Person: Kung, Andrew
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Kung
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Andrew
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Kung, Andrew
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Publication Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy(Springer Science and Business Media LLC, 2017-11-03) Church, Alanna; Calicchio, Monica; Nardi, Valentina; Skálová, Alena; Pinto, Andre; Dillon, Deborah; Gomez-Fernandez, Carmen; Manoj, Namitha; Haimes, Josh; Stahl, Joshua; Dela Cruz, Filemon; Tannenbaum-Dvir, Sarah; Glade-Bender, Julia; Kung, Andrew; DuBois, Steven; Kozakewich, Harry; Janeway, Katherine; Perez-Atayde, Antonio; Harris, MarianPublication High-Level IGF1R Expression is Required for Leukemia-Initiating Cell Activity in T-ALL and is Supported by Notch Signaling(Rockefeller University Press, 2011) Medyouf, Hind; Gusscott, Samuel; Wai, Carol; Nemirovsky, Oksana; Trumpp, Andreas; Pflumio, Francoise; Carboni, Joan; Gottardis, Marco; Pollak, Michael; Holzenberger, Martin; Weng, Andrew P.; Wang, Hongfang; Tseng, Jen-Chieh; Kung, Andrew; Aster, JonT cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K–Akt pathways. Although mutations that activate PI3K–Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. These findings suggest effects of Notch on LIC activity may be mediated in part by enhancing the responsiveness of T-ALL cells to ambient growth factors, and provide strong rationale for use of IGF1R inhibitors to improve initial response to therapy and to achieve long-term cure of patients with T-ALL.Publication Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing Sarcoma(Public Library of Science, 2007) Stegmaier, Kimberly; Wong, Jenny S; Ross, Kenneth N; Chow, Kwan T; Peck, David; Wright, Renee D; Lessnick, Stephen L; Kung, Andrew; Golub, ToddBackground: The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. Methods and Findings: A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. Conclusions: We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers.Publication Preferential Binding of HIF-1 to Transcriptionally Active Loci Determines Cell-type Specific Response to Hypoxia(BioMed Central, 2009) Xia, Xiaobo; Kung, AndrewBackground: Hypoxia-inducible factor 1 (HIF-1) plays a key role in cellular adaptation to hypoxia. To better understand the determinants of HIF-1 binding and transactivation, we used ChIP-chip and gene expression profiling to define the relationship between the epigenetic landscape, sites of HIF-1 binding, and genes transactivated by hypoxia in two cell lines. Results: We found that when cells were acutely subjected to hypoxia, HIF-1 preferentially bound to loci that were already transcriptionally active under normal growth conditions characterized by the presence of histone H3 lysine 4 methylation, the presence of RNA polymerase II, and basal production of mRNA. Cell type-specific differences in HIF-1 binding were largely attributable to differences in the basal gene expression patterns in the cells prior to the onset of hypoxia. Conclusions: These results suggest that the repertoire of genes active in a cell (for example, through lineage specific transcription factors) defines the subset of genes that are permissive for binding and transactivation by stimulus-responsive transcription factors.