Kinomic Profiling of Electromagnetic Navigational Bronchoscopy Specimens: A New Approach for Personalized Medicine

Anderson, Joshua C.; Minnich, Douglas J.; Dobelbower, M.C.; Denton, Alexander J.; Dussaq, Alex M.; Gilbert, Ashley; Rohrbach, Timothy D.; Arafat, Waleed; Welaya, Karim; Bonner, James A.; Willey, Christopher D.

doi:10.1371/journal.pone.0116388

Cited by 16 publications

(10 citation statements)

References 27 publications

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“…This large percentage of poor-signal samples is potentially due in part to extended collection time at >4C, quality of tissues collected (i.e. connective tissue/fibrosis/necrosis or other relatively kinase-inert material), or inadequate storage or transport conditions based on our previous experience with primary tumor tissues, although we did not investigate this further (Anderson, Minnich, et al, 2014). Kinase activity can be very sensitive to time and temperature variations during collection, especially prior to snap freezing of tissue.…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, signal over multiple exposure times was linearly integrated and the slope was Log2 transformed as described previously for heatmap displays (Anderson, Minnich, et al, 2014). Unsupervised hierarchical Euclidean distance metrics and complete linkage clustering of peptide signal across all, or a variance filtered subset, of the 144 substrates for the 13 samples was done using a Clustering PamApp in BioNavigator.…”

Section: Methodsmentioning

confidence: 99%

“…We, and others, have used kinomic activity profiling to identify alterations in kinase activity in tumor and other pathologic tissue, including directly-from-patient derived tissue (Anderson, Duarte, et al, 2014; Anderson, Minnich, et al, 2014; Duverger et al, 2013; Sikkema et al, 2009). Herein, we describe the kinomic signaling diversity of atypical meningiomas treated at our institution and the kinomics seen specifically in recurrent tumors.…”

Section: Introductionmentioning

confidence: 99%

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Kinomic Alterations in Atypical Meningioma

Anderson

Taylor

Fiveash

et al. 2015

MRAJ

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Background We sought to profile Atypical Meningioma in a high-throughput manner to better understand the altered signaling within these tumors and specifically the kinases altered in recurrent atypical meningioma. Kinomic Profiles could be used to identify prognostic biomarkers for responders/non-responders to classify future patients that are unlikely to benefit from current therapies. Directly these results could be used to identify drug-actionable kinase targets as well. Methods Peptide-substrate microarray kinase activity analysis was conducted with a PamStation®12 analyzing the tyrosine kinome in each tumor kinetically against ~144 target peptides. These data were then analyzed relative to clinical outcome (e.g., tumor recurrence). Results 3 major clusters of atypical meningiomas were identified with highly variant peptides primarily being targets of EGFR family, ABL, BRK and BMX kinases. Kinomic analysis of recurrent atypical meningiomas indicated patterns of increased phosphorylation of BMX, TYRO3 and FAK substrates as compared to non-recurrent tumors. Conclusion The atypical meningiomas profiled here exhibited molecular sub-clustering that may have phenotypic corollaries predictive of outcome. Recurrent tumors had increases in kinase activity that may predict resistance to current therapies, and may guide selection of directed therapies. Taken together these data further the understanding of kinomic alteration in atypical meningioma, and the processes that may not only mediate recurrence, but additionally may identify kinase targets for intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kinomic Alterations in Atypical Meningioma

Anderson

Taylor

Fiveash

et al. 2015

MRAJ

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“…Our results show that kinomic profiling data are a promising approach in lung cancer as well, that may potentially provide therapeutic drug response information prior to lung cancer patient therapy. Recently, Anderson et al [ 37 ] developed an interesting approach based on electromagnetic navigational bronchoscopy (ENB) [ 38 ] derived lung tumour specimens and kinomic data for “biologically-interrogated’’ ENB specimens using small molecule inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo multiplex profiling of protein tyrosine kinase activities in early stages of human lung adenocarcinoma

Arni

Wijn

et al. 2017

Oncotarget

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Despite constant improvement in existing therapeutic efforts, the overall survival rate of lung cancer patients remains low. Enzyme activities may identify new therapeutically targetable biomarkers and overcome the marked lack of correlation between cellular abundance of translated proteins and corresponding mRNA expression levels. We analysed tyrosine kinase activities to classify lung adenocarcinoma (LuAdCa) resection specimens based on their underlying changes in cellular processes and pathways that are agents of or result from malignant transformation. We characterised 71 same-patient pairs of early-stage LuAdCa and non-neoplastic LuAdCa resection specimen lysates in the presence or absence of a tyrosine kinase inhibitor. We performed ex vivo multiplex tyrosine phosphorylation assays using 144 selected microarrayed kinase substrates. The obtained 76 selected phosphotyrosine signature peptides were subsequently analysed in terms of follow-up treatments and outcomes recorded in the patient files. For tumour, node, metastasis (TNM) stage 1 LuAdCa patients, we noticed a larger tyrosine kinase inhibitor-induced decrease in tyrosine phosphorylation for long-term as opposed to short-term disease survivors, for which 26 of 76 selected peptides were significantly (p < 0.01, FDR < 3%) more inhibited in the long-term survivors. Using statistical class prediction analysis, we obtained a 'prognostic-signature' for long- versus short-term disease survivors and correctly predicted the survival status of 73% of our patients. Our translational approach may assist clinical disease management after surgical resection and may help to direct patients for an optimal treatment strategy.

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“…While the PamChip system lacks the quantity of phosphorylatable peptide targets found on some complementary 2D kinome microarrays, it does provide unique data in the form of kinetic phosphorylation measurements during the multiplexed in vitro kinase assay. Unfortunately, the majority of published PamChip studies do not report kinetic data, but instead, describe only the end level data (e.g., end of reaction data points) albeit with upstream kinase prediction analyses[ 11 , 12 , 14 ]. We believe the underutilization of the kinetic data is due to its relative complexity[ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Kinomics toolbox—A web platform for analysis and viewing of kinomic peptide array data

et al. 2018

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Kinomics is an emerging field of science that involves the study of global kinase activity. As kinases are essential players in virtually all cellular activities, kinomic testing can directly examine protein function, distinguishing kinomics from more remote, upstream components of the central dogma, such as genomics and transcriptomics. While there exist several different approaches for kinomic research, peptide microarrays are the most widely used and involve kinase activity assessment through measurement of phosphorylation of peptide substrates on the array. Unfortunately, bioinformatic tools for analyzing kinomic data are quite limited necessitating the development of accessible open access software in order to facilitate standardization and dissemination of kinomic data for scientific use. Here, we examine and present tools for data analysis for the popular PamChip® (PamGene International) kinomic peptide microarray. As a result, we propose (1) a procedural optimization of kinetic curve data capture, (2) new methods for background normalization, (3) guidelines for the detection of outliers during parameterization, and (4) a standardized data model to store array data at various analytical points. In order to utilize the new data model, we developed a series of tools to implement the new methods and to visualize the various data models. In the interest of accessibility, we developed this new toolbox as a series of JavaScript procedures that can be utilized as either server side resources (easily packaged as web services) or as client side scripts (web applications running in the browser). The aggregation of these tools within a Kinomics Toolbox provides an extensible web based analytic platform that researchers can engage directly and web programmers can extend. As a proof of concept, we developed three analytical tools, a technical reproducibility visualizer, an ANOVA based detector of differentially phosphorylated peptides, and a heatmap display with hierarchical clustering.

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Kinomic Profiling of Electromagnetic Navigational Bronchoscopy Specimens: A New Approach for Personalized Medicine

Cited by 16 publications

References 27 publications

Kinomic Alterations in Atypical Meningioma

Kinomic Alterations in Atypical Meningioma

Ex vivo multiplex profiling of protein tyrosine kinase activities in early stages of human lung adenocarcinoma

Kinomics toolbox—A web platform for analysis and viewing of kinomic peptide array data

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