Kübler, Eric
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Kübler, Eric
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Publikation Using GPCRs as molecular beacons to target ovarian cancer with nanomedicines(MDPI, 10.05.2022) Khetan, Riya; Dharmayanti, Cintya; Gillam, Todd A.; Kübler, Eric; Klingler-Hoffmann, Manuela; Ricciardelli, Carmela; Oehler, Martin K.; Blencowe, Anton; Garg, Sanjay; Albrecht, HugoThe five-year survival rate for women with ovarian cancer is very poor despite radical cytoreductive surgery and chemotherapy. Although most patients initially respond to platinum-based chemotherapy, the majority experience recurrence and ultimately develop chemoresistance, resulting in fatal outcomes. The current administration of cytotoxic compounds is hampered by dose-limiting severe adverse effects. There is an unmet clinical need for targeted drug delivery systems that transport chemotherapeutics selectively to tumor cells while minimizing off-target toxicity. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, and many are overexpressed in solid tumors, including ovarian cancer. This review summarizes the progress in engineered nanoparticle research for drug delivery for ovarian cancer and discusses the potential use of GPCRs as molecular entry points to deliver anti-cancer compounds into ovarian cancer cells. A newly emerging treatment paradigm could be the personalized design of nanomedicines on a case-by-case basis.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Development of a unique rapid test to detect anti-bodies directed against an extended RBD of SARS-CoV-2 spike protein(Schweizerische Chemische Gesellschaft, 28.05.2021) Brosi, Larissa; Villiger, Thomas; Bantleon, Frank; Melone, Anna; Überschlag, Marie-Eve; Dolce, Daniele; Giegelmann, Cedric; Gerspach, Michael; Dirscherl, Lorin; Panikulam, Sherin; Romann, Patrick; Weston, Anna; Kübler, Eric; Gerhold, ChristianSerological testing for antibodies directed against SARS-CoV-2 in patients may serve as a diagnostic tool to verify a previous infection and as surrogate for an elicited humoral immune response, ideally conferring immunity after infection or vaccination. Here, we present the recombinant expression of an extended receptor binding domain (RBD) of the SARS-CoV-2 Spike protein used as capture antigen in a unique rapid immunoassay to detect the presence of RBD binding antibodies with high sensitivity and specificity. As currently available vaccines focus on the Spike RBD as target, the developed test can also be used to monitor a successful immune response after vaccination with an RBD based vaccine.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Exosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro(Mary Ann Liebert, 16.09.2020) Messner, Catherine; Premand, Carine; Gaiser, Carine; Kluser, Tanja; Kübler, Eric; Suter-Dick, Laura01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Systematic Meta-Analysis Identifies Co-Expressed Kinases and GPCRs in Ovarian Cancer Tissues Revealing a Potential for Targeted Kinase Inhibitor Delivery(Elsevier, 02.09.2019) Albrecht, Hugo; Kübler, EricThe use of many anticancer drugs is problematic due to severe adverse effects. While the recent clinical launch of several kinase inhibitors led to tremendous progress, these targeted agents tend to be of non-specific nature within the kinase target class. Moreover, target mediated adverse effects limit the exploitation of some very promising kinase targets, including mitotic kinases. A future strategy will be the development of nanocarrier-based systems for the active delivery of kinase inhibitors using cancer specific surface receptors. The G-protein-coupled-receptors (GPCRs) represent the largest cell surface receptor family and some members are known to be frequently overexpressed in various cancer types. In the presented study, we used ovarian cancer tissues as an example to systematically identify concurrently overexpressed GPCRs and kinases. The rationale of this approach will guide the future design of nanoparticles, which will dock to GPCRs on cancer cells via specific ligands and deliver anticancer compounds after receptor mediated internalization. In addition to this, the approach is expected to be most effective by matching the inhibitor profiles of the delivered kinase inhibitors to the observed kinase gene expression profiles. We validated the suggested strategy in a meta-analysis, revealing overexpression of selected GPCRs and kinases in individual samples of a large ovarian cancer data set. The presented data demonstrate a large untapped potential for personalized cancer therapy using high-end targeted nanopharmaceuticals with kinase inhibitors.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Development of a DNA-based Assay to Detect and Quantify Tropane Alkaloids Producing Thornapple Contaminations in Processed Food(Schweizerische Chemische Gesellschaft, 29.05.2019) Weston, Anna; Kübler, Eric01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Large set data mining reveals overexpressed GPCRs in prostate and breast cancer: potential for active targeting with engineered anti-cancer nanomedicines(Impact Journals LLC, 05/2018) Kübler, Eric; Albrecht, HugoOver 800 G-protein-coupled receptors (GPCRs) are encoded by the human genome and many are overexpressed in tumors. GPCRs are triggered by ligand molecules outside the cell and activate internal signal transduction pathways driving cellular responses. The receptor signals are desensitized by receptor internalization and this mechanism can be exploited for the specific delivery of ligand-linked drug molecules directly into cells. Detailed expression analysis in cancer tissue can inform the design of GPCR-ligand decorated drug carriers for active tumor cell targeting. The active targeting process utilizes ligand receptor interactions leading to binding and in most cases internalization of the ligand-attached drug carrier resulting in effective targeting of cancer cells. In this report public microarray data from the Gene Expression Omnibus (GEO) repository was used to identify overexpressed GPCRs in prostate and breast cancer tissues. The analyzed data confirmed previously known cancer receptor associations and identified novel candidates for potential active targeting. Prioritization of the identified targeting receptors is also presented based on high expression levels and frequencies in cancer samples but low expression in healthy tissue. Finally, some selected examples were used in ligand docking studies to assess the feasibility for chemical conjugation to drug nanocarriers without interference of receptor binding and activation. The presented data demonstrate a large untapped potential to improve efficacy and safety of current and future anti-cancer compounds through active targeting of GPCRs on cancer cells.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Yeast‑based assays for screening 11β‑HSD1 inhibitors(Springer, 07.03.2016) Vanella, Rosario; Callari, Roberta; Weston, Anna; Heider, Harald; Schwab, Markus S.; Kübler, EricBACKGROUND: Intracellular metabolism of glucocorticoid hormones plays an important role in the pathogenesis of metabolic syndrome and regulates, among many physiological processes, collagen metabolism in skin. At the peripheral level the concentration of active glucocorticoids is mainly regulated by the 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme, involved in the conversion of cortisone into the biologically active hormone cortisol. Cortisol interacts with the glucocorticoid receptor and regulates the expression of different classes of genes within the nucleus. Due to its implication in glucocorticoid metabolism, the inhibition of 11β-HSD1 activity has become a dominant strategy for the treatment of metabolic syndrome. Moreover, inhibitors of this target enzyme can be used for development of formulations to counteract skin ageing. Here we present the construction of two yeast cell based assays that can be used for the screening of novel 11β-HSD1 inhibitors. RESULTS: The yeast Saccharomyces cerevisiae is used as a host organism for the expression of human 11β-HSD1 as well as a genetically encoded assay system that allows intracellular screening of molecules with 11β-HSD1 inhibitory activity. As proof of concept the correlation between 11β-HSD1 inhibition and fluorescent output signals was successfully tested with increasing concentrations of carbenoxolone and tanshinone IIA, two known 11β-HSD1 inhibitors. The first assay detects a decrease in fluorescence upon 11β-HSD1 inhibition, whereas the second assay relies on stabilization of yEGFP upon inhibition of 11β-HSD1, resulting in a positive read-out and thus minimizing the rate of false positives sometimes associated with read-outs based on loss of signals. Specific inhibition of the ABC transporter Pdr5p improves the sensitivity of the assay strains to cortisone concentrations by up to 60 times. CONCLUSIONS: Our yeast assay strains provide a cost-efficient and easy to handle alternative to other currently available assays for the screening of 11β-HSD1 inhibitors. These assays are designed for an initial fast screening of large numbers of compounds and enable the selection of cell permeable molecules with target inhibitory activity, before proceeding to more advanced selection processes. Moreover, they can be employed in yeast synthetic biology platforms to reconstitute heterologous biosynthetic pathways of drug-relevant scaffolds for simultaneous synthesis and screening of 11β-HSD1 inhibitors at intracellular level.01A - Beitrag in wissenschaftlicher Zeitschrift
