A Patient-Derived, Pan-Cancer EMT Signature Identifies Global Molecular Alterations and Immune Target Enrichment Following Epithelial-to-Mesenchymal Transition.
Clinical Cancer Research 22(3):609 (2016)
We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors fro...
Epidermal growth factor receptor is expressed and active in a subset of acute myeloid leukemia.
Journal of Hematology & Oncology 9(1):64 (2016)
The epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to induce complete remission of acute myeloid leukemia (AML) in two patients with concurrent lung cancer and raised attention for a role of EGFR in AML whereas a recent phase II clinical study with gefitinib in AML de...
Selecting Reliable mRNA Expression Measurements Across Platforms Improves Downstream Analysis.
Cancer Informatics 15:81 (2016)
With increasing use of publicly available gene expression data sets, the quality of the expression data is a critical issue for downstream analysis, gene signature development, and cross-validation of data sets. Thus, identifying reliable expression measurements by leveraging multiple mRNA expre...
Preclinical Evaluation of the Novel BTK Inhibitor Acalabrutinib in Canine Models of B-Cell Non-Hodgkin Lymphoma.
PLoS ONE 11(7):e0159607 (2016)
Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy simi...
MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199.
Cell Reports 13(12):2715 (2015)
Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) transl...
Phosphorylation of GSK3α/β correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients.
BBA clinical 4:59 (2015)
Acute myeloid leukemia (AML) patients with highly active AKT tend to do poorly. Cell cycle arrest and apoptosis are tightly regulated by AKT via phosphorylation of GSK3α and β isoforms which inactivates these kinases. In the current study we examine the prognostic role of AKT mediated GSK3 phosp...
Patterns of CTCF and ZFHX3 Mutation and Associated Outcomes in Endometrial Cancer.
JNCI Journal of the National Cancer Institute 107(11) (2015)
The genetic events responsible for tumor aggressiveness in endometrioid endometrial cancer (EEC) remain poorly understood. The chromosome 16q22 tumor suppressor genes CTCF and ZFHX3 are both frequently mutated in EEC, but their respective roles in outcome have not been determined.
Targeted deep ...
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Cancer Discovery 5(8):860 (2015)
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets o...
Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia.
Cancer Cell 28(1):114 (2015)
Studying mechanisms of malignant transformation of human pre-B cells, we found that acute activation of oncogenes induced immediate cell death in the vast majority of cells. Few surviving pre-B cell clones had acquired permissiveness to oncogenic signaling by strong activation of negative feedba...
drexplorer: A tool to explore dose-response relationships and drug-drug interactions.
Nonlinear dose-response models are primary tools for estimating the potency [e.g. half-maximum inhibitory concentration (IC) known as IC50] of anti-cancer drugs. We present drexplorer software, which enables biologists to evaluate replicate reproducibility, detect outlier data points, fit differ...
Development of a robust classifier for quality control of reverse-phase protein arrays.
High-throughput reverse-phase protein array (RPPA) technology allows for the parallel measurement of protein expression levels in approximately 1000 samples. However, the many steps required in the complex protocol (sample lysate preparation, slide printing, hybridization, washing and amplified ...
Loss of TRIM62 expression is an independent adverse prognostic factor in acute myeloid leukemia.
Clinical Lymphoma Myeloma and Leukemia 15(2):115 (2015)
Tripartite motif (TRIM)-62 is a putative tumor suppressor gene whose role in leukemia is unknown.
We evaluated the effect of TRIM62 protein expression in patients with acute myeloid leukemia (AML). We used reverse-phase protein array methodology to determine TRIM62 levels in leukemia-enriched pr...
The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.
Biochimica et Biophysica Acta 1843(9):1969 (2014)
We recently discovered that the protein phosphatase 2A (PP2A) B55α subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a str...
VEGF/VEGFR-2 upregulates EZH2 expression in lung adenocarcinoma cells and EZH2 depletion enhances the response to platinum-based and VEGFR-2-targeted therapy.
Clinical Cancer Research 20(14):3849 (2014)
To investigate the mechanisms of regulation and role associated with enhancer of zeste homolog 2 (EZH2) expression in lung cancer cells.
We investigated the mechanisms of EZH2 expression associated with the VEGF/VEGFR-2 pathway. Furthermore, we sought to determine the role of EZH2 in response of...
Transcriptomic architecture of the adjacent airway field cancerization in non-small cell lung cancer.
JNCI Journal of the National Cancer Institute 106(3):dju004 (2014)
Earlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC).
Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents.
JNCI Journal of the National Cancer Institute 106(2):djt440 (2014)
Acute myeloid leukemia (AML) therapy has limited long-term efficacy because patients frequently develop disease relapse because of the inability of standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we identify deregulated apoptotic components in AML stem/progenitor cell...
Latent Feature Decompositions for Integrative Analysis of Multi-Platform Genomic Data.
Computational Biology and Bioinformatics, IEEE/... 11(6):984 (2014)
Increased availability of multi-platform genomics data on matched samples has sparked research efforts to discover how diverse molecular features interact both within and between platforms. In addition, simultaneous measurements of genetic and epigenetic characteristics illuminate the roles thei...
Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition.
BMC Genomics 15:1079 (2014)
DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer.
We integrated the gene expressio...
targetHub: a programmable interface for miRNA-gene interactions.
With the expansion of high-throughput technologies, understanding different kinds of genome-level data is a common task. MicroRNA (miRNA) is increasingly profiled using high-throughput technologies (microarrays or next-generation sequencing). The downstream analysis of miRNA targets can be diffi...
Independent validation of a model using cell line chemosensitivity to predict response to therapy.
JNCI Journal of the National Cancer Institute 105(17):1284 (2013)
Methods using cell line microarray and drug sensitivity data to predict patients' chemotherapy response are appealing, but groups may be reluctant to release details to preserve intellectual property. Here we describe a case study to validate predictions while treating the methods as a "black bo...