FOR 5433:  RNA in focus (RIF): From mechanisms to novel therapeutic strategies in cancer treatment

• Subject Area: Medicine ; Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282

In this post-genomics era, it is recognized that an enormous number and diversity of transcriptional products arise from the none protein-coding genome. While we now know that these myriad non-coding RNA (ncRNA) transcripts contribute complex layers of regulation to cellular physiology, our knowledge of RNA/RBP-guided Regulation of Gene Expression (R3oGE) is far from being incorporated into our standards of diagnosis and treatment of cancer. Cancer is the second most common cause of death in Germany with increasing prevalence. Accordingly, there is high demand for novel therapeutic concepts, in particular for malignancies of dismal patient outcome. Current cancer research and treatment efforts mainly focus on protein-coding genes, largely catalytic and receptor proteins. However, technical advances in omics technologies have expedited the identification of over 1500 RNA-binding proteins (RBPs) and a continuously growing number of ncRNAs. This poses a situation in which the discovery of new ncRNAs and RBPs outstrips their functional characterization in oncogenesis – leading to a constantly increasing knowledge gap that limits our efficiency in developing therapies targeting the R3oGE. The proposed “RNA in focus” Research Unit (RU5433) will address this knowledge gap by investigating the role and therapeutic target potential of ncRNAs and RBPs in cancer. Accordingly, the ultimate aim of the RIF-RU is to evaluate and develop RNA-centered or R3oGE-directed therapeutic concepts by understanding the underlying biology, and evaluating novel strategies in pre-clinical context. Towards this aim, we plan to combine basic research on disease-associated mechanisms – for novel target identification – with research on target validation up to pre-clinically-oriented drug development and testing. Hence, while the cancer entity differs between projects, they are connected by a common research goal, molecular determinants and mechanisms studied, and techniques/methods/research platforms to achieve the respective aims. Collectively, the participating investigators provide a multidisciplinary framework of complementary tools and animal models that are essential for unraveling physiologically relevant mechanisms of R3oGE at the molecular and cellular level as well as in murine tumor models. Towards establishing a translational research consortium in the long-term perspective, some participating investigators furthermore initiated pre-clinical studies to explore the therapeutic targeting of well-studied molecular determinants of R3oGE and develop therapeutic concepts to target these. These collaborative efforts will promote research on the therapeutic potential of targeting aberrant R3oGE in cancer, with projected benefits for patients and society as a whole.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Hüttelmaier, Stefan )
• Deciphering RBP networks in high-risk subgroups of pediatric ALL and AML (Applicant Höll, Jessica )
• Deciphering the genetically interactive network of the DLK1-DIO3 ncRNA locus in the hematopoietic system and in infant leukemias (Applicant Klusmann, Jan-Henning Cornelius )
• Deciphering the role of LINC00261 and FOXA2 as transcriptional regulators shaping the expression landscape of pancreatic cancer (Applicant Hämmerle, Ph.D., Monika )
• Development of novel nanoparticle formulations for therapeutic in vivo lncRNA knockdown and circRNA-mediated oncomiR inhibition (Applicant Aigner, Achim )
• Discovery and characterization of EZH2-regulated RBP feed-forward mechanisms controlling cellular transformation (Applicant Heckl, Dirk )
• Targeting oncofetal IGF2BP proteins by small molecule drugs in cancer (Applicants Balbach, Jochen ;  Hüttelmaier, Stefan ;  Sippl, Wolfgang )
• Targeting the non-coding stem cell signature in childhood acute myeloid leukemia (Applicant Klusmann, Jan-Henning Cornelius )
• The role and target potential of IGF2BP1 in ovarian cancer progression and immune evasion (Applicant Bley, Nadine )
• The role and target potential of the RNA-binding protein MEX3A in lung adenocarcinoma (Applicants Hüttelmaier, Stefan ;  Sinz, Andrea )

• Spokesperson: Professor Dr. Stefan Hüttelmaier