Alexandra Beck
A5044738330- Computational Drug Discovery Methods
- Biosimilars and Bioanalytical Methods
- Health Systems, Economic Evaluations, Quality of Life
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Cell Image Analysis Techniques
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Advanced Proteomics Techniques and Applications
- Mathematical Biology Tumor Growth
- Advanced Breast Cancer Therapies
- Gene expression and cancer classification
- Ubiquitin and proteasome pathways
- Zoonotic diseases and public health
- Genetics, Bioinformatics, and Biomedical Research
- Cancer Research and Treatments
- Machine Learning in Bioinformatics
- 3D Printing in Biomedical Research
- Statistical Methods in Clinical Trials
- Viral Infections and Immunology Research
Wellcome Sanger Institute
2018-2024
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,...
The proteome provides unique insights into disease biology beyond the genome and transcriptome. A lack of large proteomic datasets has restricted identification new cancer biomarkers. Here, proteomes 949 cell lines across 28 tissue types are analyzed by mass spectrometry. Deploying a workflow to quantify 8,498 proteins, these data capture evidence cell-type post-transcriptional modifications. Integrating multi-omics, drug response, CRISPR-Cas9 gene essentiality screens with deep...
Transmissible cancers are clonal lineages that spread through populations via contagious cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here we perform comparative genetic and functional characterization of these lineages. The have similar patterns mutation show no evidence exposure to exogenous mutagens or viruses. Genes encoding PDGF receptors copy number gains present on extrachromosomal double minutes. Drug screening indicates causative roles for...
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...
High-throughput testing of drugs across molecular-characterised cell lines can identify candidate treatments and discover biomarkers. However, the cells’ response to a drug is typically quantified by summary statistic from best-fit dose-response curve, whilst neglecting uncertainty curve fit potential variability in raw readouts. Here, we model experimental variance using Gaussian Processes, subsequently, leverage estimates associated biomarkers with new Bayesian framework. Applied vitro...
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)....
Abstract Pairwise perturbation of gene function using the CRISPR/Cas9 system has huge potential in screening for genetic interactions and synthetic lethal pairs to identify novel combination therapies cancer. However, existing dual guide expression systems are cumbersome clone, often result a large proportion undesired have imbalance from two positions. Here, we demonstrate next-generation delivery based around tRNA spacer that allows single step cloning strategy, as little 2% pairs, highly...
Summary The proteome provides unique insights into biology and disease beyond the genome transcriptome. Lack of large proteomic datasets has restricted identification new cancer biomarkers. Here, proteomes 949 cell lines across 28 tissue types were analyzed by mass spectrometry. Deploying a clinically-relevant workflow to quantify 8,498 proteins, these data capture evidence type post-transcriptional modifications. Integrating multi-omics, drug response CRISPR-Cas9 gene essentiality screens...
<p>Supplementary Table 9 shows the top 50 combinations (all cancer types) using different % response scoring thresholds</p>
<p>Combination activity of selumetinib plus venetoclax or AZD5991 in AML. <b>A</b> and <b>B,</b> Combo Emax versus HSA scores 19 AML cell lines exposed to combined with (a) (b) AZD5991. <b>C</b> <b>D,</b> NOMO1 growth inhibition excess the combination (c) (d) <b>E</b> <b>F,</b> Western blot analysis for apoptosis markers cells following time course treatment (300 nmol/L) (e) (f) (100 nmol/L). <b>G,</b>...
<p>Supplementary Table 1 lists cell lines used in this study</p>
<p>Supplementary Table 6 shows combination-cancer type pairs with selective activity</p>
<p>Supplementary Table 13 shows significant biomarkers and emergent biomarkers</p>
<p>Supplementary Table 15 shows biomarkers associated with top 5 enriched pathways for each drug combination category used in this study (CD = cell death, CS signaling)</p>
<p>Supplementary Table 14 shows the top 100 significant emergent biomarkers</p>
<p>Capivasertib (AZD5363) plus AZD5991 combination activity in endometrial cell lines. <b>A,</b> Screening results of combo Emax versus HSA lines treated with AZD5363 AZD5991. Cell high are red. <b>B,</b> Representative growth inhibition and excess matrix plots AN3CA cells. <b>C,</b> Matrix plot measuring apoptosis at indicated doses for 6 hours AN3-CA <b>D,</b> showing viability cells pretreated DMSO or QVD (caspase inhibitor) 16 prior...
<p>AZD2811 plus venetoclax combination in DLBCL. <b>A,</b> Combo Emax versus HSA 25 B-cell NHL cell lines including 11 DLBCL lines. Cell with high activity (combo > 0.5 and 0.1) are red. <b>B,</b> Growth inhibition excess matrices line WSUDLCL2. <b>C,</b> Western blot analysis for cleaved PARP WSUDLCL2 cells treated AZD2811 or alone combination. <b>D,</b> Matrix plots indicating (measured by growth inhibition) pretreated pan caspase...
<p>Supplementary Table 4 shows combination-cancer type pairs with less than 10 percent responder cell lines</p>
<p>Supplementary Table 17 shows large effect size and significant Bliss combo Emax biomarkers for selected top hits</p>
<p>Supplementary Table 1 lists cell lines used in this study</p>
<p>Supplementary Table 12 shows the number of top combinations:cancer type pairs hits in each combination drug category</p>
<p>Supplementary Table 2 lists drugs and drug combinations used</p>
<p>Supplementary Table 7 shows the top combination-cancer type pairs in hematological cancers showing activity at least 10% of tested cell lines that specific cancer ranked based on their (% responders) and disease selectivity</p>