Abstract
A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.
Highlights
A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials
We included in the model three main platinum resistance mechanisms: reduced influx/increased efflux of platinum, enhanced DNA damage response pathway, and damaged apoptosis machinery, which accumulate during cell division because ofgenetic aberrations
The model simulation of each virtual High-grade serous ovarian cancer (HGSOC) patient was performed in accordance with neoadjuvant chemotherapy (NACT) SOC in HGSOC meaning that two types of interventions are included in the simulations: interval debulking surgery and platinum-based chemotherapy
Summary
A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. While several mechanisms lead to platinum resistance, three main categories are[9,10] (1) reduced intake or increased efflux of platinum, leading to reduced platinum bioavailability in a cell (pre-target resistance); (2) enhanced DNA repair mechanisms that overcome platinum-induced DNA adducts (on-target resistance); and (3) dysfunctional apoptosis machinery (post-target resistance) Targeting these major resistance mechanisms is an area of intensive research. Combination treatment where standard-of-care chemotherapy is supplemented with targeted drugs for the three most dominant resistant mechanisms would significantly prolong patient survival. We hypothesize here that an effective strategy to overcome platinum resistance is to combine platinum-based chemotherapy with drugs targeting the three major classes of platinum resistance mechanisms; pre-target, on-target, and post-target
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