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Jhaveri K, Modi S. Ganetespib: research and clinical development. Onco Targets Ther. 2015;8:1849-58doi: 10.2147/OTT.S65804.
Jhaveri, K., & Modi, S. (2015). Ganetespib: research and clinical development. OncoTargets and therapy, 81849-58. https://doi.org/10.2147/OTT.S65804
Jhaveri, Komal, and Modi, Shanu. "Ganetespib: research and clinical development." OncoTargets and therapy vol. 8 (2015): 1849-58. doi: https://doi.org/10.2147/OTT.S65804
Jhaveri K, Modi S. Ganetespib: research and clinical development. Onco Targets Ther. 2015 Jul 24;8:1849-58. doi: 10.2147/OTT.S65804. eCollection 2015. PMID: 26244021; PMCID: PMC4521669.
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Onco Targets Ther. 2015 Jul 24;8:1849-58. doi: 10.2147/OTT.S65804. eCollection 2015.

Ganetespib: research and clinical development.

OncoTargets and therapy

Komal Jhaveri, Shanu Modi

Affiliations

  1. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

PMID: 26244021 PMCID: PMC4521669 DOI: 10.2147/OTT.S65804

Abstract

Under stressful conditions, the heat shock protein 90 (HSP90) molecular chaperone protects cellular proteins (client proteins) from degradation via the ubiquitin-proteasome pathway. HSP90 expression is upregulated in cancers, and this contributes to the malignant phenotype of increased proliferation and decreased apoptosis and maintenance of metastatic potential via conservation of its client proteins, including human epidermal growth factor receptor 2, anaplastic lymphoma kinase, androgen receptor, estrogen receptor, Akt, Raf-1, cell cycle proteins, and B-cell lymphoma 2 among others. Hence, inhibition of HSP90 leads to the simultaneous degradation of its many clients, thereby disrupting multiple oncogenic signaling cascades. This has sparked tremendous interest in the development of HSP90 inhibitors as an innovative anticancer strategy. Based on the wealth of compelling data from preclinical studies, a number of HSP90 inhibitors have entered into clinical testing. However, despite enormous promise and anticancer activity reported to date, none of the HSP90 inhibitors in development has been approved for cancer therapy, and the full potential of this class of agents is yet to be realized. This article provides a review on ganetespib, a small molecule HSP90 inhibitor that is currently under evaluation in a broad range of cancer types in combination with other therapeutic agents with the hope of further enhancing its efficacy and overcoming drug resistance. Based on our current understanding of the complex HSP90 machinery combined with the emerging data from these key clinical trials, ganetespib has the potential to be the first-in-class HSP90 inhibitor to be approved as a new anticancer therapy.

Keywords: HSP90; breast cancer; colorectal cancer; lung cancer

References

  1. Biochim Biophys Acta. 2012 Mar;1823(3):742-55 - PubMed
  2. Bioorg Med Chem. 2009 Mar 15;17(6):2225-35 - PubMed
  3. Mol Cell Biol. 1984 Dec;4(12):2802-10 - PubMed
  4. J Med Chem. 2010 Jan 14;53(1):3-17 - PubMed
  5. Cancer Discov. 2013 Apr;3(4):430-43 - PubMed
  6. J Mol Diagn. 2008 Nov;10 (6):493-5 - PubMed
  7. Clin Cancer Res. 2013 Nov 1;19(21):6020-9 - PubMed
  8. J Cell Physiol. 2001 Sep;188(3):281-90 - PubMed
  9. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20330-5 - PubMed
  10. Clin Cancer Res. 2013 Jun 1;19(11):3068-77 - PubMed
  11. Clin Cancer Res. 2012 Sep 15;18(18):4973-85 - PubMed
  12. Mol Cancer Ther. 2012 Dec;11(12):2633-43 - PubMed
  13. Pathol Res Pract. 2000;196(10):665-73 - PubMed
  14. Br J Haematol. 2010 Aug;150(4):428-37 - PubMed
  15. Breast Cancer Res Treat. 2013 May;139(1):107-13 - PubMed
  16. Expert Opin Investig Drugs. 2014 May;23(5):611-28 - PubMed
  17. Nat Rev Cancer. 2005 Oct;5(10):761-72 - PubMed
  18. Clin Cancer Res. 2014 Jan 15;20(2):413-24 - PubMed
  19. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9 - PubMed
  20. Invest New Drugs. 2012 Dec;30(6):2201-9 - PubMed
  21. Curr Cancer Drug Targets. 2003 Oct;3(5):301-23 - PubMed
  22. ACS Chem Biol. 2006 Jun 20;1(5):279-84 - PubMed
  23. Mol Cancer Ther. 2012 Feb;11(2):475-84 - PubMed
  24. Cancer Res. 2002 Dec 1;62(23):6997-7000 - PubMed
  25. Mol Cancer Ther. 2014 Feb;13(2):353-63 - PubMed
  26. Clin Cancer Res. 2012 Sep 15;18(18):5090-8 - PubMed
  27. Cancer Res. 2014 Mar 1;74(5):1294-300 - PubMed
  28. Int J Cancer. 2010 Mar 1;126(5):1216-25 - PubMed
  29. Biopolymers. 2013 Nov;99(11):846-59 - PubMed
  30. Clin Cancer Res. 2012 Sep 1;18(17):4508-13 - PubMed
  31. Clin Cancer Res. 2012 Jan 1;18(1):64-76 - PubMed
  32. J Mol Med (Berl). 2004 Aug;82(8):488-99 - PubMed
  33. Adv Protein Chem. 2001;59:157-86 - PubMed
  34. Expert Opin Ther Pat. 2014 May;24(5):501-18 - PubMed
  35. Nature. 2006 Apr 20;440(7087):1013-7 - PubMed
  36. Nat Chem Biol. 2011 Sep 25;7(11):818-26 - PubMed
  37. PLoS One. 2011 Apr 14;6(4):e18552 - PubMed
  38. Nature. 2012 Oct 4;490(7418):61-70 - PubMed
  39. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40 - PubMed
  40. Clin Cancer Res. 2001 Aug;7(8):2228-36 - PubMed
  41. J Biol Chem. 1996 Sep 13;271(37):22796-801 - PubMed
  42. Cancer Detect Prev. 1998;22(6):549-55 - PubMed
  43. Clin Cancer Res. 2013 Sep 15;19(18):5053-67 - PubMed
  44. J Clin Oncol. 2010 Nov 20;28(33):4953-60 - PubMed
  45. Expert Opin Biol Ther. 2002 Jan;2(1):3-24 - PubMed
  46. Adv Pharmacol. 2012;65:471-517 - PubMed
  47. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3749-55 - PubMed
  48. Blood. 2006 Feb 1;107(3):1092-100 - PubMed
  49. Br J Haematol. 2011 Jun;153(6):729-40 - PubMed
  50. Ann Thorac Surg. 2001 Aug;72(2):371-8; discussion 378-9 - PubMed
  51. Cancer Res. 2003 May 1;63(9):2139-44 - PubMed
  52. Clin Breast Cancer. 2014 Jun;14(3):154-60 - PubMed
  53. BMC Cancer. 2013 Mar 25;13:152 - PubMed
  54. Lancet Oncol. 2013 Aug;14(9):e358-69 - PubMed

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