An information-intensive approach to the molecular pharmacology of cancer

Science

Volumn 275, Issue 5298, 1997, Pages 343-349

  Weinstein, John N ^a   Myers, Timothy G ^a   O'Connor, Patrick M ^a   Friend, Stephen H ^a   Fornace Jr , Albert J ^a   Kohn, Kurt W ^a   Fojo, Tito ^a   Bates, Susan E ^a   Rubinstein, Lawrence V ^a   Anderson, N Leigh ^a   Buolamwini, John K ^a   Van Osdol, William W ^a   Monks, Anne P ^a   Scudiero, Dominic A ^a   Sausville, Edward A ^a   Zaharevitz, Daniel W ^a   Bunow, Barry ^a   Viswanadhan, Vellarkad N ^a   Johnson, George S ^a   Wittes, Robert E ^a   Paull, Kenneth D ^a   more..

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AZACITIDINE; BRUCEANTIN; BUSULFAN; CARBOPLATIN; CHLORAMBUCIL; CHLORMETHINE; CHLOROZOTOCIN; CISPLATIN; CYTARABINE; DAUNORUBICIN; DIAZIQUONE; DOXORUBICIN; FLUDARABINE; FLUOROURACIL; HYDROXYUREA; MELPHALAN; METHOTREXATE; MITOMYCIN C; MITOXANTRONE; PHENYLHYDRAZONE DERIVATIVE; PIPERAZINEDIONE; PLATINUM DERIVATIVE; TAXANE DERIVATIVE; TETRAPLATIN; THIOSEMICARBAZONE DERIVATIVE; THIOTEPA; TIOGUANINE; TRIMETREXATE; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER CHEMOTHERAPY; CANCER RESEARCH; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CYTOTOXICITY; DATA BASE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; INFORMATION SYSTEM; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; STRUCTURE ACTIVITY RELATION;

ALGORITHMS; ANTINEOPLASTIC AGENTS; CLUSTER ANALYSIS; COMPUTATIONAL BIOLOGY; COMPUTER COMMUNICATION NETWORKS; DATABASES, FACTUAL; DRUG SCREENING ASSAYS, ANTITUMOR; GENES, P53; HUMANS; MOLECULAR STRUCTURE; MUTATION; SOFTWARE; TUMOR CELLS, CULTURED; TUMOR SUPPRESSOR PROTEIN P53;

EID: 0031035181     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.275.5298.343     Document Type: Article

References (64)

1. M. R. Boyd, Princ. Pract. Oncol. Update 3, 1 (1989); A. Monks et al., J. Natl. Cancer Inst. 83, 757 (1991); M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol. 19, 622 (1992); S. F. Stinson et al., Anticancer Res. 12, 1035 (1992); M. R. Boyd, in Current Therapy in Oncology, J. E. Neiderhuber, Ed. (Mosby, St. Louis, MO, 1992), pp. 11-22.
2. M. R. Boyd, Princ. Pract. Oncol. Update 3, 1 (1989); A. Monks et al., J. Natl. Cancer Inst. 83, 757 (1991); M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol. 19, 622 (1992); S. F. Stinson et al., Anticancer Res. 12, 1035 (1992); M. R. Boyd, in Current Therapy in Oncology, J. E. Neiderhuber, Ed. (Mosby, St. Louis, MO, 1992), pp. 11-22.
3. M. R. Boyd, Princ. Pract. Oncol. Update 3, 1 (1989); A. Monks et al., J. Natl. Cancer Inst. 83, 757 (1991); M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol. 19, 622 (1992); S. F. Stinson et al., Anticancer Res. 12, 1035 (1992); M. R. Boyd, in Current Therapy in Oncology, J. E. Neiderhuber, Ed. (Mosby, St. Louis, MO, 1992), pp. 11-22.
4. M. R. Boyd, Princ. Pract. Oncol. Update 3, 1 (1989); A. Monks et al., J. Natl. Cancer Inst. 83, 757 (1991); M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol. 19, 622 (1992); S. F. Stinson et al., Anticancer Res. 12, 1035 (1992); M. R. Boyd, in Current Therapy in Oncology, J. E. Neiderhuber, Ed. (Mosby, St. Louis, MO, 1992), pp. 11-22.
5. M. R. Boyd, Princ. Pract. Oncol. Update 3, 1 (1989); A. Monks et al., J. Natl. Cancer Inst. 83, 757 (1991); M. R. Grever, S. A. Schepartz, B. A. Chabner, Semin. Oncol. 19, 622 (1992); S. F. Stinson et al., Anticancer Res. 12, 1035 (1992); M. R. Boyd, in Current Therapy in Oncology, J. E. Neiderhuber, Ed. (Mosby, St. Louis, MO, 1992), pp. 11-22.
6. K. D. Paull et al., J. Natl. Cancer Inst. 81, 1088 (1989); H. N. Jayaram, Biochem. Biophys. Res. Commun. 186, 1600 (1992); K. D. Paull, E. Hamel, L. Malspeis, in Cancer Chemotherapeutic Agents, W. E. Foye, Ed. (American Chemical Society, Washington, DC, 1993), pp. 1574-1581; M. R. Boyd and K. D. Paull, Drug Dev. Res. 34, 91 (1995).
7. K. D. Paull et al., J. Natl. Cancer Inst. 81, 1088 (1989); H. N. Jayaram, Biochem. Biophys. Res. Commun. 186, 1600 (1992); K. D. Paull, E. Hamel, L. Malspeis, in Cancer Chemotherapeutic Agents, W. E. Foye, Ed. (American Chemical Society, Washington, DC, 1993), pp. 1574-1581; M. R. Boyd and K. D. Paull, Drug Dev. Res. 34, 91 (1995).
8. K. D. Paull et al., J. Natl. Cancer Inst. 81, 1088 (1989); H. N. Jayaram, Biochem. Biophys. Res. Commun. 186, 1600 (1992); K. D. Paull, E. Hamel, L. Malspeis, in Cancer Chemotherapeutic Agents, W. E. Foye, Ed. (American Chemical Society, Washington, DC, 1993), pp. 1574-1581; M. R. Boyd and K. D. Paull, Drug Dev. Res. 34, 91 (1995).
9. K. D. Paull et al., J. Natl. Cancer Inst. 81, 1088 (1989); H. N. Jayaram, Biochem. Biophys. Res. Commun. 186, 1600 (1992); K. D. Paull, E. Hamel, L. Malspeis, in Cancer Chemotherapeutic Agents, W. E. Foye, Ed. (American Chemical Society, Washington, DC, 1993), pp. 1574-1581; M. R. Boyd and K. D. Paull, Drug Dev. Res. 34, 91 (1995).
10. M. Gupta et al., Mol. Pharmacol. 48, 658 (1995); E. Solary et al., Biochem. Pharmacol. 45, 2449 (1993); F. Leteurtre, G. Kohlhagen, K. D. Paull, Y. Pommier, J. Natl. Cancer Inst. 86, 1239 (1994); F. Leteurtre et al., Biochem. Pharmacol. 49, 1283 (1995).
11. M. Gupta et al., Mol. Pharmacol. 48, 658 (1995); E. Solary et al., Biochem. Pharmacol. 45, 2449 (1993); F. Leteurtre, G. Kohlhagen, K. D. Paull, Y. Pommier, J. Natl. Cancer Inst. 86, 1239 (1994); F. Leteurtre et al., Biochem. Pharmacol. 49, 1283 (1995).
12. M. Gupta et al., Mol. Pharmacol. 48, 658 (1995); E. Solary et al., Biochem. Pharmacol. 45, 2449 (1993); F. Leteurtre, G. Kohlhagen, K. D. Paull, Y. Pommier, J. Natl. Cancer Inst. 86, 1239 (1994); F. Leteurtre et al., Biochem. Pharmacol. 49, 1283 (1995).
13. M. Gupta et al., Mol. Pharmacol. 48, 658 (1995); E. Solary et al., Biochem. Pharmacol. 45, 2449 (1993); F. Leteurtre, G. Kohlhagen, K. D. Paull, Y. Pommier, J. Natl. Cancer Inst. 86, 1239 (1994); F. Leteurtre et al., Biochem. Pharmacol. 49, 1283 (1995).
14. E. S. Cleveland et al., Biochem. Pharmacol. 49, 947 (1995).
15. R. Bai et al., J. Biol. Chem. 266, 15882 (1991); K. D. Paull, C. M. Lin, L. Malspeis, E. Hamel, Cancer Res. 52, 3892 (1992); S. C. Kuo et al., J. Med. Chem. 36, 1146 (1993); E. Hamel, C. M. Lin, H. K. Wang, K. H. Lee, K. D. Paull, Biochem. Pharmacol. 3, 53 (1996).
16. R. Bai et al., J. Biol. Chem. 266, 15882 (1991); K. D. Paull, C. M. Lin, L. Malspeis, E. Hamel, Cancer Res. 52, 3892 (1992); S. C. Kuo et al., J. Med. Chem. 36, 1146 (1993); E. Hamel, C. M. Lin, H. K. Wang, K. H. Lee, K. D. Paull, Biochem. Pharmacol. 3, 53 (1996).
17. R. Bai et al., J. Biol. Chem. 266, 15882 (1991); K. D. Paull, C. M. Lin, L. Malspeis, E. Hamel, Cancer Res. 52, 3892 (1992); S. C. Kuo et al., J. Med. Chem. 36, 1146 (1993); E. Hamel, C. M. Lin, H. K. Wang, K. H. Lee, K. D. Paull, Biochem. Pharmacol. 3, 53 (1996).
18. R. Bai et al., J. Biol. Chem. 266, 15882 (1991); K. D. Paull, C. M. Lin, L. Malspeis, E. Hamel, Cancer Res. 52, 3892 (1992); S. C. Kuo et al., J. Med. Chem. 36, 1146 (1993); E. Hamel, C. M. Lin, H. K. Wang, K. H. Lee, K. D. Paull, Biochem. Pharmacol. 3, 53 (1996).
19. J. N. Weinstein et al., Science 258, 447 (1992).
20. J. N. Weinstein et al., Stem Cells 12, 13 (1994); B. A. Chabner, J. N. Weinstein, K. D. Paull, M. R. Grever, in Cancer Treatment, an Update, P. Banzet, J. F. Holland, D. Khayat, M. Weil, Eds. (Springer-Verlag, Paris, 1994), pp. 10-16; A. D. Koutsoukos et al., Stat. Med. 13, 719 (1994); S. E. Bates et al., J. Cancer Res. Clin. Oncol. 121, 495 (1995).
21. J. N. Weinstein et al., Stem Cells 12, 13 (1994); B. A. Chabner, J. N. Weinstein, K. D. Paull, M. R. Grever, in Cancer Treatment, an Update, P. Banzet, J. F. Holland, D. Khayat, M. Weil, Eds. (Springer-Verlag, Paris, 1994), pp. 10-16; A. D. Koutsoukos et al., Stat. Med. 13, 719 (1994); S. E. Bates et al., J. Cancer Res. Clin. Oncol. 121, 495 (1995).
22. J. N. Weinstein et al., Stem Cells 12, 13 (1994); B. A. Chabner, J. N. Weinstein, K. D. Paull, M. R. Grever, in Cancer Treatment, an Update, P. Banzet, J. F. Holland, D. Khayat, M. Weil, Eds. (Springer-Verlag, Paris, 1994), pp. 10-16; A. D. Koutsoukos et al., Stat. Med. 13, 719 (1994); S. E. Bates et al., J. Cancer Res. Clin. Oncol. 121, 495 (1995).
23. J. N. Weinstein et al., Stem Cells 12, 13 (1994); B. A. Chabner, J. N. Weinstein, K. D. Paull, M. R. Grever, in Cancer Treatment, an Update, P. Banzet, J. F. Holland, D. Khayat, M. Weil, Eds. (Springer-Verlag, Paris, 1994), pp. 10-16; A. D. Koutsoukos et al., Stat. Med. 13, 719 (1994); S. E. Bates et al., J. Cancer Res. Clin. Oncol. 121, 495 (1995).
24. W. W. van Osdol, T. G. Myers, K. D. Paull, K. W. Kohn, J. N. Weinstein, J. Natl. Cancer Inst. 86, 1853 (1994). A Kohonen neural network was used to generate self-organized 2D maps in which the distances among compounds reflected the differences in their patterns of activity.
25. NSC numbers 638850, 607097, 630176, 650426, and 649890, respectively. These compounds were selected for development in part because their patterns of activity in the screen were unlike those of any agent already in the clinic.
26. Database resources currently available on the World Wide Web include the following. (i) http:// epnws1.ncifcrf.gov:2345/dis3d/cancer_screen/ stdmech.html: mechanism of action assignments and chemical structures for a set of 122 standard agents based on (6) and (8). Clicking on a mechanism of action displays a list of the relevant compounds. (ii) ftp://helix.nih.gov/ncidata/canscr/std-agnt.tar.Z: activity patterns for standard agents based on (6) and (8). (iii) http://epnws1.ncifcrf.gov: 2345/dis3d/itb/stdagnt.html: searching by chemical name or NSC number in a set of 175 standard agents. (iv) http://epnws1.ncifcrf.gov:2345/dis3d/ cancer_screen/nsc4.html: retrieval by NSC number of "mean graph" representations (2) of activity patterns and COMPARE lists for approximately 20,000 nonconfidential compounds. (v) http:// epnws1.ncifcrf.gov:2345/dis3d/cancer_screen/ cmpmatrix.html: generation of an A·A′ matrix (non-clustered) for any choice of nonconfidential compounds. (vi) http://epnws1.ncifcrf.gov:2345/dis3d/ itb/pubtarget.html: published molecular target measurements, along with the ability to use the measurements as seeds in COMPARE searches of the activity databases for synthetic compounds and for natural product extracts.
27. G. W. A. Milne, M. C. Nicklaus, J. S. Driscoll, S. Wang, D. W. Zaharevitz, J. Chem. Inf. Comput. Sci. 34, 1219 (1994) and World Wide Web page by D. W. Zaharevitz (http://epnws1.ncifcrf.gov:2345/dis3d/ 3Ddatabase/dis3d.html).
28. See, for example, S. Wang et al., J. Med. Chem. 37, 4479 (1994).
29. CiP1/Waf1, Mdm2, H-Ras, K-Ras, N-Ras, Raf, Src, Nm23, Pgp/Mdr-1, Mdr-2, Rb, Mrp, Lrp, telomerase, telomere length, alkylguanine transferase, metallothionein, phosphoinositol 3-kinase, thioredoxin, aldehyde dehydrogenase, epidermal growth factor receptor, transforming growth factor-α, c-ErbB2, fibroblast growth factor receptor, vascular endothelial growth factor receptor, human growth factor receptor, transforming growth factor-β receptor type II, Bcl-2, Bax, Bcl-X, DNA methylation, DT diaphorase, p450 reductase, b5 reductase, thymidylate synthetase, mismatch repair defects, topoisomerase II, galectin, p15, p16, and glutathione transferase isoenzymes.
30. J. K. Buolamwini et al., in preparation; T. G. Myers, et al., Electrophoresis, in press. The 2D-PAGE approach can identify correlations with drug activity for cellular proteins not previously recognized to be functionally important (for example, p53, whose significance was not known until long after the molecule was discovered in 1979). Proteins identified to date on ISO-DALT gels (Large Scale Biology, Rockville, MD) for our database include Hsp60, Hsc70, Hsp90, Grp75, Grp78, protein disulfide isomerase, lamin B, β-actin, γ-actin, β-tubulin, three cytokeratins, two myosin light chains, tropomyosin, proliferating cell nuclear antigen, β-F1ATPase, calmodulin, endoplasmin, and calreticulin.
31. J. K. Buolamwini et al., in preparation; T. G. Myers, et al., Electrophoresis, in press. The 2D-PAGE approach can identify correlations with drug activity for cellular proteins not previously recognized to be functionally important (for example, p53, whose significance was not known until long after the molecule was discovered in 1979). Proteins identified to date on ISO-DALT gels (Large Scale Biology, Rockville, MD) for our database include Hsp60, Hsc70, Hsp90, Grp75, Grp78, protein disulfide isomerase, lamin B, β-actin, γ-actin, β-tubulin, three cytokeratins, two myosin light chains, tropomyosin, proliferating cell nuclear antigen, β-F1ATPase, calmodulin, endoplasmin, and calreticulin.
32. M. R. Wilkins et al., Biotechnol. Gene Eng. Rev. 13, 19 (1995). The term "proteome" was introduced, by analogy with "genome," to denote in an aggregate sense the protein complement of a cell or organism.
33. L. Wu et al., Cancer Res. 52, 3029 (1992).
34. J.-S. Lee et al., Mol. Pharmacol. 46, 627 (1994); M. Alvarez et al., J. Clin. Invest. 95, 2205 (1995).
35. J.-S. Lee et al., Mol. Pharmacol. 46, 627 (1994); M. Alvarez et al., J. Clin. Invest. 95, 2205 (1995).
36. M. A. Izquierdo et al., Int. J. Cancer 65, 230 (1996).
37. S. Scala et al., Proc. Am. Assoc. Cancer Res. 37, 325 (1996).
38. T. G. Myers et al., ibid. 36, 305 (1995); ibid. 37, 299 (1996).
39. T. G. Myers et al., ibid. 36, 305 (1995); ibid. 37, 299 (1996).
40. All cluster analyses were performed by the average linkage method with Pearson correlation coefficient as metric. Other methods (single linkage, complete linkage, centroid-based algorithms) and metrics (Euclidean) also yield coherent patterns but emphasize different features. DISCOVERY uses SAS (Statistics Analysis Systems Institute, Carry, NC) or S-Plus (MathSoft, Seattle, WA) scripting and routines for some of these calculations. Neither the 60 cell lines nor the compounds tested represent random samples from defined underlying populations; hence, all of the statistical parameters used in this article should be considered as heuristic indices.
41. This set appears to be mechanistically different from the well-known anticancer α-formylpyridine thiosemicarbazones, 3-HP and 5-HP (3-and 5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone), which are ribonucleotide reductase inhibitors. The latter two compounds and four of their analogs appear side by side in a separate group (compounds 3037 to 3042). Two structural features distinguish the group of 72 from the HP family: Most are synthetically derived from α-acetyl (rather than α-formyl) heterocyclics and generally have a large, lipophilic moiety at the end distal to the imine linkage.
42. L. Pendyala and P. J. Creaven, Cancer Res. 53, 5970 (1993).
43. Autocorrelation analysis was performed on a set of 43 consecutive screenings of doxorubicin (which is used as a routine control in each experiment) performed over a period of 8 months. The Pearson correlation coefficient for any pair of tests was essentially independent of time elapsed between the tests (36).
44. K.-V. Chin, I. Pastan, M. M. Gottesman, Adv. Cancer Res. 60, 157 (1993); M. M. Gottesman and I. Pastan, Annu. Rev. Biochem. 62, 385 (1993).
45. K.-V. Chin, I. Pastan, M. M. Gottesman, Adv. Cancer Res. 60, 157 (1993); M. M. Gottesman and I. Pastan, Annu. Rev. Biochem. 62, 385 (1993).
46. The linear methods described here cannot capture nonlinear, interactive aspects of the biological phenomena. However, the matrix multiplication used to obtain Fig. 2 can be replaced by any chosen nonlinear mathematical operator, statistical operator, or artificial intelligence-based algorithm. The various matrices summarize patterns of information, but the robustness of correlations is also examined on a number-by-number basis, and nonparametric boot-strap confidence limits for the correlation coefficient estimates are calculated when desired.
47. M. Hollstein, D. Sidransky, B. Vogelstein, C. C. Harris, Science 253, 49 (1991); A. J. Levine, J. Momand, C. A. Finlay, Nature 351, 453 (1991); M. S. Greenblatt, W. P. Bennett, M. Hollstein, C. C. Harris, Cancer Res. 54, 4855 (1994).
48. M. Hollstein, D. Sidransky, B. Vogelstein, C. C. Harris, Science 253, 49 (1991); A. J. Levine, J. Momand, C. A. Finlay, Nature 351, 453 (1991); M. S. Greenblatt, W. P. Bennett, M. Hollstein, C. C. Harris, Cancer Res. 54, 4855 (1994).
49. M. Hollstein, D. Sidransky, B. Vogelstein, C. C. Harris, Science 253, 49 (1991); A. J. Levine, J. Momand, C. A. Finlay, Nature 351, 453 (1991); M. S. Greenblatt, W. P. Bennett, M. Hollstein, C. C. Harris, Cancer Res. 54, 4855 (1994).
50. G. P. Zambetti and A. J. Levine, FASEB J. 7, 855 (1993).
51. See, for example, S. Friend, Science 265, 334 (1994); L. H. Hartwell and M. B. Kastan, ibid. 266, 1821 (1994); M. L. Smith and A. J. Fornace Jr., Mutat. Res. 340, 109 (1996); C. C. Harris, Carcinogenesis 17, 1187 (1996).
52. See, for example, S. Friend, Science 265, 334 (1994); L. H. Hartwell and M. B. Kastan, ibid. 266, 1821 (1994); M. L. Smith and A. J. Fornace Jr., Mutat. Res. 340, 109 (1996); C. C. Harris, Carcinogenesis 17, 1187 (1996).
53. See, for example, S. Friend, Science 265, 334 (1994); L. H. Hartwell and M. B. Kastan, ibid. 266, 1821 (1994); M. L. Smith and A. J. Fornace Jr., Mutat. Res. 340, 109 (1996); C. C. Harris, Carcinogenesis 17, 1187 (1996).
54. See, for example, S. Friend, Science 265, 334 (1994); L. H. Hartwell and M. B. Kastan, ibid. 266, 1821 (1994); M. L. Smith and A. J. Fornace Jr., Mutat. Res. 340, 109 (1996); C. C. Harris, Carcinogenesis 17, 1187 (1996).
55. P. M. O'Connor et al., in preparation.
56. Modified from S. Marsoni et al., Cancer Treat. Rep. 71, 71 (1987).
57. This finding is consistent with observations by S. Fan et al. [Cancer Res. 54, 5824 (1994)] in Burkitt's lymphoma cells. Interestingly, the small, highly Mdr-1 -susceptible subgroup seen in Fig. 2 as compounds 3043 to 3069 includes nine anthracyclines, among them doxorubicin, deoxydoxorubicin, daunomycin, and rubidazone. The apparent differences between antimitotics and DNA-damaging agents are increased somewhat by confounding correlations with Mdr-1, as indicated when cell lines high in Mdr-1 were excluded from the p53 analyses.
58. One such set of criteria included the Pearson correlation coefficient and Wilcoxon P value (as defined for Fig. 4) with respect to p53 sequence, the median difference in sensitivity between p53 wild-type and p53-mutant cell lines, and the mean potency of the compound. Additional triage was done on the basis of availability of the compound for testing and uniqueness of activity pattern and molecular structure. To cite one example, a subset of the ellipticines scored well with respect to those criteria.
59. The p53 isogenic sets used here include p53 wild-type parental cells, p53-disrupted derivatives, and control cells [see, for example, S. Fan et al., Cancer Res. 55, 1649 (1995)]. The results obtained can depend markedly on the cell type and genotypic context.
60. Molecular characterization of clinical tumor cells is central to the NCI's recently announced Cancer Genome Anatomy Project (CGAP).
61. T. G. Myers and J. N. Weinstein, data not shown.
62. K. Wosikowski et al., in preparation.
63. H.-M. Koo et al., Cancer Res. 56, 5211 (1996).
64. For continuing collaboration on the screening endeavors, we thank the staff of the DTP and SAIC NCI-FCRDC, especially J. Mayo, V. Narayanan, R. Schultz, R. Camalier, J. Johnson, K. Hite, A. Chiausa, P. Svetlik, and D. Segal. LMP was part of the DTP when much of this work was done. The molecular target data discussed here are the contributions of many others, including J. Jackman, I. Bae, M. Alvarez, and K. Wosikowski. We thank L. Muenz for critique of the statistical issues, and M. R. Boyd, R. Shoemaker, M. Alley, B. A. Chabner, G. Vande Woude, M. R. Grever, and S. A. Schepartz for developing the current screening program and supporting the molecular targets enterprise.