ColoSYS - A Systems Approach to Preventing Drug Resistance in Colon Cancer

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Project description

Colon cancer (CC) is a major cause of death. Current treatment uses chemotherapy combined with anti-EGFR or VEGF drugs, and radiotherapy. Screening for biomarkers can indicate whether EGFR-inhibitors will be effective in patients but otherwise biomarkers for personalising patient treatment are scarce.

First-line combinations of chemotherapy and EGFR-inhibitors for stratified patients being RAS wild-type have led to an increase in overall survival to more than 30 months, but most patients develop RAS mutations under anti-EGFR therapy, or do not respond to EGFRi for unknown reasons. The majority of patients develop resistance and succumb to the disease.

We still have a poor understanding of how gene networks drive cancer, how they modulate response, and how they induce resistance to treatment. Good disease models that can provide insight are simply lacking. With the availability of large public data resources, our unique collection of patient samples and patient-derived models and with computational and experimental approaches becoming mature, the COLOSYS consortium aims to develop in silico therapy response predictors that allow precision medicine, based on patient-specific driver and resistance mechanisms. We will identify new CC tumor driver genes by integration of multiple data types from large public tumor and cell line repositories. A high quality, open repository of data and knowledge (knowledge commons) will be assembled and used to construct multiscale computer models of the molecular networks that underlie cancerous cell proliferation. Logical model simulations will predict the effect of drugs in cancer cell lines and patient tumors. We will test these predictions on cell lines as well as patient derived cell cultures, organoids and mouse xenografts, and perform preliminary testing in patients. The combined computational, experimental and clinical testing will provide understanding of resistance mechanisms, and allow personalised treatment of colon cancer.

yH2AX and 53BP1 Immunofluorescence


Consortium

Coordinator:

Prof. Martin Kuiper
Norwegian University of Science and Technology
Trondheim, Norway

Co-Investigators:

  1. Prof. Christine Sers
    Molecular Tumor Pathology, CharitéUniversitätsmedizin Berlin
  2. Dr. Emmanuel Barillot Institut Curie
    Paris, Frankreich
  3. Prof. Alfonso Valencia
    Spanish National Center for Cancer Research (CNIO)
    Madrid, Spanien
  4. Prof. Lodewyk Wessels
    The Netherlands Cancer Institute, Amsterdam

Further Information on the ColoSYS Project.