Publications by authors named "Anna Ringler"

11 Publications

  • Page 1 of 1

5-Arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones with selective inhibitory activity against some leukemia cell lines.

Arch Pharm (Weinheim) 2021 Apr 25;354(4):e2000342. Epub 2020 Nov 25.

Department of Pharmaceutical, Organic, and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine.

The data on the pharmacology of 4-thiazolidinones showed that 5-ene-2-(imino)amino-4-thiazolidinones are likely to comprise one of the most promising groups of compounds possessing anticancer properties. A series of 5-arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones was designed, synthesized, and studied against 10 leukemia cell lines, including the HL-60, Jurkat, K-562, Dami, KBM-7, and some Ba/F3 cell lines. The structure-activity relationship analysis shows that almost all tested 5-arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones were characterized by ІС values lower or comparable to that of the control drug chlorambucil. Among the tested compounds, (5Z)-5-(2-methoxybenzylidene)- (12), (5Z)-(2-ethoxybenzylidene)- (21), (5Z)-5-(2-benzyloxybenzylidene)- (25), and (5Z)-5-(2-allyloxybenzylidene)-2-(4-hydroxyphenylamino)thiazol-4(5H)-ones (28) possessed the highest antileukemic activity at submicromolar concentrations (ІС  = 0.10-0.95 µM).
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http://dx.doi.org/10.1002/ardp.202000342DOI Listing
April 2021

Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human cancers.

Nat Genet 2019 09 19;51(9):1399-1410. Epub 2019 Aug 19.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Aberrations in genes coding for subunits of the BRG1/BRM associated factor (BAF) chromatin remodeling complexes are highly abundant in human cancers. Currently, it is not understood how these mostly loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer-type-specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knockout cell lines deficient for 22 BAF subunits. We observe strong, specific and sometimes discordant alterations dependent on the targeted subunit and show that these explain intracomplex codependencies, including the synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest approaches to therapeutically target BAF-mutant cancers.
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http://dx.doi.org/10.1038/s41588-019-0477-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952272PMC
September 2019

MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.

Nat Genet 2019 06 27;51(6):990-998. Epub 2019 May 27.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression; pharmacological inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin associated suggests a direct role for nuclear metabolism in the control of gene expression.
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http://dx.doi.org/10.1038/s41588-019-0413-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952269PMC
June 2019

Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.

Nat Chem Biol 2019 03 28;15(3):232-240. Epub 2019 Jan 28.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
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http://dx.doi.org/10.1038/s41589-018-0205-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746620PMC
March 2019

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Cancer Cell 2019 01;35(1):125-139.e9

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Electronic address:

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.ccell.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335503PMC
January 2019

CDK6 Antagonizes p53-Induced Responses during Tumorigenesis.

Cancer Discov 2018 07 13;8(7):884-897. Epub 2018 Jun 13.

Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.

Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages, the CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate (encoding p53) to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53 antagonists , and The findings are relevant to human patients: Tumors with low levels of CDK6 have mutations in significantly more often than expected. CDK6 acts at the interface of p53 and RB by driving cell-cycle progression and antagonizing stress responses. While sensitizing cells to p53-induced cell death, specific inhibition of CDK6 kinase activity may provoke the outgrowth of p53-mutant clones from premalignant cells. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031305PMC
July 2018

Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study.

Lancet Haematol 2017 Dec 15;4(12):e595-e606. Epub 2017 Nov 15.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.

Background: Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited.

Methods: We investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821.

Findings: Pharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88·1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24·38 [95% CI 3·99-125·4], p=0·0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1·3 or higher, and median progression-free survival increased by four times, from 5·7 (95% CI 4·1-12·1) weeks to 22·6 (7·4-34·0) weeks (hazard ratio 3·14 [95% CI 1·37-7·22], p=0·0075).

Interpretation: Routine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation.

Funding: Austrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation.
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http://dx.doi.org/10.1016/S2352-3026(17)30208-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719985PMC
December 2017

Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH.

Mol Cell 2017 Nov;68(4):797-807.e7

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria. Electronic address:

DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death.
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http://dx.doi.org/10.1016/j.molcel.2017.10.021DOI Listing
November 2017

A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor.

Nat Chem Biol 2017 Jul 22;13(7):771-778. Epub 2017 May 22.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for γ-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.
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http://dx.doi.org/10.1038/nchembio.2382DOI Listing
July 2017

Global survey of the immunomodulatory potential of common drugs.

Nat Chem Biol 2017 06 24;13(6):681-690. Epub 2017 Apr 24.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Small-molecule drugs may complement antibody-based therapies in an immune-oncology setting, yet systematic methods for the identification and characterization of the immunomodulatory properties of these entities are lacking. We surveyed the immumomodulatory potential of 1,402 small chemical molecules, as defined by their ability to alter the cell-cell interactions among peripheral mononuclear leukocytes ex vivo, using automated microscopy and population-wide single-cell image analysis. Unexpectedly, ∼10% of the agents tested affected these cell-cell interactions differentially. The results accurately recapitulated known immunomodulatory drug classes and revealed several clinically approved drugs that unexpectedly harbor the ability to modulate the immune system, which could potentially contribute to their physiological mechanism of action. For instance, the kinase inhibitor crizotinib promoted T cell interactions with monocytes, as well as with cancer cells, through inhibition of the receptor tyrosine kinase MSTR1 and subsequent upregulation of the expression of major histocompatibility complex molecules. The approach offers an attractive platform for the personalized identification and characterization of immunomodulatory therapeutics.
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http://dx.doi.org/10.1038/nchembio.2360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438060PMC
June 2017

TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML.

Oncotarget 2017 Apr;8(14):23061-23072

Department of Laboratory Medicine, Medical University of Vienna, Austria.

In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.
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http://dx.doi.org/10.18632/oncotarget.15481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410285PMC
April 2017
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