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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - MESI-STRAT (Systems Medicine of Metabolic-Signaling Networks: A New Concept for Breast Cancer Patient Stratification)

Teaser

Summary

Breast cancer (BC) is a complex disease with high prevalence in the EU. BC claims the lives of 92,000 Europeans per year (33.4/100,000 inhabitants) and accounts for the highest costs of all cancer-related healthcare. Each year 332,000 new cases are registered (incidence 62.8/100,000). 75 Ì¶ 80% of them are estrogen receptor-positive (ER+), and are treated with endocrine therapies (ET). ET block ER-driven tumor growth and show high efficacy. Yet, a significant proportion of the patients eventually relapses with metastatic breast cancer, and the recurrence rates remain almost constant for up to 20 years. To tackle this challenge, the MESI-STRAT consortium develops new models for knowledge-based stratification of patients into subgroups with different ET resistance mechanisms. We aim to establish predictive pipelines for (1) patient stratification prior and during ET; (2) recurrence risk assessment when ending ET; (3) marker panels to guide established targeted therapies for ET-resistant patients; (4) novel ET resistance mechanism-based therapy design. The unique collection of matched BC tissue, serum, and >10 years follow-up from the patient organization and MESI-STRAT co-coordinator PATH is essential for the longitudinal analysis of ET resistance and relapse.

Work performed

WP1 provides the biological samples, pre-clinical models, clinical samples, and data for model development, and to derive and validate marker panels for clinical decision making in ER+BC. The main effort in months 1 â€“ 18 was to provide a comprehensive overview of available resources in the consortium, and to set up the MESI-Repository. Furthermore, WP1 collaborated with WP2 to develop the MESI-STRAT data management plan (DMP).

WP2 curates and preserves the generated data and makes it available to all MESI-STRAT partners and external users in a user-friendly and securely accessible format. The key aim of MESI-STRAT data management is the adherence to the H2020 Program guidelines on FAIR Data Management, and participation in the open data pilot. In months 1 â€“ 18, the DMP was a key deliverable, which was completed on time, submitted and approved. MESI databases, namely the MESI-Repository for clinical data (WP1) and MESI-SEEK for research data have been initiated in line with the DMP. The testing phase for MESI-SEEK has been completed, and HITS has planned and carried out training sessions for partners.

WP3 is dedicated to the investigation of signaling networks relevant for ER+BC progression and therapy response. In months 1 â€“ 18, basic characterization of relevant cell lines reflecting the tissue situation in ER+BC was carried out and delivered to WP1. First datasets for parameterizing ER+BC signaling models were provided to WP5.

WP4 conducts quantitative analyses of key molecules in metabolic networks important in ER+BC. WP4 closely collaborates with WP3 to gather matched metabolic and signaling data. In months 1 â€“ 18, perturbations and analytical procedures for measurements of metabolite intermediates in cell culture and clinical samples have been established. A first set of data was provided to WP5 for model parametrization.

WP5 uses mathematical modeling and network analyses to predict ER+BC patients subgroups with differences in ET resistance mechanisms and therapy response, and determine specific MESI-marker panels and alternative treatment options. In months 1 â€“ 18, MESI-STRAT efforts focused on adapting existing dynamic models of signaling and metabolism for ER+BC. Furthermore, we devised a pipeline for model integration into MESI-SEEK. MESI-STRAT model development consequently focused toward the applicability for the pharma sector.

WP6 runs preclinical and clinical trials without drug treatments to derive MESI marker panels that identify clinically relevant ER+BC patient subgroups. Work in months 1 â€“ 18 focused on the setup of preclinical, patient-derived models for ER+BC, including primary breast cancer organoids and patient-derived xenografts, immunocompetent xenograft models, and a bioreactor for analysis of primary ER+BC tissues.

WP7 validates the predictive power of the MESI models and marker panels in preclinical and clinical intervention trials. Work in months 1 â€“ 18 focused on setting up two clinical MESI-STRAT trials. Those are (1) the MESI-STRAT prospective and interventional window of opportunity trial of 3 weeks neoadjuvant anastrozole in postmenopausal women with ER+BC (MESI-STRAT-WOO, EudraCT number 2018-000112-21) (https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000112-21/DE); and (2) the MESI-STRAT Endocrine Therapy Termination Trial (ET Termination Trial, DRKS-ID: DRKS00014942) (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00014942).

WP8 implements the management plan to coordinate all MESI-STRAT actions. A key deliverable in months 1 â€“ 18 was the management plan. A kickoff meeting at UMCG in Groningen (NL) was held in March 2018, the first board meeting was held in September 2018 at DKFZ in Heidelberg (DE), and the first annual meeting was held in March 2019 at HITS in Heidelberg (DE). Regular expert meetings by teleconference and additional project meetings between the partners ensure the data and information flow across the cons

Final results

Our team of oncologists, modelers, bioinformaticians and experimentalists will develop new computational models in combination with network analyses and pharmacogenomics, to integrate multi-omics data and explore metabolic and signaling (MESI) networks driving ET resistance. Metabolite marker panels measured in biological fluids will enable patient stratification, resistance monitoring and clinical decision-making. This is a new concept as BC metabolism is poorly explored for diagnostics and therapy. Upon successful validation in preclinical models, the predictive marker panels and related treatments will be jointly investigated by our clinical and industrial partners in clinical studies.