A1 Refereed original research article in a scientific journal
Mathematical Modeling Predicts Response to Chemotherapy and Drug Combinations in Ovarian Cancer
Authors: Emilia Kozłowska, Anniina Färkkilä, Tuulia Vallius, Olli Carpén, Jukka Kemppainen, Seija Grénman, Rainer Lehtonen, Johanna Hynninen, Sakari Hietanen, Sampsa Hautaniemi
Publisher: AMER ASSOC CANCER RESEARCH
Publication year: 2018
Journal: Cancer Research
Journal name in source: CANCER RESEARCH
Journal acronym: CANCER RES
Volume: 78
Issue: 14
First page : 4036
Last page: 4044
Number of pages: 9
ISSN: 0008-5472
eISSN: 1538-7445
DOI: https://doi.org/10.1158/0008-5472.CAN-17-3746
Abstract
Platinum-based chemotherapy constitutes the backbone of clinical care in advanced solid cancers such as high-grade serous ovarian cancer (HGSOC) and has prolonged survival of millions of patients with cancer. Most of these patients, however, become resistant to chemotherapy, which generally leads to a fatal refractory disease. We present a comprehensive stochastic mathematical model and simulator approach to describe platinum resistance and standard-of-care (SOC) therapy in HGSOC. We used pre- and posttreatment clinical data, including F-18-FDG-PET/CT images, to reliably estimate the model parameters and simulate "virtual patients with HGSOC." Treatment responses of the virtual patients generated by our mathematical model were indistinguishable from real-life patients with HGSOC. We demonstrated the utility of our approach by evaluating the survival benefit of combination therapies that contain up to six drugs targeting platinum resistance mechanisms. Several resistance mechanisms were already active at diagnosis, but combining SOC with a drug that targets the most dominant resistance subpopulation resulted in a significant survival benefit. This work provides a theoretical basis for a cancer treatment paradigm in which maximizing platinum's killing effect on cancer cells requires overcoming resistance mechanisms with targeted drugs. This freely available mathematical model and simulation framework enable rapid and rigorous evaluation of the benefit of a targeted drug or combination therapy in virtual patients before clinical trials, which facilitates translating preclinical findings into clinical practice.Significance: These findings present a comprehensive mathematical model for platinum resistance and standard-of-care therapy in a solid cancer, allowing virtual evaluation of novel therapy regimens. (C) 2018 AACR.
Platinum-based chemotherapy constitutes the backbone of clinical care in advanced solid cancers such as high-grade serous ovarian cancer (HGSOC) and has prolonged survival of millions of patients with cancer. Most of these patients, however, become resistant to chemotherapy, which generally leads to a fatal refractory disease. We present a comprehensive stochastic mathematical model and simulator approach to describe platinum resistance and standard-of-care (SOC) therapy in HGSOC. We used pre- and posttreatment clinical data, including F-18-FDG-PET/CT images, to reliably estimate the model parameters and simulate "virtual patients with HGSOC." Treatment responses of the virtual patients generated by our mathematical model were indistinguishable from real-life patients with HGSOC. We demonstrated the utility of our approach by evaluating the survival benefit of combination therapies that contain up to six drugs targeting platinum resistance mechanisms. Several resistance mechanisms were already active at diagnosis, but combining SOC with a drug that targets the most dominant resistance subpopulation resulted in a significant survival benefit. This work provides a theoretical basis for a cancer treatment paradigm in which maximizing platinum's killing effect on cancer cells requires overcoming resistance mechanisms with targeted drugs. This freely available mathematical model and simulation framework enable rapid and rigorous evaluation of the benefit of a targeted drug or combination therapy in virtual patients before clinical trials, which facilitates translating preclinical findings into clinical practice.Significance: These findings present a comprehensive mathematical model for platinum resistance and standard-of-care therapy in a solid cancer, allowing virtual evaluation of novel therapy regimens. (C) 2018 AACR.
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