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Denise A Chan,
Patrick D Sutphin,
Phuong Nguyen,
Sandra Turcotte,
Edwin W Lai,
Alice Banh,
Gloria E Reynolds,
Jen-Tsan Chi,
Jason Wu, David E Solow-Cordero,
Muriel Bonnet,
Jack U Flanagan,
Donna M Bouley,
Edward E Graves,
William A Denny,
Michael P Hay,
Amato J Giaccia
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ABSTRACT: Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [(18)F]fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.
Science translational medicine 08/2011; 3(94):94ra70. · 7.80 Impact Factor
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Ioanna Papandreou,
Nicholas C Denko,
Michael Olson,
Heleen Van Melckebeke,
Sofie Lust,
Arvin Tam, David E Solow-Cordero,
Donna M Bouley,
Fritz Offner,
Maho Niwa,
Albert C Koong
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ABSTRACT: Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.
Blood 11/2010; 117(4):1311-4. · 9.90 Impact Factor
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Joel M Hyman,
Ari J Firestone,
Vivi M Heine,
Yun Zhao,
Cory A Ocasio,
Kyuho Han,
Mark Sun,
Paul G Rack,
Surajit Sinha,
Jason J Wu, David E Solow-Cordero,
Jin Jiang,
David H Rowitch,
James K Chen
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ABSTRACT: Inappropriate activation of the Hedgehog (Hh) signaling pathway has been implicated in a diverse spectrum of cancers, and its pharmacological blockade has emerged as an anti-tumor strategy. While nearly all known Hh pathway antagonists target the transmembrane protein Smoothened (Smo), small molecules that suppress downstream effectors could more comprehensively remediate Hh pathway-dependent tumors. We report here four Hh pathway antagonists that are epistatic to the nucleocytoplasmic regulator Suppressor of Fused [Su(fu)], including two that can inhibit Hh target gene expression induced by overexpression of the Gli transcription factors. Each inhibitor has a unique mechanism of action, and their phenotypes reveal that Gli processing, Gli activation, and primary cilia formation are pharmacologically targetable. We further establish the ability of certain compounds to block the proliferation of cerebellar granule neuron precursors expressing an oncogenic form of Smo, and we demonstrate that Hh pathway inhibitors can have tissue-specific activities. These antagonists therefore constitute a valuable set of chemical tools for interrogating downstream Hh signaling mechanisms and for developing chemotherapies against Hh pathway-related cancers.
Proceedings of the National Academy of Sciences 09/2009; 106(33):14132-7. · 9.68 Impact Factor
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Renee D Paulsen,
Deena V Soni,
Roy Wollman,
Angela T Hahn,
Muh-Ching Yee,
Anna Guan,
Jayne A Hesley,
Steven C Miller,
Evan F Cromwell, David E Solow-Cordero,
Tobias Meyer,
Karlene A Cimprich
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ABSTRACT: Signaling pathways that respond to DNA damage are essential for the maintenance of genome stability and are linked to many diseases, including cancer. Here, a genome-wide siRNA screen was employed to identify additional genes involved in genome stabilization by monitoring phosphorylation of the histone variant H2AX, an early mark of DNA damage. We identified hundreds of genes whose downregulation led to elevated levels of H2AX phosphorylation (gammaH2AX) and revealed links to cellular complexes and to genes with unclassified functions. We demonstrate a widespread role for mRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrant RNA-DNA structures. Furthermore, we connect increased gammaH2AX levels to the neurological disorder Charcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damage response. These data indicate that preservation of genome stability is mediated by a larger network of biological processes than previously appreciated.
Molecular cell 08/2009; 35(2):228-39. · 14.61 Impact Factor
