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2007 CompTox Forum

Abstract - Integrative Pharm-Tox and the NCI-60: Genomics, Proteomics, and Bioinformatics

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John Weinstein, M.D., Ph.D.
National Cancer Institute, National Institutes of Health
Laboratory of Molecular Pharmacology, Center for Cancer Research
Genomics & Bioinformatics Group
Building 37, Room 5068
9000 Rockville Pike, Bethesda, MD 20892
Phone: 301-496-9571
E-mail: weinstein@dtpax2.ncifcrf.gov

In November 2006, we and our collaborators launched the "Spotlight on Molecular Profiling" series in the journal Molecular Cancer Therapeutics. The series highlights integrative pharmacomic and toxicomic profiling studies, focused initially on the NCI-60 cell line panel. The NCI-60 panel, used by the National Cancer Institute (NCI) Developmental Therapeutics Program to screen more than 100,000 compounds and natural products for anticancer activity, is the most comprehensively characterized set of cells anywhere. Our molecular profilings completed or in progress have included transcript expression using cDNA arrays, Affymetrix arrays (HU6800, U95, and U133), spotted oligo arrays, and real-time RT-PCR; microRNA expression by oligo array; protein expression by 2-D gels and reverse-phase lysate microarrays; BAC, Agilent, and NimbleGen array CGH; spectral karyotyping; DNA methylation by bisulfite sequencing and HELP assay; mutations by resequencing and Affymetrix SNP chip. The overall profiling enterprise can be considered as a forerunner to The Cancer Genome Atlas project – with more diverse molecular characterizations but in the easier context of cultured cells. The various types of molecular information are presented in CellMiner (http://discover.nci.nih.gov/cellminer (Shankavaram, in preparation)), a user-friendly relational database of molecular data and metadata on the NCI-60. Proofs of principle for 'integromic' analysis in the contexts of pharmacology and toxicology include: (i) identification of candidate biomarkers for differential diagnosis of ovarian and colon metastases; (ii) analyses that led to clinical development of oxaliplatin, now standard-of-care for colon cancer; (iii) discovery of "MDR1-inverse" compounds, which, paradoxically, are more potent in cells that express MDR1; (iv) development of the "Permissive Apoptosis-Resistance" model for acquired resistance to cancer drugs and xenobiotic toxicants; and, (v) identification of asparagine synthetase as a potential 'causal' biomarker for treatment of ovarian cancer with L-asparaginase. We thank our many other collaborators in the overall enterprise. http://discover.nci.nih.gov.

References

  1. Weinstein, Spotlight on molecular profiling: 'integromic' analysis of the NCI-60 cancer cell lines. Mol. Cancer Ther. 2006; 5: 2601.
  2. Lorenzi, et al., ibid 2006; 5: 2613.
  3. Ikediobi, et al., ibid 2006; 5: 2606.
  4. Ludwig and Weinstein, Nature Rev. Cancer 2005; 5: 845.

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