Cross-Country Collaboration: Targeting Resistant Cancers with New Therapeutics
A collaborative research project between scientists from Helmholtz Munich, Goethe University Frankfurt, Ludwig Maximilian University Munich, and Technion, the Israel Institute of Technology in Haifa, on “Understanding and Targeting Degradation-resistant Cancers” is funded with 1.655 million Euro as part of the German-Israeli Project Cooperation (DIP). DIP was inaugurated in 1997 by the German Federal Ministry for Education and Research (BMBF) to strengthen excellence in German-Israeli research cooperation. The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) has taken over and continues the program while BMBF continues to provide funding for the five-year project.
The project will investigate the increased stabilization of short-lived degradable oncoproteins, which is a hallmark of aggressive and therapy-resistant cancers 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 clinical need.
Three project partners from Technion, Professors Ashraf Brik (Ubiquitin chemistry), Amir Orian, Director Rappaport Technion Integrative Cancer Research Center (ubiquitin dependent protein stability) and Dan Bracha (phase separation) are involved from Israel. On the German side, IBC2 Director Ivan Đikić (Autophagy and small molecule development) and LMU Professor and Helmholtz Munich Group Leader Markus E. Diefenbacher will bring together synergistic expertise to discover fundamental mechanisms that drive oncoprotein stabilization and tumorigenesis. High-end chemical and biochemical methods in the field of targeted protein degradation, combined with fly and mouse genetics and connected to clinical samples and data will be utilized to discover novel layers of protein regulation, including enzymes and mechanisms that are fundamental to the tumorigenesis of degradation-resistant tumors.
In the implementation of the project, the Institute for Lung Health and Immunity (LHI) at Helmholtz Munich and the Experimental Pneumology at the Medical Faculty of the Ludwig Maximilan University Munich, play a key role as an innovation hub. The group of Prof. Diefenbacher will provide access to state-of-the-art technologies, including adeno-associated viruses for gene delivery, along with somatic engineered and genetically tailored preclinical model systems. Via close collaboration with clinicians at the LMU University Hospital and at Asklepios, patient-derived organoids of lung cancer, together with in vivo and ex vivo models, will play pivotal roles in the discovery of new vulnerabilities in cancer and allow the consortium to test innovative, early stage, therapeutics.
Gaining a comprehensive and fundamental understanding of the underlying molecular mechanisms of degradation-resistant tumors will enable the group of scientists to develop novel inhibitors and degraders (PROTACs), which will have direct implications for the future development of ubiquitin-related therapeutics.
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