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Expert Opinion on Investigational Drugs Volume 14, 2005 - Issue 6
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Review

Heat-shock protein 90 inhibitors in antineoplastic therapy: is it all wrapped up?

Jennifer S Isaacs Urologic Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, MD, USA. [email protected]
Pages 569-589 | Published online: 11 Jul 2005

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  • ••Important first paper documenting therelationship between Hsp90 inhibition and impairment of oncogenic signalling.
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  • •Second paper confirming direct drug binding by Hsp90.
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  • •These four papers illustrate the depletion of potent clinically relevant oncogenic proteins by Hsp90 inhibition.
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  • ••Important report that demonstrates thatHIF-1 is activated by RT and that this is correlated with a radioresistant phenotype.
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  • •Nice demonstration of the ability of Hsp90 to potentiate signalling by activating eNOS and further recruiting Akt into this complex.
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  • •Demonstration that Hsp90 inhibition with 17-DMAG potently inhibits angiogenesis mediated by several pathways.
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  • ••Important demonstration that Hsp90from tumour cells is hyperactivated with a significantly higher affmity for Hsp90-targeted agents.
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  • •Demonstration that new small-molecule Hsp90 inhibitors also possess selective affinity for tumour Hsp90.
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  • ••Demonstration of the tumour-specific rolefor Hsp90 at the cell surface.
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  • ••Demonstration of the involvement of cell-surface Hsp90 in mediating a humoural response in advanced cancer.
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  • •These three papers demonstrate the ability of HDAC inhibitors to modulate Hsp90 function and promote client depletion.
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  • •These five papers illustrate the ability of Hsp90 inhibitors to sensitise cancer cells and/or tumours to RT.
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  • •Nice work providing a rationale to use Hsp90 inhibition with certain classes of chemotherapeutic agents.
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  • •Well-documented report demonstrating the importance of the schedule-dependent effects of 17-AAG administration and identification of specific proteins that attenuate drug efficacy.
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  • •These two papers identify circulating biomarkers for monitoring angiogenesis.
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  • •Another nice documentation of the clinical utility of Hsp90 inhibition following treatment failure.
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Websites

  • http://www.Picard.ch/DP/downloads/ Hsp90interactors.pdf National Cancer Institue website.
  • hdp://www.cancengoy/clinicaltrials/ developments/anti-angio-table National Cancer Institue website.
  • http://www.angio.org/common/ druglist_trial.html List of antiangiogenic drugs in clinical trial for cancer.

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