In vitro screening methodologies.

Current projects include the operation of the NCI three-cell line prescreen and the 60-cell line primary cancer screen. Presently, various cell based and cell free high-throughput molecular target-based assays are under development. We have initiated three cell-based high-throughput screening paradigms. Utilizing a cell line engineered to express a HIF-1 promoter with a luciferase reporter gene, we have developed a 384-well plate high-throughput assay to identify inhibitors of HIF-1 induction. Similarly, testing a transfected cell line inducible for the expression of CEBPalpha, we are screening compounds for their induction potential. We have developed a high-throughput 384-well plate assay to screen for inhibitors of the Met receptor kinase-hepatocyte growth factor/scatter factor signaling system. DTP's publicly available set (~2000 compounds) of chemically diverse compounds ("diversity set") have been screened in all three of these assays and screening data will soon be available on the DTP Web page. Additional molecular target based screens including cell-free assays based on fluorescence polarization are under development. These efforts include screening modalities designed to find inhibitors of DNA binding by transcription factors, protein-protein binding, and protein kinase activity. Our laboratory processes the 60 human tumor cell lines of the primary screen for the production of RNA, DNA, frozen cell pellets, and cryopreserved cells for the use of collaborators involved in the molecular target characterization of the cell line panel. In addition, we utilize flow cytometric methodologies to measure potential cell cycle effects induced by compounds of interest to the Cancer Biological Evaluation Committee.

Credentials

Dr. Scudiero received a B.A. in Biology from St. Mary's University, Winona, MN and a M.S. and Ph.D. in Radiation Biophysics from the University of Kansas at the Nuclear Reactor Center, Lawrence, KS. He was awarded a United States Public Health Service Genetics Postdoctoral Fellowship and spent four years at the University of Chicago, Department of Microbiology in the Laboratory of Dr. Bernard S. Strauss. He came to the National Institutes of Health as a Senior Staff Fellow in the Laboratory of Molecular Carcinogenesis where he extended his studies of mammalian DNA repair mechanisms. He continued this research as Head of the DNA Repair Group at the National Cancer Institute-Frederick (NCI-Frederick) with studies of human genetic diseases with a high predisposition to cancer. He is currently head of the National Cancer Institute's Developmental Therapeutics Program In Vitro Cancer Drug Screening at the NCI-Frederick.

Recent Publications

NCBI PubMed listing of publications by Dominic Scudiero.

Rapisarda A, Uranchimeg B, Scudiero DA, Selby M, Sausville EA, Shoemaker RH, Melillo G. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 2002 Aug 1;62(15):4316-24.

Xu Z, Chen ZP, Malapetsa A, Alaoui-Jamali M, Bergeron J, Monks A, Myers TG, Mohr G, Sausville EA, Scudiero DA, Aloyz R, Panasci LC. DNA repair protein levels vis-a-vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program. Anticancer Drugs. 2002 Jun;13(5):511-9.

Shoemaker, R., Scudiero, D., Melillo, G., Currens, M., Monks, A., Rabow, A., Covell, D., Sausville, E. Application of high-throughput, molecular-targeted screening to anticancer drug discovery. Curr. Top. Med. Chem. 2: 229-246, 2002

Meinhold-Heerlein, I., Stenner-Liewen F., Liewen, H., Kitada, S., Krajewska, M., Krajewski, S., Zapata, J., Monks, A., Scudiero, D., Bauknecht, T., Reed, J. Expression and potential role of Ras-associated phosphatase-1 in ovarian cancer. Am. J. Pathol. 158: 1335-1344, 2001.

Yu, L., Matias, J., Scudiero, D., Hite, K., Monks, A., Sausville, E., Wasman, D. P450 enzyme expression patterns in the NCI human tumor cell line panel. Drug Metab. Dispos. 29: 304-312, 2001.

Tamm, I., Kornblau, S., Segall, H., Krajewski, S., Welsh, K., Kitada, S., Scudiero, D., Tudor, G., Qui, Y., Monks, A., Andreeff, M., Reed, J. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin. Cancer Res. 6: 1796-1803, 2000.

Amundson, S., Myers, T., Scudiero, D., Kitada, S., Reed, J., Fornace, A. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60: 6101-6110, 2000.

Scherf, U., Ross, D., Waltham, M., Smith, L., Lee, J., Tanabe, L., Kohn, K., Reinhold, W., Myers, T., Andrews, D., Scudiero, D., Eisen, M., Sausville, E., Pommier, Y., Botstein, D., Brown, P., Weinstein, J. A gene expression database for the molecular pharmacology of cancer. Nature Genetics 24: 236-243, 2000.

Tamm, I., Wang, Y., Sausville, E., Scudiero, D.A., Vigna, N., Oltersdorf, T., Reed, J.C. IAP-family protein survivin inhibits caspase activity and apoptosis induced by FAS (CD95), Bax, caspases, and anticancer drugs. Cancer Res 58(23): 5315-20, 1998.

Scudiero, D.A., Monks, A., Sausville, E.A. Cell line designation change: multidrug-resistant cell line in the NCI anticancer screen. J Natl Cancer Inst 90(11): 862, 1998.

Monks, A., Scudiero, D.A., Johnson, G.S., Paull, K.D., Sausville, E.A. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des 12(7): 533-41 1997.

Review. O'Connor, P.K., Jackman, J., Bae, I., Myers, T.G., Fan, S., Mutoh, M., Scudiero, D.A., Monks, A., Sausville, E.A., Weinstein, J.N., Friend, S., Fornance, A.J. Jr., Kohn, K.W. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57(19): 4285-4300, 1997.

Myers, T.G., Anderson, N.L., Waltham, N.M., Li, G., Buolamwini, M., Scudiero, D.A., Paull, K.D., Sausville, E.A., Weinstein, J.N. A protein expression database for the molecular pharmacology of cancer. Electrophoresis 18(3-4): 647-653, 1997.