UNDERSTANDING AND TARGETING RESISTANCE IN GLIOBLASTOMA - UNITE

The natural disease course in glioblastoma is invariably grim, in adults as well as in children. To date, there are no options for primary, secondary or tertiary prevention. However, unlike the fatalistic approach generally taken, we underscore that there are subgroups of patients or individuals clearly benefitting over a variable time from current treatments, radiation and alkylating chemotherapy, as well as experimental precision or immune interventions. This heterogeneity in treatment response reflects the biological heterogeneity of the disease and identifies primary and acquired treatment resistance as the key challenge in the field of glioblastoma. Importantly, even for most conventional treatments the basic molecular mechanisms for primary or secondary resistance are unknown or incompletely understood. The principal investigators assembled in this CRC have contributed fundamental insights into genetic, epigenetic, subcellular, connectivity-based, and immunological aspects of glioma biology, spearheaded the evolution of molecular pathological and imaging diagnostics and developed novel treatment concepts and innovative clinical trials. The CRC is triggered by the strong vision that glioblastoma is treatable. This needs a concerted approach driven by innovation, strong structural bonds within a broad intellectual frame and a focus on clinical implementation. The Heidelberg campus and selected partners present a unique environment to tackle this challenge.

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The UNITE work packages (WP) will focus on unraveling mechanisms of intrinsic resistance (Focus A) and mechanisms of resistance conferred by the microenvironment (Focus B). Utilizing state-of the art technological innovation, novel high-throughput technologies, preclinical models, and analytical tools will be developed, applied, and shared as a resource within the initiative (Focus C). Integrated cores for tissue material, including a core set of jointly used patient-derived models, and integrative data analysis (D) will support work package leaders to efficiently use personal multi-dimensional-omic data for therapy guidance and precision medicine. For 100 selected tissue samples – the UNITE Core Collection - a uniform, integrated data matrix, consisting of multi-omics, imaging and clinical data, will be generated to understand initiation, progression and therapy resistance of glioblastomas at a molecular basis of patient-derived tissues. By drawing a multidimensional map of therapy resistance, UNITE aims to develop concepts to predict and monitor treatment response.

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