A5018837401- Advanced Breast Cancer Therapies
- Computational Drug Discovery Methods
- Gene Regulatory Network Analysis
- PI3K/AKT/mTOR signaling in cancer
- Bioinformatics and Genomic Networks
- HER2/EGFR in Cancer Research
- Cancer-related Molecular Pathways
- Gene expression and cancer classification
- Cell Image Analysis Techniques
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Single-cell and spatial transcriptomics
- Cancer Genomics and Diagnostics
- Estrogen and related hormone effects
- Monoclonal and Polyclonal Antibodies Research
- Advanced Biosensing Techniques and Applications
- Pharmacogenetics and Drug Metabolism
- Advanced Fluorescence Microscopy Techniques
- Epigenetics and DNA Methylation
- Chronic Myeloid Leukemia Treatments
- Cancer therapeutics and mechanisms
- RNA modifications and cancer
- Microbial Metabolic Engineering and Bioproduction
- Genomics and Chromatin Dynamics
- Advanced Proteomics Techniques and Applications
Harvard University
2015-2025
Center for Systems Biology
2015-2025
Genentech
2025
Bioinformatics Institute
2022
Ideaya Biosciences (United States)
2019
University of California, San Francisco
2019
Boston University
2013
École Polytechnique Fédérale de Lausanne
2009-2012
SIB Swiss Institute of Bioinformatics
2009-2012
University of Zurich
2009-2012
For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using L1000 technology have been produced. The is a cost-effective method to profile in large scale. LINCS Canvas Browser (LCB) an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating currently available data. LCB implements two compacted layered canvases, one visualize clustered data, other display enrichment analysis results 30...
The library of integrated network-based cellular signatures (LINCS) L1000 data set currently comprises over a million gene expression profiles chemically perturbed human cell lines. Through unique several intrinsic and extrinsic benchmarking schemes, we demonstrate that processing the with characteristic direction (CD) method significantly improves signal to noise compared MODZ used compute signatures. CD processed are served through state-of-the-art web-based search engine application...
Abstract The Hippo pathway is a key growth control that conserved across species. downstream effectors of the pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation survival. Based on premise sustained interactions between YAP/TAZ TEADs enhanced associate domain) central their transcriptional activities, we discovered potent small-molecule inhibitor (SMI), GNE-7883, allosterically blocks...
Abstract When cells are exposed to death ligands such as TRAIL , a fraction undergoes apoptosis and survives; if surviving re‐exposed fractional killing is once again observed. Therapeutic antibodies directed against receptors also cause killing, even at saturating concentrations, limiting their effectiveness. Fractional arises from cell‐to‐cell fluctuations in protein levels (extrinsic noise), but how this results clean bifurcation between life remains unclear. In paper, we identify...
Highlights•Implementing FAIR data standards requires identification of experimental confounders•Five labs performed the same experiment on mammalian cells and compared results•Several factors affecting reproducibility were explored•Biological context had an unexpected impact robustness cell-based assaysSummaryEvidence that some high-impact biomedical results cannot be repeated has stimulated interest in practices generate findable, accessible, interoperable, reusable (FAIR) data. Multiple...
Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality morbidity, but there is no high throughput in vitro method predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated rendering them desirable use such systems. To identify a reliable biomarker nephrotoxicity, we conducted multiplexed gene expression profiling HPTECs after exposure six different...
Quantifying the response of cell lines to drugs or other perturbagens is cornerstone pre-clinical drug development and pharmacogenomics as well a means study factors that contribute sensitivity resistance. In dividing cells, traditional metrics derived from dose-response curves such IC
More effective use of targeted anti-cancer drugs depends on elucidating the connection between molecular states induced by drug treatment and cellular phenotypes controlled these states, such as cytostasis death. This is particularly true when mutation a single gene inadequate predictor response. The current paper describes data set ~600 cell line pairs collected part NIH LINCS Program ( http://www.lincsproject.org/ ) in which (reduced dimensionality transcript L1000 profiles) were recorded...
As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical precision oncology. Using real-world data (RWD) profiling from 5910 metastatic HR+/HER2- BC, we investigated evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 more often altered tumors exposed at...
Identifying factors responsible for variation in drug response is essential the effective use of targeted therapeutics. We profiled signaling pathway activity a collection breast cancer cell lines before and after stimulation with physiologically relevant ligands, which revealed variability network among cells known genotype molecular subtype. Despite receptor-based classification subtypes, we found that abundance proteins unstimulated (basal profile), as well stimulated (signaling varied...
A biological system's robustness to mutations and its evolution are influenced by the structure of viable space, region space biochemical parameters where it can exert function. In systems with a large number parameters, regions potentially complex geometries fill tiny fraction whole parameter space. This hampers explorations based on "brute force" or Gaussian sampling. We here propose novel algorithm characterize spaces efficiently. The combines global local exploration involves an...
Libraries of well-annotated small molecules have many uses in chemical genetics, drug discovery, and therapeutic repurposing. Multiple libraries are available, but few data-driven approaches exist to compare them design new libraries. We describe an approach scoring creating based on binding selectivity, target coverage, induced cellular phenotypes as well structure, stage clinical development, user preference. The approach, available via the online tool http://www.smallmoleculesuite.org,...
Abstract PIK3CA is one of the most frequently mutated oncogenes; p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting PI3K catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and manageable safety profile patients PIK3CA-mutant breast cancer. However, preclinical shown that pathway inhibition releases negative feedback activates receptor tyrosine kinase signaling, reengaging...
To characterize the behavior and robustness of cellular circuits with many unknown parameters is a major challenge for systems biology. Its difficulty rises exponentially number circuit components. We here propose novel analysis method to meet this challenge. Our identifies region high-dimensional parameter space where displays an experimentally observed behavior. It does so via Monte Carlo approach guided by principal component analysis, in order allow efficient sampling space. This...
In mammals, the suprachiasmatic nucleus (SCN) of hypothalamus constitutes central circadian pacemaker. The SCN receives light signals from retina and controls peripheral clocks (located in cortex, pineal gland, liver, kidney, heart, etc.). This hierarchical organization system ensures proper timing physiological processes. each neuron, interconnected transcriptional translational feedback loops enable expression clock genes. Although all neurons have same genotype, oscillations individual...
Abstract Traditional means for scoring the effects of anti-cancer drugs on growth and survival cell lines is based relative number in drug-treated control samples seriously confounded by unequal division rates arising from natural biological variation differences culture conditions. This problem can be overcome computing drug sensitivity a per-division basis. The normalized rate inhibition (GR) approach yields metrics potency ( GR 50 ) efficacy max that are analogous to more familiar IC E...
Abstract Measuring the potencies of small‐molecule drugs in cell lines is a critical aspect preclinical pharmacology. Such experiments are also prototypical high‐throughput multi‐well plates. The procedure simple principle, but many unrecognized factors can affect results, potentially making data unreliable. procedures for measuring drug response described here were developed by NIH LINCS program to improve reproducibility. Key features include maximizing uniform growth during assay period,...
Abstract High-throughput measurement of cells perturbed using libraries small molecules, gene knockouts, or different microenvironmental factors is a key step in functional genomics and pre-clinical drug discovery. However, it remains difficult to perform accurate single-cell assays 384-well plates, limiting many studies well-average measurements (e.g., CellTiter-Glo®). Here we describe public domain Dye Drop method that uses sequential density displacement microscopy multi-step on living...