Epigenetic maintenance of the redox balance in therapy-persisting tumor cell states

• Applicant: Professor Dr. Alexander Roesch
• Subject Area: Dermatology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257

Reciprocal alterations in the epigenome and metabolism affect the molecular rewiring in cancer and facilitate adaptive cell state transitions during therapy and immune resistance of patients. However, the molecular processes that control the dynamic switch towards or between already resistant tumor cell phenotypes are poorly understood. In the first funding period (FP1) of the Clinical Research Unit 337 PhenoTImE, we saw that histone demethylases (KDMs) can act as cancer-overarching regulators of early therapy resistance in melanoma, pancreatic carcinoma, and glioblastoma. Genetic and chemical manipulation of KDM5B prolonged tumor responses to long-term MAPKi treatment in our pre-clinical melanoma models, especially when combined at therapy onset. On the molecular level, we have found that KDM5B transcriptionally controls the dynamic switch between cell differentiation and immunogenicity programs. With the KDM5B-regulated thioredoxin/peroxiredoxin antioxidant system, we have identified a novel epigenetic-metabolic axis and potential vulnerability of melanoma persister cells for further translational investigation in FP2. As part of PhenoTImE, our subproject benefits from mechanistic and technologic collaboration on longitudinal assessment and visualization of cell states, biosampling strategies, as well immunobiological and bioinformatic expertise of the other groups. We will continue to contribute to the consortium our conceptual understanding and related molecular models of epigenetic-metabolic mechanisms determining resistant tumor cells across cancers. In FP2, we specifically aim at unraveling molecular targets within the KDM5B-ROS-defense-axis for potential therapeutic exploitation and a better understanding of the associated effects on the immunogenicity of drug-tolerant persister states. Such deepened understanding of the interconnection 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.

• 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 Partners: Professor Dr. Meenhard Herlyn; Dr. Eric Ramirez-Salazar