Healthcare systems around the world are facing incredible challenges due to the ageing population and the related disability, and the increasing use of technologies and citizen’s expectations. Improving health outcomes while containing costs acts as a stumbling block. In this context, Big Data can help healthcare providers meet these goals in unprecedented ways. The potential of Big Data in healthcare relies on the ability to detect patterns and to turn high volumes of data into actionable knowledge for precision medicine and decision makers. In several contexts, the use of Big Data in healthcare is already offering solutions for the improvement of patient care and the generation of value in healthcare organizations. This approach requires, however, that all the relevant stakeholders collaborate and adapt the design and performance of their systems. They must build the technological infrastructure to house and converge the massive volume of healthcare data, and to invest in the human capital to guide citizens into this new frontier of human health and well-being. The present work reports an overview of best practice initiatives in Europe related to Big Data analytics in public health and oncology sectors, aimed to generate new knowledge, improve clinical care and streamline public health surveillance.

Information technology (IT) can enhance or change many scenarios in cancer research for the better. In this paper, we introduce several examples, starting with clinical data reuse and collaboration including data sharing in research networks. Key challenges are semantic interoperability and data access (including data privacy). We deal with gathering and analyzing genomic information, where cloud computing, uncertainties and reproducibility challenge researchers. Also, new sources for additional phenotypical data are shown in patient-reported outcome and machine learning in imaging. Last, we focus on therapy assistance, introducing tools used in molecular tumor boards and techniques for computer-assisted surgery. We discuss the need for metadata to aggregate and analyze data sets reliably. We conclude with an outlook towards a learning health care system in oncology, which connects bench and bedside by employing modern IT solutions.

Introduction: The receptor tyrosine kinases (RTKs) c-MET and RON and more importantly their crosstalk, play a crucial role in mediating local invasion, systemic dissemination and resistance in different types of cancer. Both RTKs are activated by the ligands HGF and MSP respectively and homo- or heterodimerize with each other. The RTK VEGFR-2 is the most important receptor for angiogenesis in solid epithelial tumors. CD44v6, a member of the CD44 family of transmembrane glycoproteins, was identified as an essential co-receptor for activation of c-MET, RON and VEGFR-2. AMC303, a peptide based allosteric and selective inhibitor of CD44v6, was investigated for its inhibitory effects on c-MET, RON and VEGFR-2 pathways in vitro and its effect on tumor growth and metastases in vivo. Methods: Affinity was determined using Microscale Thermophoresis. For in vitro blocking assays AMC303 was added 30 min prior to induction with the ligands. Analysis of RTK activation was carried out by western blot. Analysis of cell migration and invasion was performed with Boyden Chamber assays. VEGF-A induced tube formation was microscopically analyzed. For in vivo studies nude mice were orthotopically implanted with human tumor cells (L3.6pl). Animals were treated with AMC303 i.v. at 0.1, 1, 10 mg/kg QOD or QWK for 3 weeks. Regression of metastases was investigated at 1 mg/kg QOD. HPLC was used to detect the amount of AMC303 in the primary tumor lysates. Results: AMC303 binds to the ectodomain of CD44v6 with high affinity. In various pancreatic, breast, colon, lung and HNSCC tumor cell lines activation of c-MET and RON by their ligands was inhibited by AMC303 in vitro and consequently ligand induced cell scattering, migration and invasion was significantly reduced. In endothelial cells, activation of VEGFR-2 and VEGF-A induced formation of a tubular network was blocked by AMC303 treatment. In vivo treatment with AMC303 inhibited tumor growth in a dose dependent manner. The metastatic spreading of the primary tumor was prevented when animals were treated at early disease stage. Most strikingly, a marked regression of established liver metastases was observed at progressed disease state when animals were treated with AMC303 at 1 mg/kg QOD for 3 weeks. Conclusions: AMC303 inhibits activation of the RTKs c-MET and RON allosterically in different epithelial tumor cells and VEGFR-2 in endothelial cells by extracellular binding to CD44v6. This unique and novel mode of action results in a strong anti-tumor and anti-metastatic effect in vivo which together with its wide safety and tolerability window in preclinical toxicity studies is strongly supporting the clinical investigation. AMC303 is currently tested in a Phase I study in patients with solid epithelial tumors. Citation Format: Vanessa Al-Rawi, Thorsten Laeufer, Katrin Glocker, Yvonne Heneka, Alexandra Matzke-Ogi. Allosteric inhibition of the Receptor Tyrosine Kinases c-MET, RON and VEGFR-2 via the co-receptor CD44v6 by the novel compound AMC303 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4911. doi:10.1158/1538-7445.AM2017-4911