In this project we propose to develop predictive "regulation signatures" which should overcome shortcomings of existing methods of molecular diagnostics. As a proof of concept, in Phase I we will develop regulation signatures for the sensitivity of cancer cell lines to the inhibitors of EGF receptor and will test their accuracy using publicly available datasets. This goal will be accomplished in two stages. First, we will build and optimize focused network model for global Erb family signaling using well-defined training data and knowledge content. In the second step we will test performance of the developed Erb signaling network model on publicly available sets of gene expression profiles from the variety of non-small cell lung carcinoma cell lines with variable drug sensitivity. Analysis will be performed to identify sets of key signaling proteins associated with drug resistance. Using these proteins predictive "regulation signatures" will be developed and their performance will be tested. If successful, the methodology could be replicated for developing predictive models for sensitivity to a broad range of targeted therapies, leading to a number of diagnostic applications such as specialized molecular tests, systems for formulating combination therapies and procedures for selecting patient cohorts for clinical trials.
Public Health Relevance: In this project we will develop novel "regulation signatures" to predict sensitivity to the inhibitors of EGF receptor and identify mechanisms of drug resistance. Project will utilize public gene expression data in combination with knowledge base on protein interactions and our recently developed network analysis algorithm. If successful, the methodology could lead to a number of diagnostic applications.
Public Health Relevance Statement: In this project we will develop novel "regulation signatures" to predict sensitivity to the inhibitors of EGF receptor and identify mechanisms of drug resistance. Project will utilize public gene expression data in combination with knowledge base on protein interactions and our recently developed network analysis algorithm. If successful, the methodology could lead to a number of diagnostic applications.
Project Terms: Algorithms; Biological; Cancer cell line; Carcinoma Cell; Carcinoma, Non-Small-Cell Lung; Cell Communication and Signaling; Cell Line; Cell Lines, Strains; Cell Signaling; CellLine; Cells; Clinical; Clinical Trials; Clinical Trials, Unspecified; Combined Modality Therapy; Data; Data Set; Dataset; Diagnostic; Disease Progression; Drug resistance; Drugs; EGF; EGF gene; EGFR; ERBB Protein; ERBB1; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Evaluation; Expression Profiling; Expression Signature; Family; Gene Expression; Gene Proteins; Goals; HER1; Heterogeneity; Individual; Intracellular Communication and Signaling; Knowledge; Lead; Malignant Epithelial Cell; Medication; Method LOINC Axis 6; Methodology; Methods; Modeling; Molecular; Molecular Diagnostic Methods; Molecular Diagnostic Technics; Molecular Diagnostic Techniques; Molecular Fingerprinting; Molecular Profiling; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; NSCLC; NSCLC - Non-Small Cell Lung Cancer; Network Analysis; Network-based; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Pathway Analysis; Pathway interactions; Patients; Pb element; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Procedures; Process; Protein Gene Products; Proteins; Receptor Protein; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Regulation; Regulatory Protein; Resistance; Sampling; Scoring Method; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Protein; Staging; System; System, LOINC Axis 4; Technology; Testing; Training; Transforming Growth Factor alpha Receptor; URG; Validation; Weight; Work; base; biological signal transduction; c-erbB-1; c-erbB-1 Protein; clinical investigation; cohort; combination therapy; combined modality treatment; combined treatment; computer based prediction; cultured cell line; drug resistant; drug sensitivity; drug/agent; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; gene product; genetic regulatory protein; heavy metal Pb; heavy metal lead; inhibitor; inhibitor/antagonist; knowledge base; molecuar profile; molecular signature; multimodality therapy; network models; nonsmall cell lung cancer; novel; pathway; performance tests; predictive modeling; process optimization; protein expression; proto-oncogene protein c-erbB-1; public health relevance; receptor; regulatory gene product; resistance to Drug; resistant; resistant to Drug; response; success; therapeutic target
