A5054337449- Computational Drug Discovery Methods
- Melanoma and MAPK Pathways
- Cytokine Signaling Pathways and Interactions
- Mathematical Biology Tumor Growth
- Biosimilars and Bioanalytical Methods
- PI3K/AKT/mTOR signaling in cancer
- Synthesis and biological activity
- Health Systems, Economic Evaluations, Quality of Life
- Cancer Mechanisms and Therapy
- Chronic Myeloid Leukemia Treatments
- Cancer Genomics and Diagnostics
- Sarcoma Diagnosis and Treatment
- Bioinformatics and Genomic Networks
- Radiomics and Machine Learning in Medical Imaging
- CRISPR and Genetic Engineering
- Colorectal Cancer Treatments and Studies
- Chronic Lymphocytic Leukemia Research
- Gene Regulatory Network Analysis
- Advanced Breast Cancer Therapies
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Cell Image Analysis Techniques
- Cancer-related Molecular Pathways
- Protease and Inhibitor Mechanisms
- Single-cell and spatial transcriptomics
Wellcome Sanger Institute
2017-2024
Novartis (Switzerland)
2024
University Children's Hospital Zurich
2014-2019
University Medical Center Hamburg-Eppendorf
2015
Universität Hamburg
2015
Abstract Combinations of anti-cancer drugs can overcome resistance and provide new treatments 1,2 . The number possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active the tissues molecular contexts in which they are most effective accelerate development combination treatments. Here we evaluate potency efficacy 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast,...
Abstract CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary adequately represent heterogeneity human cancers and assemble comprehensive map genetic vulnerabilities. Here, we integrated two largest public independent date (at Broad Sanger institutes) by assessing, comparing, selecting methods...
Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity 127 TFs through analysis RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey total 1,056 lines and 9,250 primary tumors. Predicted TF activities are supported their agreement independent shRNA essentiality...
The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available pharmacologic agents bind into lipid pocket TEAD, targeting indirectly via allosteric changes. However, consequences a direct pharmacological disruption interface between and TEADs remain largely unexplored. Here, we present IAG933 its analogs as potent first-in-class selective disruptors with suitable properties to enter clinical trials. Pharmacologic abrogation all...
Abstract Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible is vast be context-specific. Systematic screens identify clinically relevant, actionable in defined patient subtypes. We present data 109 anticancer from AstraZeneca's oncology small molecule portfolio screened 755 pan-cancer cell lines. Combinations were a 7 × concentration matrix, with more than 4 million measurements sensitivity, producing an...
Abstract Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects its role as a biomarker in cancer is missing, comprehensive analysis the clinical significance SLFN11 predictive DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies mechanistic studies...
Current treatment regimens for rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer, rely on conventional chemotherapy, and although they show clinical benefit, there is a significant risk of adverse side effects secondary tumors later in life. Therefore, identifying targeting sub-populations with higher tumorigenic potential self-renewing capacity would offer improved patient management strategies. Hedgehog signaling has been linked to development embryonal RMS (ERMS)...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
Abstract Drug combinations can expand therapeutic options and address cancer’s resistance. However, the combinatorial space is enormous precluding its systematic exploration. Therefore, synergy prediction strategies are essential. We here present an approach to prioritise drug in high-throughput screens stratify synergistic responses. At core of our observation that likelihood increases when targeting proteins with either strong functional similarity or dissimilarity. estimate applying a...
Corrigendum16 June 2020Open Access Patient-specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies Federica Eduati orcid.org/0000-0002-7822-3867 Search for more papers by this author Patricia Jaaks Jessica Wappler Thorsten Cramer orcid.org/0000-0002-6462-239X Christoph A Merten Mathew J Garnett orcid.org/0000-0002-2618-4237 Julio Saez-Rodriguez orcid.org/0000-0002-8552-8976 Author Information Eduati, Jaaks, Wappler,...
Abstract The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of are poorly understood at a genome-wide level. Parallel CRISPR screens 3 PTEN-null cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). dominant mechanism causing reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion...
Abstract Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads expression of chimeric oncoprotein EWS-FLI1 which uniquely expressed in all cells maintains their survival. Constant protein turnover regulated by ubiquitin proteasome system. Here, we now identified specific protease 19 (USP19) as a regulator stability using siRNA based screening approach....
Combining drugs can enhance their clinical efficacy, but the number of possible combinations and inter-tumor heterogeneity make identifying effective challenging, while existing approaches often overlook clinically relevant activity. We screen one largest cell line panels (N = 757) with 51 identify responses at level individual lines tissue populations. establish three response classes to model cellular effects beyond monotherapy: synergy, Bliss additivity, independent drug action (IDA)....
The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and frequently dysregulated human cancers, primarily by mutations BRAF or RAS genes. clinical benefit of inhibitors this as single agents has only been realized BRAF-mutant melanoma, with limited effect single-agent KRAS-mutant tumors. Combined inhibition multiple nodes within pathway, such MEK1/2 ERK1/2, may be necessary to effectively suppress tumors achieve meaningful benefit. Here, we report...
The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates and furin-like PCs play a role proliferation, metastasis invasion. Some them are involved progression pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, particular furin, expressed RMS cell lines. To investigate functional generated lines with modulated activity. Silencing or stable inhibition delayed tumor...
Our goal was to improve vincristine (VCR) based rhabdomyosarcoma (RMS) therapy by encapsulating the drug into liposomes. A targeting strategy attempted enhance tumor accumulation.VCR loaded in control and peptide-decorated liposomes via an active method. The interaction of RMS-specific peptide with presumed target furin cellular uptake both liposomal groups were studied vitro. Pharmacokinetics biodistribution VCR-containing assessed RMS xenograft mouse model.Liposomes ensured high VCR...
Inositol‐1,4,5‐trisphosphate‐3‐kinase‐A (ITPKA) has been considered as an actin bundling protein because its N‐terminal binding domain (ABD) induces formation of linear bundles. Since in many cancer cell lines ITPKA is essential for lamellipodia, which consist cross‐linked filaments, here we analyzed if full length‐ITPKA may induce more complex structures. Indeed, found that incubation F‐actin with resulted dense, branched networks. Based on our result does not exhibit additional C‐terminal...
Abstract Low success rates during drug development are due in part to the difficulty of defining mechanism-of-action and molecular markers therapeutic activity. Here, we integrated 199,219 sensitivity measurements for 397 unique anti-cancer drugs genome-wide CRISPR loss-of-function screens 484 cell lines systematically investigate cellular mechanism-of-action. We observed an enrichment positive associations between knockout their nominal targets, by leveraging protein-protein networks...
// Patricia Jaaks 1 , Gianmarco Meier Nagjie Alijaj Eva Brack Peter Bode 2 Ewa Koscielniak 3 Marco Wachtel Beat W. Schäfer Michele Bernasconi Department of Oncology and Children's Research Center, University Hospital Zurich, Switzerland Surgical Pathology, Oncology/Hematology/Immunology, Olgahospital, Klinikum Stuttgart, Germany Correspondence to: Bernasconi, email: michele.bernasconi@kispi.uzh.ch Keywords: furin, proprotein convertases, rhabdomyosarcoma, apoptosis, IGF1R Received: February...
Abstract Transcriptional dysregulation is a key feature of cancer. Transcription factors (TFs) are the main link between signalling pathways and transcriptional regulatory machinery cell, positioning them as oncogenic inductors therefore potential targets therapeutic intervention. We implemented computational pipeline to infer TF activities from basal gene expression applied it publicly available newly generated RNA-seq data collection 1,010 cancer cell lines 9,250 primary tumors. show that...
Abstract CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary adequately represent heterogeneity human cancers and assemble comprehensive map genetic vulnerabilities. Here, we integrated two largest public independent date (at Broad Sanger institutes) by assessing, comparing, selecting methods...