Project Details
Projekt
Targeting clonally expanding drug-resistant tumor cells in recurrent glioblastoma – FP 2: Co-clinical exploitation of epigenetic maintenance.
Applicant
Professor Dr. Björn Scheffler
Subject Area
Dermatology
Molecular and Cellular Neurology and Neuropathology
Molecular and Cellular Neurology and Neuropathology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257
Glioblastoma is a malignant brain tumor that is treated according to precise, evidence-based guidelines, but it almost always recurs quickly, presenting with increased resistance to therapy. During the first funding period (FP1) of the Clinical Research Unit 337 PhenoTImE, we have focused on epigenetic switches that appear to reprogram individual cells under the influence of therapeutic pressure. In a collaborative approach with other groups of this consortium, we identified histone demethylases (KDMs) as cancer-overarching regulators of early therapy resistance in melanoma and pancreatic carcinoma cells as well. In glioblastoma, the reprogramming affects unique intracellular survival mechanisms that we currently continue to investigate. In FP2, we aim to interfere precise and timely with KDM-mediated signaling in these dynamic cells. We have developed lineage-tracing tools that allow to tag and track these identities for protracted periods of time during the course of progression and therapy. We don’t know yet the full spectrum of epigenetic maintenance and the survival strategies of the cells that have persisted first-line therapy. Deep multi-omics investigation will characterize their functional states and their cellular nature. In the proposed experiments, we will also monitor for individual response patterns. Specifically, we will learn how the dynamics of rare cells can change the overall tumor cell composition under the influence of therapeutic pressure. Data will reveal predictors for the course of human disease, but most importantly, we expect to discover vulnerable time points to interfere with malignant progression. This will enable the preclinical design and tailoring of very specific treatment schemes involving unique combinations of drugs and individualized schedules of drug application. Because our project is ideally positioned within the collaborative CRU 337 at the University Hospital Essen, we will aim for immediate clinical translation by exploiting individual patient-derived cells and tissue in a ‘real life’ scenario.
DFG Programme
Clinical Research Units
