Systems Medicine approach to identify biomarkers when treating gastric cancer

Building on the success of the CANCERMOTISYS project, Biomax deepened their commitment to cancer research with the SYS-Stomach project. Biomax, the Technische Universität München and four other partners formed the consortium to identify biomarkers and specific cell differences that can be used to predict a patient’s response or resistance to the drugs cetuximab or trastuzumab. The ultimate goal is to improve targeted therapies, and consequently, patient responses.

The consortium uses the BioXM™ Knowledge Management Environment to develop a semantic knowledge network that will be used to build computational models of treatment responses. In combination with biostatistics methods, the BioXM platform will be used to extract multi-modal patient stratification and biomarker profiles, and so enable better therapeutic advice.

Gastric cancer is estimated to be the fourth most common cancer and second leading cause of death from cancer worldwide. Treatment options for gastric cancer patients include surgery, chemotherapy and radiation therapy. Novel drugs targeting members of a family of receptor tyrosine kinases including HER2 and EGFR have shown mixed success in clinical trials. While the HER2 antibody trastuzumab has been approved for gastric cancer treatment, the EGFR antibody cetuximab recently failed in a phase III clinical trial as a gastric cancer treatment, but is approved for colorectal cancer treatment.

The SYS-Stomach project builds on the knowledge gained regarding cetuximab in an earlier BMBF project, CANCERMOTISYS, to further systematically characterize gastric cancer cell lines in response to treatment with cetuximab and trastuzumab. In contrast to similar projects, which rely on omics data only, the SYS-Stomach project assesses both cellular motility and invasiveness phenotypes and uses them to generate biomarkers and computational models, respectively. The effects of the treatment will be determined both on the phenotypic level (motility and invasion assays) and on the molecular level (transcriptomics, epigenomics, proteomics). Time-resolved effects of the treatment on the EGFR and HER2 signaling pathways will be monitored. Candidate response and risk factors to targeted therapy will be validated in vitro and in vivo.

The SYS-Stomach project uses the BioXM Knowledge Management Environment to semantically integrate the following:

  • Current knowledge on gastric carcinoma
  • Systematic molecular measurements (e.g., epigenetics, gene expression and protein regulation)
  • All relevant aspects of tumor behavior, including morphology, adhesion, proliferation, metastatic potential and motility-focused cell phenotype measurements

The knowledge network can be used to build computational models of treatment response and, in combination with biostatistics methods, extract multi-modal patient stratification biomarker profiles. The response predictors will be validated using tumor samples collected from gastric cancer patients treated with either cetuximab or trastuzumab, which will further inform the knowledge network in an iterative process.

Funded by the German Federal Ministry of Education and Research (BMBF), the SYS-Stomach consortium aims to answer clinical questions about predictive factors regarding gastric carcinoma HER2-positive trastuzumab responders, cetuximab responders, and specific differences in reaction to HER2 and EGFR targeted treatments. Biomax is joined by five other partners in the consortium.