SFB 1399:  Mechanisms of drug sensitivity and resistance in small cell lung cancer

• Subject Area: Biology ; Chemistry ; Medicine
• Term: since 2019
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413326622

Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and little progress has been made in understanding the molecular mechanisms causing this devastating disease. No mechanistic explanation exists for a central clinical hallmark: While SCLC typically presents with initial sensitivity against chemotherapy, the disease almost inevitably relapses. In the first funding period, members of CRC 1399 have made groundbreaking discoveries providing new insights into the underlying mechanisms of these and other properties of SCLC. For the second funding period, we propose to leverage on this knowledge and launch an orchestrated pursuit of mechanistic analyses aimed at advancing our understanding of the molecular pathogenesis of SCLC with the goal of transferring our novel discoveries into clinical application. Our consortium is highly interdisciplinary, covering expertise in biochemistry, metabolism and cell signaling, structural biology, and structure-guided drug design, cancer immunology, mouse models, cancer genomics, computational genomics, molecular pathology, as well as clinical trials. Members of our consortium have a track record of interdisciplinary, cross-faculty collaboration. We build our consortium on a portfolio of established technological platforms involving genomics, immunomics, metabolomics, cellular models, genetic mouse models and imaging, as well as computational efforts to understand the molecular evolution of SCLC. Particular emphasis is placed on functionally interrogating the discoveries made in high-throughput assays in subsequent mechanistic experiments. Our scientific efforts are intimately linked to the clinic through a translational platform, which facilitates the longitudinal molecular monitoring of patients, thus providing mechanisms of evolution and adaptation to therapy. We anticipate that these efforts will reveal possible entry routes for targeted therapeutic intervention that can overcome drug resistance in this cancer, thus paving the way for curative therapeutic approaches in the future. In addition to our scientific goals, this CRC will strengthen the precision medicine lighthouse in Cologne and help connecting interdisciplinary research across different cancer entities. A significant part of this endeavor therefore is to create measures for training of young scientists and clinicians as well as dedicated and focused support of women in science.

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Identification and characterization of molecular vulnerabilities in SCLC (Project Heads Beleggia, Filippo ;  Reinhardt, Christian ;  Wunderlich, Frank Thomas )
• A03 - Targeting telomere maintenance mechanisms in SCLC (Project Head Fischer, Matthias )
• A04 - Inflammatory and necroptotic signaling in SCLC (Project Head Pasparakis, Manolis )
• A05 - Immuno-editing via programmed cell death in SCLC (Project Head von Karstedt, Silvia )
• A07 - Targeting key drivers in SCLC for the development of new therapeutic concepts (Project Head Knapp, Stefan )
• A08 - Targeted exploitation of inflammatory programs in SCLC (Project Head Sos, Martin )
• A09 - Mechanism of resistance in SCLC defined by pyroptotic-to-apoptotic switch (Project Head Peltzer, Ph.D., Maria de las Nieves )
• B01 - Mechanisms of drug sensitivity and resistance in SCLC (Project Heads George, Julie ;  Thomas, Roman )
• B02 - Clonal evolution of SCLC (Project Head Peifer, Ph.D., Martin )
• B05 - Decoding epigenetic subtypes, resistance mechanisms and vulnerabilities of small cell lung cancer (Project Head Hänsel-Hertsch, Ph.D., Robert )
• B06 - The relevance of helicase activity for genome stability changes within small cell lung cancer (Project Head Paeschke, Katrin )
• B07 - Characterization of metabolic repro-gramming in Small Cell Lung Cancer subtype plasticity and progression (Project Head Frezza, Christian )
• B08 - Metabolic characterization of innate lymphoid cells in small cell lung cancer (Project Head Surace, Ph.D., Laura )
• B09 - SCLC response to chemotherapy and ionizing 𝛾-radiation (Project Head Cartolano, Maria )
• C01 - Molecular characterization of the immunogenic profile in SCLC tumors (Project Head George, Julie )
• C03 - Harnessing molecular vulnerabilities to promote an antitumor immune microenvironment (Project Heads Gouttefangeas, Cécile ;  Rammensee, Hans-Georg )
• C04 - Immunopeptidomics of small cell lung carcinoma (Project Head Hölzel, Michael )
• C05 - T cell recognition and immune editing in SCLC (Project Heads Kolb, Ph.D., Laura ;  Sahin, Ugur )
• C06 - Understanding and therapeutically harnessing the tumor-supportive and immune-suppressive functions of TRAIL and CD95L in SCLC (Project Heads Liccardi, Gianmaria ;  Walczak, Ph.D., Henning )
• C07 - Exploiting innate nucleic acid receptor pathways to enhance immunotherapy in SCLC (Project Head Braegelmann, Johannes )
• INF2 - Bioinformatics, Research-Data Management, IT Infrastructure and Optimization (Project Heads Peifer, Ph.D., Martin ;  Schenk, Jasmin ;  Wesner, Stefan )
• INFZ01 - A translational platform for longitudinal molecular studies of SCLC under therapy (Project Heads Höpker, Katja ;  Lang, Ulrich ;  Peifer, Ph.D., Martin ;  Wesner, Stefan ;  Wolf, Jürgen )
• Z03 - In vivo Imaging of Tumors (Project Head Grüll, Holger )
• Z04 - Translational Pathology Core (Project Heads Büttner, Reinhard ;  Quaas, Alexander ;  Schultheis, Anne M. ;  Siebolts, Udo )
• Z05 - Central administration (Project Head Thomas, Roman )

Completed projects

• A02 - MYC gene family members as modulators of tumorigenesis and druggable signaling pathways in SCLC (Project Head Sos, Martin )
• A06 - CDK9 inhibition for the treatment of drug resistance in SCLC (Project Head Peltzer, Ph.D., Maria de las Nieves )
• B03 - Mutations in epigenetic modifiers and their impact on tumorigenesis and drug response in SCLC (Project Head Schweiger, Michal-Ruth )
• B04 - Chemical biology analysis of epigenetics in SCLC (Project Head Knapp, Stefan )
• C02 - Harnessing molecular vulnerabilities to promote an antitumor immune microenvironment (Project Heads Herter-Sprie, Grit Sophie ;  Reinhardt, Christian )

• Applicant Institution: Universität zu Köln
• Participating University: Eberhard Karls Universität Tübingen; Goethe-Universität Frankfurt am Main; Johannes Gutenberg-Universität Mainz; Rheinische Friedrich-Wilhelms-Universität Bonn; Universität Duisburg-Essen
• Participating Institution: TRON - Translationale Onkologie; an der Universitätsmedizin der Johannes Gutenberg-Universität Mainz
• Spokesperson: Professor Dr. Roman Thomas