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HIF-1α. Studies of endothelial cells have defined an HIF-1α–dependent autocrine signaling loop important for angiogenesis. The hope is that by increasing understanding of the role of HIF-1α in tumor and normal cells and identifying and characterizing novel inhibitors, targeted therapy can be optimized. Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNAbinding activity. Cancer Res 2005;65:9047–55. Calvani M, Rapisarda A, Uranchimeg B, Shoemaker RH, Melillo G. Hypoxic induction of an HIF-1α-dependent bFGF autocrine loop drives angiogenesis in human endothelial cells. Blood 2006;107:2705–12. Natural Products–Based Drug Discovery Progress has been made in coupling cell-based, molecular-targeted highthroughput screens and crude natural product extracts for anticancer drug discovery. Screening campaigns of the DTP Natural Products Repository of some 70,000 extracts were carried out using three distinct molecular-targeted screens: the HIF-1α, CEBPα, and IkB kinase (IKK) signaling pathways. HIF-1α is a key regulator of hypoxic cell signaling. CEBPα is a regulator of differentiation of myeloid and other cell types. The IKK signaling pathway is of particular importance in the pathogenesis of diffuse, large B-cell lymphomas. High-throughput screening data were analyzed to identify active extracts to prioritize potential compounds for bioassay-directed isolation of active constituents. Selected extracts were then fractionated by high-pressure liquid chromatography in conjunction with spectroscopic monitoring to generate samples for testing in the molecular- targeted screen of interest. It has been possible to track activity through successive chemical separation steps and isolate chemical entities responsible for the activity. Camptothecin derivatives were isolated from a plant never before reported to produce such compounds. D E V E L O P M E N T A L T H E R A P E U T I C S P R O G R A M ■ 117
This included a camptothecin derivative never before found in nature. Structure elucidation work is in progress for compounds isolated from all three screens. Two novel antifungal compound series were reported in 2005. These represented the conclusion of work under a CRADA with SAIC for antimicrobial drug discovery. DTP Screening Technologies Branch (STB) investigators developed a novel fermentation process to produce the antitumor lead pleurotin and supported a large-scale plant recollection effort to isolate novel tropane alkaloids. Meragelman TL, Tucker KD, McCloud TG, Cardellina JH 2nd, Shoemaker RH. Antifungal flavonoids from Hildegardia barteri. J Nat Prod 2005;68:1790–2. Klausmeyer P, McCloud TG, Tucker KD, Cardellina JH 2nd, Shoemaker RH. Aspirochlorine class compounds from Aspergillus flavus inhibit azole-resistant Candida albicans. J Nat Prod 2005;68:1300–2. Chin YW, Jones WP, Waybright TJ, McCloud TG, Rasoanaivo P, Cragg GM, Cassady JM, Kinghorn AD. Tropane aromatic ester alkaloids from a large-scale re-collection of Erythroxylum pervillei stem bark obtained in Madagascar. J Nat Prod 2006;69:414–7. Shipley SM, Barr AL, Graf SJ, Collins RP, McCloud TG, Newman DJ. Development of a process for the production of the anticancer lead compound pleurotin by fermentation of Hohenbuehelia atrocaerulea. J Ind Microbiol Biotechnol 2006;33:463–8. 118 ■ P R O G R A M A C C O M P L I S H M E N T S 2 0 0 6 Development of Novel High- Throughput Screening Technology for Identification of Inhibitors of Transcription Factor-DNA Binding STB investigators worked with Dr. Charles Vinson, CCR Laboratory of Metabolism, to develop, optimize, and characterize a screen for four of the B-Zip family of transcription factors that are known to have oncogenic effects. A high-throughput screen of the NCI diversity set identified a single chemotype effective in disrupting B-Zip–DNA interactions. Further work is in progress to define the activity of this chemotype in cell-based reporters for B-Zip activity and to evaluate additional leads identified in high-throughput screening of chemical libraries. STB investigators have generalized this technology to develop a screen for inhibitors of ASPL- TFE3 chimeric transcription factor-DNA interaction. This chimeric transcription factor results from a chromosomal translocation characteristic of alveolar soft-part sarcoma. In sarcoma and in other pediatric tumors, such as alveolar rhabdomyosarcoma, the chromosomal translocation and associated chimeric transcription factor present a potentially exploitable therapeutic target. Rishi V, Potter T, Laudeman J, Reinhart R, Silvers T, Selby M, Stevenson T, Krosky P, Stephen AG, Acharya A, Moll J, Oh WJ, Scudiero D, Shoemaker RH, Vinson C. A high-throughput fluorescenceanisotropy screen that identifies small molecule inhibitors of the DNA binding of B-ZIP transcription factors. Anal Biochem 2005;340:259–71.
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National Cancer Institute U.S. DEPA
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ii ■ P R O G R A M A C C O M P L
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Clinical trials performed using an
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Dr. James H. Doroshow, Director Jam
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Cancer Diagnosis Program Dr. Sheila
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DCTD Research Grants 6 ■ P R O G
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disease-specific steering committee
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■ The DCTD Developmental Therapeu
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P A R T N E R S H I P S A N D C O L
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laboratories. Dr. Kevin Dobbin, BRB
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Simon R. DNA microarrays for diagno
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Microarray Myths and Truths Myths
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target, is sensitive to the agent.
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NCI Visuals Online, Terese Winslow,
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Association of American Cancer Inst
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Food and Drug Administration and Ce
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Dr. Edward A. Neuwelt, Oregon Healt
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