The section Molecular Cell Biology (Prof. Hüttelmaier) characterizes RNA-guided mechanisms controlling gene expression in cancer. These studies center on RNA-binding proteins (RBPs) as well as non-coding RNAs, such as microRNAs. The main goals of this research are to identify, evaluate and progress (1) new biomarkers for tumor diagnostics, (2) therapeutic targets, as well as (3) therapeutic concepts for targeted cancer therapy based on small molecule drugs and circular RNAs.
The human IGF2 mRNA binding protein (IGF2BPs) family comprises three members, IGF2BP1-3. IGF2BP1 und 3 are bona fide oncofetal proteins. They are highly abundant in embryogenesis, barely observed in adult tissues, but severely upregulated or even de novo synthesized in several cancers. In various tumor models, IGF2BP1/3 promote tumor growth and metastasis by regulating mRNA turnover and translation. Our recent work unravels the huge potential of IGF2BP1 and 3 in cancer diagnosis, especially aggressive cancer subtypes, and their suitability as targets for cancer therapy. In current studies, we further characterize the molecular basis of IGF2BP function in cancer. These studies aim to set the stage and support ongoing efforts to develop IGF2BP-centered targeted therapies based on small molecule drugs as well as PROTACs (proteolysis targeting chimeras). Main cancers this research focuses on comprise lung cancer, neuroblastoma, ovarian cancer, pancreatic cancer, and anaplastic thyroid cancer.
MicroRNAs (miRNAs) control the vast majority of mRNAs by promoting their decay and impairing translation. In tumors a variety of oncomiRs have been identified. Their main role is to interfere with the expression of tumor suppressors. In tumor models, we recently have demonstrated that such oncomiRs can be inhibited by circular RNA decoys (ciRs). Application of ciRs formulated in polymeric nanoparticles are effectively transported in cancer cells where they reprogram gene expression – of major interest is the reactivation of tumor suppressor synthesis. This is associated with severely reduced tumor growth in animal tumor models. Current projects aim to identify oncomiRs druggable by ciRs and to improve the efficiency and applicability of ciR-based therapies in cancer treatment. Main cancers this research focuses on comprise lung carcinomas, neuroblastoma, ovarian cancer, pancreatic cancer, and anaplastic thyroid carcinoma.
Identification and characterization of oncoRBPs
The characterization of IGF2 mRNA binding proteins (IGF2BPs) in cancer unraveled the huge diagnostic and therapeutic potential of RBPs in cancer therapy. RBPs promoting cancer initiation and/or progression, like IGF2BPs, are termed oncoRBPs. In current projects, we aim to identify additional oncoRBPs in solid cancers and evaluate their suitability as diagnostic markers and therapeutic targets in cancer treatment. Next to IGF2BPs, these studies currently focus on the MEX3 und MSI RBP families and the following cancers: lung carcinomas, neuroblastoma, ovarian cancer, pancreatic cancer, and anaplastic thyroid carcinoma.
Therapeutic inhibition of oncoRBPs by covalent inhibitors
The inhibition of oncoRBPs remains challenging due to the common lack of catalytic activity and high conservation of RNA-binding domains. To overcome these limitations, we develop an innovative and efficient approach based on developing RBP-inhibitors utilizing covalent protein modification. Preliminary studies already led to a covalent IGF2BP1 inhibitor, termed J5 (EU-Patent application, EP20159945) and initiated the development of covalent PROTACs (proteolysis targeting chimera).
Therapeutic inhibition of oncoRBPs by reversible inhibitors
Next to covalent inhibitors, we established interdisciplinary research efforts aiming to develop reversible inhibitors of oncoRBPs, mainly IGF2BPs. In current studies the therapeutic potential of such inhibitors (lead compounds) was validated in experimental animal tumor models. Current projects aim to improve the potency, efficacy and specificity of these lead compounds. Next to the direct inhibition of protein function, we also evaluate PROTACs (proteolysis targeting chimera) to induce degradation of target oncoRBPs.
OncoRBP-Inhibitors in combined therapies
Oncofetal RBPs (oncoRBPs) regulate various cancer hallmark pathways. In recent analyses, we could demonstrate that oncoRBPs not only promote tumor cell proliferation and impair apoptosis, but also promote tumor cell immune evasion (Dr. Bley). In current studies, we characterize the molecular mechanisms underlying these regulatory roles. These efforts set the stage to explore the synergy of oncoRBPs inhibition with other targeted cancer therapies, including PD-L1/PD1 immunotherapies.
The RNA-binding protein RAVER1 was described by Hüttelmaier et al. in 2001. RAVER1 associates with the splicing regulator PTB in membrane-free (liquid droplet-like) perinucleolar compartments (PNC) and influences alternative splicing. In cancer models, RAVER1 serves pro-oncogenic roles involving the regulation of interferon-, NFKB-, and potentially TP53-signaling. In studies funded within the framework of the RTG2467, the role of RAVER1 in cancer and its regulation via intrinsically disordered regions (IDRs), mediating association with PTB, is investigated.
RNA-binding proteins (RBPs) are key modulators of tumor cell fate and influence inflammatory signaling. Studies funded within the framework of the RTG2751 , aim to characterize the role of RBPs in early, inflammation-driven carcinogenesis of pancreatic cancer as well as immune evasion mechanisms.