TRR 387:  Functionalizing the Ubiquitin System against Cancer - UbiQancer

• Subject Area: Medicine ; Biology ; Chemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514894665

Despite the success of targeted therapies and the advent of immune therapies, cancer remains the second most common cause of death. The exploration of fundamentally new therapeutic approaches is therefore needed. While cancer genomics have transformed our understanding of tumor pathophysiology and maintenance, cancer is not purely a genetic disease, but rather a disease of dysregulated cellular functions that result from aberrant protein interaction networks. The concept of this CRC/TRR is based on the view that the “language” by which proteins communicate is deregulated in cancer, thereby positioning post-translational modifications (PTMs) at the center of cancer development, maintenance and as a therapeutic avenue. The post-translational modification by ubiquitin (Ub) is orchestrated by more than 1000 genes in the human genome and controls degradation and function of the majority of proteins, thereby directing all dimensions of cellular life. Aberrations of this system have been linked to tumorigenesis, yet a comprehensive understanding of the ubiquitin system within cancer is needed to promote faster and efficient translation into the clinical use. The overarching long-term goal driving this CRC is to deliver a foundation for novel treatment strategies based on a mechanistic understanding of aberrant ubiquitin dependent processes in defined tumor entities: AML and B cell neoplasms as well as non-small-cell lung and colorectal cancer. We postulate that validated vulnerabilities among members of the ubiquitin system define new target structures for anti-cancer approaches. Furthermore, the degradative nature of the ubiquitin proteasome system (UPS) enables technologies which allow to pursue the concept of targeted protein degradation, particularly proteolysis targeting chimera (PROTAC) technology. We aim to generate an exploratory hub towards Ub-biology driven discovery of relevant and functionalized vulnerabilities (Research Area A) and the application of these insights to develop compounds directed towards validated ubiquitin targets and by engineering PROTAC tools against oncoproteins that evade inhibition (Research Area B). For optimal support, this CRC establishes interlaced and dedicated core platforms. Z01 (target and compound profiling) will enable discovery projects to screen for cellular phenotypes while allowing later projects to ascertain whether new compounds are on target. The Z02 drug/probe discovery platform will provide compound screening for validated targets as well as hit-to-lead development and specifically PROTAC development for defined oncoproteins. The infrastructure for hit validation in large patient cohorts with a focus on novel spatial resolution technologies such as CODEX and functional Ub-specific activity assays will be enabled by Z3 (functional pathology). Combined, this CRC/TRR anticipates to position ubiquitylation of proteins at the forefront of drug discovery to establish novel avenues of cancer treatment.

• DFG Programme: CRC/Transregios

Current projects

• A01 - Role of FBXO41 in maintaining the undifferentiated state in acute myeloid leukemia (Project Head Bassermann, Florian )
• A02 - Function and targeting of membrane-bound E3 ligases in AML (Project Heads Dikic, Ivan ;  Krause, Daniela )
• A03 - SLC-regulating E3 ligases as therapeutic targets in AML (Project Head Eichner, Ph.D., Ruth )
• A04 - Role of premature transcription termination in colorectal tumorigenesis (Project Heads Beli, Petra ;  Eilers, Martin )
• A05 - Contribution of the ubiquitin proteasome system to ferroptosis resistance in non-small cell lung cancers (Project Head Friedmann Angeli, José Pedro )
• A06 - Targeting the oxidative stress response of non-small cell lung cancers (Project Head Bremm, Anja )
• A07 - Reprogramming of the E3 ligase/DUB network during oncogenic transformation (Project Heads Diefenbacher, Markus Elmar ;  Dikic, Ivan )
• A08 - The role of RNF213 and its variants in lung tumor (Project Heads Imkeller, Katharina ;  Münch, Christian )
• A09 - Discovery and targeting of ubiquitin-dependent synthetic vulnerabilities in NSCLC (Project Heads Kaulich, Ph.D., Manuel ;  Rad, Roland )
• A10 - Structural mechanisms underlying MYC ubiquitylation (Project Head Schulman, Brenda )
• A11 - Cross-species screens and investigation of UPS vulnerabilities in high grade lymphoma (Project Head Schmidt-Supprian, Marc )
• A12 - Understanding and breaking proteasome inhibitor resistance in multiple myeloma patients (Project Heads Kortüm, Martin ;  Küster, Bernhard )
• A13 - Deciphering vulnerabilities in the USP1/Fanconi anemia axis as anticancer target in AML (Project Heads Buettner, Ph.D., Florian ;  Illert, Lena )
• B01 - Harnessing novel E3 ligases for cancer-specific degradation of oncogenic targets by PROTACs (Project Heads Schindelin, Hermann ;  Wolf, Elmar )
• B02 - Targeting E3 ligase functions in AML (Project Heads Knapp, Stefan ;  Müller, Stefan )
• B03 - Organogold compounds as “smart” residue specific chemical modifiers: towards new generation Gold-PROTACs (Project Head Casini, Angela )
• B04 - Understanding ubiquitylation and FATylation by UBA6 in lung cancer (Project Heads Diefenbacher, Markus Elmar ;  Schindelin, Hermann )
• B05 - Targeting OTUD6B in multiple myeloma (Project Heads Bassermann, Florian ;  Hadian, Ph.D., Kamyar )
• B06 - Design of potent and selective USP25 and USP28 inhibitors (Project Heads Kisker, Caroline ;  Proschak, Eugen )
• B07 - Analyzing and targeting non-catalytic functions of Aurora-A in AML (Project Heads Büchel, Gabriele ;  Wolf, Elmar )
• B08 - Targeted proteasomal degradation of m6A-reader proteins in colorectal carcinoma (Project Heads Brunschweiger, Andreas ;  Papadopoulos, Dimitrios )
• IRTG - Integrated Research Training Group (Project Heads Bremm, Anja ;  Büchel, Gabriele )
• Z01 - Target and compound profiling (Project Heads Schülein-Völk, Christina ;  Stolz, Alexandra ;  Wilhelm, Stephanie )
• Z02 - Drug/probe discovery platform (Project Heads Brunschweiger, Andreas ;  Hadian, Ph.D., Kamyar ;  Plettenburg, Oliver ;  Popowicz, Grzegorz )
• Z03 - Functional human and mouse pathology (Project Heads Gerhard-Hartmann, Elena ;  Rosenwald, Andreas ;  Steiger, Katja )
• Z04 - Central Tasks (Project Head Bassermann, Florian )

• Applicant Institution: Technische Universität München (TUM)
• Co-Applicant Institution: Goethe-Universität Frankfurt am Main; Julius-Maximilians-Universität Würzburg
• Participating Institution: Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Max-Planck-Institut für Biochemie (MPIB)
• Participating University: Christian-Albrechts-Universität zu Kiel; Johannes Gutenberg-Universität Mainz
• Spokesperson: Professor Dr. Florian Bassermann