Skip to main content
SpringerLink
Log in

Pharmacological Intervention With Multistep Oncogenesis

Potential Role for HSP90 Molecular Chaperone Inhibitors

  • Chapter
Cancer Chemoprevention

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The first part of this chapter reviews current challenges involved in attacking multistep oncogenesis and discusses the consequences for therapeutic and chemopreventive strategies, highlighting in particular the probable need to inhibit multiple oncogenic targets in a combinatorial fashion to obtain therapeutic benefit in the majority of cancers. The second part of the chapter will describe the potential role of inhibitors of the heat shock protein (HSP90) molecular chaperone.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Workman P. Scoring a bull’s-eye against genome targets. Curr Opin Pharmacol 2001;1:342–352.

    Article  PubMed  CAS  Google Scholar 

  2. Workman P. Changing times: developing drugs in genomeland. Curr Opin Investig Drugs 2001;2:1128–1135.

    PubMed  CAS  Google Scholar 

  3. Reddy A, Kaelin WG. Using cancer genetics to guide the selection of anticancer drug targets. Curr Opin Pharmacol 2002;2:366–373.

    Article  PubMed  CAS  Google Scholar 

  4. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science 2001;291:1304–1351.

    Article  PubMed  CAS  Google Scholar 

  5. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001;409:860–921.

    Article  Google Scholar 

  6. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2001;417:949–954.

    Article  Google Scholar 

  7. Workman P and Kaye SB (eds.) A Trends Guide to Cancer Therapeutics. Trends Mol Med 2002;8:S1–S73.

    Google Scholar 

  8. Mills GB, Lu Y, Kohn EC. Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci USA 2001;98:10,031–10,033.

    CAS  Google Scholar 

  9. Ponder BA. Cancer genetics. Nature 2002;411:336–341.

    Article  Google Scholar 

  10. Volgestein B, Kinzler K. The multiple nature of cancer. Trends Genet 1993;9:138–141.

    Article  Google Scholar 

  11. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer research. Nature 2001;411:342–348.

    Article  PubMed  CAS  Google Scholar 

  12. Weinstein IB. Addiction to oncogenes. Science 2002;297:63–64.

    Article  PubMed  CAS  Google Scholar 

  13. Druker BJ. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med 2001;8:4 (Suppl):S14–S18.

    Article  Google Scholar 

  14. De Bono J, Rowinsky EK. The ErbB receptor family: a therapeutic target for cancer. Trends Mol Med 2001;4 (Suppl): S19–S26.

    Google Scholar 

  15. Giaconne G, Johnson DH, Manegold C, et al. A Phase III clinical trial of ZD1839 (‘Iressa’) in combination with gemacitabine and cisplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (INTACT I). Ann Oncol 2002;13 Suppl 5:40.

    Google Scholar 

  16. Johnson DH, Herbst R, Giacoone G, et al. ZD1839 (Iressa) in combination with paclitaxel & carboplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC): results from a Phase III trial (INTACT 2). Ann Oncol 2002;13 Suppl 5: 4680.

    Google Scholar 

  17. Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther 2002;2:3–24.

    Article  PubMed  CAS  Google Scholar 

  18. Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 2001;8:S55–S61.

    Article  Google Scholar 

  19. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  20. Rutherford LI, Lindquist S. Hsp90 as a capacitator for morphological evolution. Nature 1998;396:336–342.

    Article  PubMed  CAS  Google Scholar 

  21. Queitshc C, Sangster TA, Linquist S. Hsp90 as a capacitor variation. Nature 2002;417:618–624.

    Article  Google Scholar 

  22. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH. Geldanamycin, a new antibiotic. J Antibiot 1970;23:442–447.

    Article  PubMed  CAS  Google Scholar 

  23. Uehara U, Hori M, Takeuchi T, Umezawa H. Phenotypic change from transformed to normal induced by benzoquinoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus. Mol Cell Biol 1986;6:2198–2206.

    PubMed  CAS  Google Scholar 

  24. Whitesell L, Mimnaugh EG, Decosta B, et al. Inhibition of heat shock protein HSP90–pp60-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 1994;91:8324–8328.

    Article  PubMed  CAS  Google Scholar 

  25. Prodromou C, Roe SM, O’Brien R, et al. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 1997;90:65–75.

    Article  PubMed  CAS  Google Scholar 

  26. Stebbins CE, Russo AA, Schneider C, et al. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 1997;89:239–250.

    Article  PubMed  CAS  Google Scholar 

  27. Prodromou C, Panaretou B, Chohan S et al. The ATPase cycle of Hsp90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domains. EMBO J 2000;19:4383–4392.

    Article  PubMed  CAS  Google Scholar 

  28. Brunton VG, Steele G, Lewis AD, Workman P. Geldanamycin-induced toxicity in human colon-cancer cell lines: evidence against the involvement of c-Src or DT diaphorase. Cancer Chemother Pharmacol 1998;41:417–422.

    Article  PubMed  CAS  Google Scholar 

  29. Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumour agent. Cancer Chemother Pharmacol 1995;36:305–310.

    Article  PubMed  CAS  Google Scholar 

  30. Schnur RC, Corman ML, Gallascun RJ, et al. Inhibition of the oncogene product p 185erbB2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives. J Med Chem 1995;38:3806–3812.

    Article  PubMed  CAS  Google Scholar 

  31. Schnur RC, Corman ML, Gallascun RJ, et al. ErbB2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships. J Med Chem 1995;38:3813–3820.

    Article  PubMed  CAS  Google Scholar 

  32. Schulte TW, Neckers LM. The benzoquinone ansamycin 17allylamino-17-deemthoxygeldanamcyin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 1998;42:273–279.

    Article  PubMed  CAS  Google Scholar 

  33. Kelland L, Sharp S, Rogers P, et al. DT diaphorase expression and tumour cell sensitivity to 17-allylamino, 17demethoxygeldanamycin, and inhibitor of heat shock protein 90. J Natl Cancer Inst 1999;91:1940–1949.

    Article  PubMed  CAS  Google Scholar 

  34. Strethapakdi M, Liu F, Tavorath R, Rosen N. Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest. Cancer Res 2000;60:3940–3946.

    Google Scholar 

  35. Munster PN, Basso A, Solit D, et al. Modulation of Hsp90 function by ansamycins sensitises breast cancer cells to chemotherapy-induced apoptosis in an RB-and scheduledependent manner. Clin Cancer Res 2001;7:2228–2236.

    PubMed  CAS  Google Scholar 

  36. Clarke P, Hostein I, Banerji U, et al. Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamno-17demethoxygeldanamycin, an inhibitor of hsp90 molecular chaperone. Oncogene 2000;19:4125–4133.

    Article  PubMed  CAS  Google Scholar 

  37. Hostein I, Robertson D, Di Stefano F, et al. Inhibition of signal transduction by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 2001;61:4003–4009.

    PubMed  CAS  Google Scholar 

  38. Morimoto RI. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 1998;12:3788–3796.

    Article  PubMed  CAS  Google Scholar 

  39. Fitzsimmons SA, Workman P, Grever M, et al. Reductase enzyme expression across the National Cancer Institute tumour cell line panel: correlation with sensitivity to mitomycin C and EO9. J Natl Cancer Inst 1996;88:259–269.

    Article  PubMed  CAS  Google Scholar 

  40. Smith V, Hobbs S, Court W, et al. ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin. Anticancer Res 2002;22:1993–2000.

    PubMed  CAS  Google Scholar 

  41. Banerji U, Walton M, Raynaud F, et al. Validation of pharmacodynamic endpoints for the Hsp90 molecular chaperone inhibitor 17-allylamino 17-demethoxygeldanamycin (17AAG) in a human tumor xenograft model. Proc Am Assoc Cancer Res 2001;42:4473.

    Google Scholar 

  42. Wilson RH, Takimoto CH, Agnew EB et al. Phase I pharmacologic study of 17-(Allylamino)-17-demethoxygeldanamycin (AAG) in adult patients with advanced solid tumors. Proc Am Soc Clin Oncol 2001;20:325.

    Google Scholar 

  43. Banerji U, O’Donnell A, Scurr M et al. Phase I trial of the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxy-geldanamycin (17AAG). Pharmacokinetic (PK) profile and pharmacodynamic (PD) endpoints. Proc Am Soc Clin Oncol 2001;20:326.

    Google Scholar 

  44. Munster PN, Tong W, Schwartz L, et al. Phase I trial of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) in patients (Pts) with advanced solid malignancies. Proc Am Soc Clin Oncol 2001;20:327.

    Google Scholar 

  45. Erlichman C, Toft D, Reid J, et al. A Phase I trial of 17-allylamino-geldanamycin in patients with advanced cancer. Proc Am Assoc Cancer Res 2001;42:4474.

    Google Scholar 

  46. Chung YL, Troy H, Banerji U, et al. The pharmacodynamic effects of 17-AAG on HT29 xenografts in mice monitored by magnetic resonance spectroscopy. Proc Am Assoc Cancer Res 2002;43:73, abstr 371.

    Google Scholar 

  47. Lui D, Hutchinson OC, Osman S, et al. Use of radiolabelled choline as a pharmacodynamic marker for the signal transduction inhibitor geldanamycin. Br J Cancer 2002;87:783–789.

    Article  Google Scholar 

  48. Workman P. Challenges of PK/PD measurements in modern drug development. Eur J Cancer 2002;38:2189–2193.

    Article  PubMed  CAS  Google Scholar 

  49. Workman P. How much gets there and what does it do? The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development. Curr Pharm Des 2003;9:891–902.

    Article  PubMed  CAS  Google Scholar 

  50. Smith V, Sausville EA, Camalier RF, et al. 17-DMAG (NSC 707545), a water soluble geldanamycin analog, has superior in vitro and in vivo activity compared to the HSP90 inhibitor 17-AAG. Eur J Cancer 2002;38:S60, abs. 189.

    Google Scholar 

  51. Chiosis G, Timaul MN, Lucas B, et al. A small molecule designed to bind to the adenine nucleotide pocket of HSP90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol 2001;8:289–299.

    Article  PubMed  CAS  Google Scholar 

  52. Chiosis G, Huezo H, Lucas B, Rosen N. Development of a purine-based novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase. Bioorg Med Chem 2002;10:3555–3564.

    Article  PubMed  CAS  Google Scholar 

  53. Rowlands MG, Newbatt YM, Turlais F, et al. High throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity. Clin Cancer Res 2001;7:3749s, abst 475.

    Google Scholar 

  54. Beroza P, Meng F, Bears DJ, et al. Efficient discovery of novel small molecule cancer drugs using Telik’s target-related affinity profiling (TRAP(tm)) technology. Proc Am Assoc Cancer Res 2002;43:37, abst 191.

    Google Scholar 

  55. Banerji U, Walton M, Judson P, Workman P. Combination of the heat shock protein 90 (HSP90) chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin (17AAG) and conventional cytotoxic agents in an ovarian cancer cell line model. Eur J Cancer 2002;38:S52 abst 161.

    Google Scholar 

  56. Whitesell L, Bagatell R, Falsey R. The stress response: implications for the clinical development of Hsp90 inhibitors. Current Drug Targets 2003;3:349–358.

    Article  CAS  Google Scholar 

  57. Price PJ, Sk WA, Skeen PC, et al. Geldanamycin inhibition of 3-methylcholantrene-induced rat embryo cell transformation. Proc Soc Exp Biol Med 1977;155:461–463.

    PubMed  CAS  Google Scholar 

  58. Workman P. The opportunities and challenges of personalized genome-based molecular theropies for cancer: targets, technologies and molecular chaperones. Cancer Chemother Pharmacol 2003;52:S45—S60.

    Article  Google Scholar 

  59. Workman V. Overview Translating Hsp 90 biology into Hsp 90 drugs. Curr Canc. Drug Targets 2003;3:297–300.

    Article  CAS  Google Scholar 

Download references

Authors
  1. Paul Workman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. National Institutes of Health, Rockville, MD, USA

    Gary J. Kelloff MD  & Ernest T. Hawk MD, MPH  & 

  2. CCS Associates, Mountain View, CA, USA

    Caroline C. Sigman PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Science+Business Media New York

About this chapter

Cite this chapter

Workman, P. (2004). Pharmacological Intervention With Multistep Oncogenesis. In: Kelloff, G.J., Hawk, E.T., Sigman, C.C. (eds) Cancer Chemoprevention. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-767-3_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-767-3_22

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-342-8

  • Online ISBN: 978-1-59259-767-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation