To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy.

Autor:	Strobl MAR; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA; Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH, USA. Electronic address: stroblm@ccf.org., Martin AL; Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN, USA; Division of Gynecologic Oncology, West Cancer Center and Research Institute, Memphis, TN, USA., West J; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA., Gallaher J; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA., Robertson-Tessi M; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA., Gatenby R; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA; Cancer Biology and Evolution Program, Moffitt Cancer Center, Tampa, FL, USA., Wenham R; Gynecologic Oncology Program, Moffitt Cancer Center, Tampa, FL, USA., Maini PK; Wolfson Centre for Mathematical Biology, University of Oxford, Oxford, UK. Electronic address: maini@maths.ox.ac.uk., Damaghi M; Department of Pathology, Stony Brook Medicine, SUNY, Brookhaven, NY, USA; Stony Brook Cancer Center, Stony Brook Medicine, SUNY, Brookhaven, NY, USA. Electronic address: mehdi.damaghi@stonybrookmedicine.edu., Anderson ARA; Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA. Electronic address: alexander.anderson@moffitt.org.
Jazyk:	angličtina
Zdroj:	Cell systems [Cell Syst] 2024 Jun 19; Vol. 15 (6), pp. 510-525.e6. Date of Electronic Publication: 2024 May 20.
DOI:	10.1016/j.cels.2024.04.003
Abstrakt:	Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. In vivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information. Competing Interests: Declaration of interests M.A.R.S. is now a postdoctoral research fellow at the Cleveland Clinic, OH, but all work presented in this article was conducted at the H. Lee Moffitt Cancer Center & Research Institute. R.W. reports grants and consulting fees from Merck; consulting fees from Tesaro/GSK; consulting fees from Genentech; consulting fees from Legend Biotech; grants and consulting fees from AbbVie; grants and consulting fees from AstraZeneca; consulting fees from Novacure; consulting fees, grants, and stock from Ovation Diagnostics; honoraria from Clovis Oncology; consulting fees and grants from Eisai; consulting fees from Seagen; consulting fees from Shattuck Labs; consulting fees from Immunogen; and consulting fees and grants from Regeneron (all outside the submitted work). (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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