Phenotypic Therapy and Immune Escape in Cancer
Project 1Epigenetic-metabolic reprogramming as a universal strategy in therapy resistant tumor cell phenotypes
Alterations in the epigenome and metabolism both affect molecular rewiring in cancer and facilitate adaptive cell state transitions during therapy and immune resistance. However, the molecular processes that control the dynamic switch towards or even between resistant cell phenotypes are poorly understood. The overall hypothesis of project P1 is that resistant tumor cell phenotypes, probably irrespective of their genetic background, share a common epigenetic-metabolic (‘epi-metabolic’) basis. Thus, the translational goal is to unravel the axis between epigenetics and metabolism and to identify superior therapeutic targets and biomarkers for rapid transfer into the clinics. Our preliminary work indicates that the histone H3K4 demethylase JARID1B/KDM5B is involved in both multi-drug resistance in melanoma patients and the regulation of crucial metabolic pathways including, but not limited to oxidative phosphorylation and the glutamine metabolism/glutathione-redox-system. Specifically, we hypothesize that the selection for JARID1Bhigh cells represents the initial event and prerequisite in longitudinal development of drug and immune resistance of patients. The exact contribution of the JARID1B-dependent epi-metabolic circuitry in priming surviving cells for further adaptive cell state transitions is not yet understood. The particular setting of collaborations and research goals proposed in the Clinical Research Unit PhenoTImE is an ideal platform to unravel both the molecular details of this bi-directional epi-metabolic circuitry and ways to exploit it as a superior target for overcoming tumor resistance also beyond melanoma. A deeper understanding of the link between epigenetics and metabolism could lead to novel drugs with significant improvement in cancer treatment, especially when sequentially combined with potent tumor-debulking drugs. This has immediate implications for the design of personalized clinical trials and could also lead to the development of new biomarkers and companion diagnostics in the near future.
Prof. Dr. med. Alexander Roesch
Department of Dermatology
German Cancer Consortium (DKTK)
University Hospital Essen