Project Details
Projekt
Understanding and targeting degradation-resistant cancers
Applicants
Professor Ashraf Brik, Ph.D.; Professor Dr. Ivan Dikic
Subject Area
Biochemistry
Cell Biology
Cell Biology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 529726222
Background: Increased stabilization of short-lived degradable oncoproteins is a hallmark of aggressive and therapy-resistant cancers, that is present in a significant group of patients. Unveiling the molecular and cellular basis of oncoprotein stabilization pathways and developing therapeutics targeting these cancer entities (termed “degradation resistant cancers”), is an urgent and unmet need in the clinic. In part, pathological oncoprotein stabilization may stem passively from mutated degradation recognition signals (termed degrons) or inactivation of the physiological degradation machinery. However, active protein stabilization pathways are emerging as critical tumor drivers. Among these pathways are; (1) Pathological activation of oncogenic de-ubiquitinating enzymes (DUBs), (2) Ubiquitin (Ub)-dependent protein stabilization pathway that stabilizes and potentiates oncoprotein activity (3) Aberrant Ub-related mitophagy and autophagy. These pathological mechanisms result in degradation-resistant tumor cells that accumulate multiple active oncoproteins with prolonged half-lives. This poses a major therapeutic challenge. Interestingly, key proteins within these pathways were recently found to play central roles in the assembly, dynamics, and physiology of diverse phase-separated liquid bodies. However, the underlying biophysical forces promoting evasion from degradation and oncoprotein stabilization have so far been overlooked. Thus, understanding these tumors is a fundamental question in cancer biology, and this level of regulation is attractive for translational medicine. Yet, the biology of this tumor entity, including the proteins, mechanisms and pathways involved, are largely unknown. Our broad goal: Together, we will discover fundamental mechanisms that drive oncoprotein stabilization and tumorigenesis. Towards this aim, we will combine our synergistic expertise, ranging from single enzyme(s) biochemistry, understanding of biomolecular condensates to advanced tumor biology. Moreover, we will discover critical components of the oncoprotein stabilizing pathways, using fly and mouse genetics that are tightly connected to clinical samples and data. Having a comprehensive and fundamental understanding of the underlying molecular mechanisms of degradation resistant tumors will enable us to develop novel inhibitors and degraders (PROTACs) via our state-of-the-art screening platforms of small molecules. Hence, this will enable the elimination of these clinically challenging tumor entity. To tackle this broad goal, we resected it to operational questions that will be addressed experimentally as outlined. (....)
DFG Programme
DIP Programme
International Connection
Israel
