Building health intelligence with complex data on tumor cell states and therapy resistance

• Applicants: Dr. Susanne Horn; Professor Dr. Dirk Schadendorf
• Subject Area: Dermatology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257

A comprehensive characterization of the molecular biological background and immunological pathways involved in the immunotherapy of cancer, in our case melanoma, are the basis for developing diagnostics and therapeutics. We perform research in the context of modern immune checkpoint inhibitors and strive to establish and validate predictive markers that can detect long-term survival benefit in a subpopulation of patients. Our biosampling and extensive annotation of clinical data allows us to perform multivariate analyses with additional co-variables such as mutational burden, LDH levels and immune infiltrates. Within the anticipated profiling of molecular tumor heterogeneity of bulk tumors and single cells we are especially interested in site-related molecular differences of melanoma metastases from brain, lung, and skin. We will further expand our data collection by annotating epigenetic and metabolomic information to already annotated datasets, with e.g. methylation, HLA allele status and toxicity profiles. These analyses are empowered by the development of software and easy-to-use webtools extending our PhenoTImE data share (‘translational hub’). Specifically, we aim at extending the Cox proportional hazards model with a bayesian framework to better predict time-to-event data across multiple cohorts as artificial neural networks do not yet perform well to predict survival under immune checkpoint blockade from transcriptomics in various analyzed melanoma cohorts. To this end, the facilitation of exchanging large datasets is crucial. Hence, we support the merging of quantifications from raw ‘omics’ data with phenotypic profiles generated by us and other projects in the research unit. Thereby we aid collaborative, timely analyses with the necessary interconnection of data and metadata. We also administrate and maintain the compute-server cluster that we established in the first funding phase for the analysis of datasets open to all members of the consortium and to collaborators. With these efforts, we extend our research to additional tumor entities beyond melanoma where our pipelines eventually will merge into larger institutional platforms such as multi-omics tumor tissue profiling and inter-disciplinary tumor boards.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 337: Phenotypic Therapy and Immune Escape in Cancer (PhenoTImE): pre-clinical and translational advance of the CRU 337
• International Connection: USA
• Cooperation Partner: Dr. David Liu