Chemical Biology of Oncogenic Gene Regulation
Our lab is interested in understanding the molecular basis of aberrant gene regulation in cancer. We think of cancer as an enormously complex and heterogeneous disease that is characterized by a set of phenotypic hallmarks that are initiated and maintained via dysregulated transcriptional programs. In order to identify, characterize and mechanistically dissect novel oncogenic transcriptional circuits, we are using and developing chemical biology centric approaches in a highly integrated fashion with the ultimate goal of advancing chemical modulation of oncogenic gene regulation as a therapeutic approach.
Targeted Protein Degradation
Chemical modulation of transcription factors and transcriptional co-activators remains a historic challenge in the field of ligand discovery chemistry. Acting at the interface of DNA and chromatin, these proteins are commonly perceived as chemically intractable as they often operate as molecular scaffolds in multi-protein complexes, lack a pharmacologically tractable enzymatic domain, or function via protein-protein or protein-DNA interactions. In order to overcome inherent limitations of traditional medicinal chemistry, we recently devised phthalimide conjugation as an approach that prompts ligand-dependent target protein degradation by modulating the activity of the CLR4CRBN E3 ubiquitin ligase complex. Targeted protein degradation combines the kinetic advantages of small molecule approaches with the holistic nature of genetic perturbation strategies and is thus ideally suited to measure and interpret acute changes in gene regulatory programs and assay for new transcriptional addictions in cancer. We are aiming to apply this technology to a comprehensive set of transcriptional regulators implicated in cancer as well as further develop strategies that enable genome-scale applications.
Forward genetic screens based on RNA interference or insertional mutagenesis have successfully been deployed to identify novel therapeutic targets, elucidate the mechanism of action of drugs and discover biomarkers for patient stratification. Genetic screens based on CRISPR-Cas9 genome engineering hold promise as they (i) outperform RNA interference based approaches in loss of function settings, (ii) allow inferring phenotypically relevant domains and (iii) enable the disruption of cis regulatory elements. We designed a protein-domain focused, deep-coverage sgRNA library that targets 700 genes implicated in transcriptional regulation that we will deploy in order to identify novel dependencies in transcriptionally dysregulated cancers. Focusing on chromatin-acting small molecules, we want to elucidate resistance mechanisms as well as drug-sensitizing perturbations to inform patient stratification as well as rational drug combinations. Gene-drug interactions derived from such screens will enable us to discover novel insights in aberrant transcriptional regulation as well as to understand connectivity between different gene-regulatory networks implicated in the pathophysiology of cancer.
Georg Winter studied Biotechnology and performed his undergraduate studies with Thomas Jenuwein at the IMP in Vienna. He undertook his graduate studies with Giulio Superti-Furga at CeMM and continued his training as a postdoctoral fellow with James Bradner at the Dana Farber Cancer Institute/ Harvard Medical School. He joined CeMM in 2016.
Winter, G. E.*, Buckley, D. L.*, Paulk, J., Roberts, J., Souza, A., De-Phagano, S., and Bradner, J. E. (2015) Phthalimide Conjugation as a Strategy for in vivo Target Protein Degradation. Science 348, 1376-81. (abstract)
Dixon, S. J.*,Winter, G. E.*, Musavi, L. S., Lee, E. D., Snijder, B., Rebsamen, M., Superti-Furga, G., Stockwell, B. R. (2015) Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chemical Biology 10 (7), pp 1604–1609. (abstract)
Winter, G. E., Radic, B., Mayor-Ruiz, C., Blomen, V. A., Trefzer, C., Kandasamy, R. K., Huber, K. V., Gridling, M., Chen, D., Klampfl, T., Kralovics, R., Kubicek, S., Fernandez-Capetillo, O., Brummelkamp, T. R., and Superti-Furga, G. (2014) The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nature Chemical Biology 10, 768-773. (abstract)
Winter, G. E.*, Rix, U.*, Carlson, S. M., Gleixner, K. V., Grebien, F., Gridling, M., Muller, A. C., Breitwieser, F. P., Bilban, M., Colinge, J., Valent, P., Bennett, K. L., White, F. M., and Superti-Furga, G. (2012) Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nature Chemical Biology 8, 905-912. (abstract)