Platinum-resistant ovarian cancer cells exhibited diminished fitness when drug was absent in vitro and in vivo, which caused selective decline of resistant populations due to reduced proliferation and increased apoptosis. Conversely, fitter, sensitive cells regrew when drug was withdrawn. Using a bioinformatics pipeline that exploits copy number changes to quantify the emergence of treatment resistance, analysis of cell-free DNA obtained longitudinally from patients with ovarian cancer during treatment showed subclonal selection through therapy, and measurements of resistant population growth correlated strongly with disease burden. These preclinical findings pave the way for future clinical testing of personalized adaptive therapy regimens tailored to the evolution of carboplatin resistance in individual patients with ovarian cancer. SIGNIFICANCE: Carboplatin adaptive therapy improves treatment efficacy without increasing daily dose due to reduced fitness of drug-resistant populations, which can be tracked using cfDNA and could direct adaptive therapy in future clinical trials. See related commentary by Gatenby, p. 3373.
Author
Helen Hockings
Barts Cancer Institute
Eszter Lakatos
Barts Cancer Institute
Chalmers, Mathematical Sciences, Applied Mathematics and Statistics
Institute of Cancer Research
Weini Huang
Queen Mary University of London
Maximilian Mossner
Institute of Cancer Research
Barts Cancer Institute
Mohammed A. Khan
Institute of Cancer Research
Barts Cancer Institute
Nikolina Bakali
Barts Cancer Institute
Jacqueline McDermott
NHS Foundation Trust
Kane Smith
Institute of Cancer Research
Barts Cancer Institute
Ann Marie Baker
Institute of Cancer Research
Barts Cancer Institute
Trevor A. Graham
Institute of Cancer Research
Barts Cancer Institute
Michelle Lockley
Barts Cancer Institute
Cancer Research
0008-5472 (ISSN) 15387445 (eISSN)
Vol. 85 18 3503-3517Subject Categories (SSIF 2025)
Cancer and Oncology
DOI
10.1158/0008-5472.CAN-25-0351
PubMed
40299825