Hsp90 Inhibitors in the Clinic

Pacey, Simon; Banerji, Udai; Judson, Ian; Workman, Paul

doi:10.1007/3-540-29717-0_14

Cited by 102 publications

(99 citation statements)

References 107 publications

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“…Encouragingly, we observed prolonged stable disease in two patients with advanced, metastatic malignant melanoma, which led to a phase II clinical trial being initiated at our institution and the Royal Marsden Hospital in collaboration with the Royal Free Hospital, London. In addition to melanoma, evidence of clinical activity has also been reported by others in breast and prostate cancer (Pacey et al 2006).…”

Section: Clinical Evaluation Of 17-aagmentioning

confidence: 55%

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

Powers

Workman²

2006

Endocr Relat Cancer

268

213

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The last decade has seen the molecular chaperone heat shock protein 90 (HSP90) emerge as an exciting target for cancer therapy. This is because HSP90 is involved in maintaining the conformation, stability, activity and cellular localisation of several key oncogenic client proteins. These include, amongst others, ERBB2, C-RAF, CDK4, AKT/PKB, steroid hormone receptors, mutant p53, HIF-1a, survivin and telomerase hTERT. Therefore, modulation of this single drug target offers the prospect of simultaneously inhibiting all the multiple signalling pathways and biological processes that have been implicated in the development of the malignant phenotype. The chaperone function of HSP90 requires the formation of a multichaperone complex, which is dependent on the hydrolysis of ATP and ADP/ATP exchange. Most current inhibitors of HSP90 act as nucleotide mimetics, which block the intrinsic ATPase activity of this molecular chaperone. The first-in-class inhibitor to enter and complete phase I clinical trials was the geldanamycin analogue, 17-allylamino-17-demethoxygeldanamycin. The results of these trials have demonstrated that HSP90 is a valid drug target. Evidence of clinical activity has been seen in patients with melanoma, breast and prostate cancer. This article provides a personal perspective of the present efforts to increase our understanding of the molecular and cellular consequences of HSP90 inhibition, with examples from work in our own laboratory. We also review the discovery and development of novel small-molecule inhibitors and discuss alternative approaches to inhibit HSP90 activity, both of which offer exciting prospects for the future.Endocrine-Related Cancer (2006) 13 S125-S135

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Section: Clinical Evaluation Of 17-aagmentioning

confidence: 55%

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

Powers

Workman²

2006

Endocr Relat Cancer

268

213

View full text Add to dashboard Cite

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“…At 24 h after transfection, cells were incubated for 1 h in heat shock (42 1C) and/or 1 mM 17-AAG, where applicable. 17-AAG, a geldanamycin derivative, is a specific inhibitor of Hsp90 (Schulte and Neckers, 1998), currently tested in clinical trials as an antitumor drug (Pacey et al, 2006).…”

Section: Resultsmentioning

confidence: 99%

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

et al. 2009

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p53 as an unstable protein in vitro likely requires stabilizing factors to act as a tumor suppressor in vivo. Here, we show that in human cells transfected with wildtype (WT) p53, Hsp90 and Hsp70 molecular chaperones maintain the p53 native conformation under heat-shock conditions (42 1C) as well as assist p53 refolding at 37 1C, during the recovery from heat shock. We also show that the interaction of WT p53 with WAF1 promoter in cells is sensitive to Hsp70 and Hsp90 inhibition already at 37 1C and further decreased on heat shock. The influence of chaperones on p53 binding to the WAF1 promoter sequence has been confirmed in vitro, using highly purified proteins. Hsp90 stabilizes the binding of p53 to the promoter sequence at 37 1C, whereas under heat-shock conditions the requirement for the Hsp70-Hsp40 system and its cooperation with Hsp90 increases. Hop co-chaperone additionally stimulates these reactions. Interestingly, the combined Hsp90 and Hsp70-Hsp40 allow for a limited in vitro restoration of the DNA-binding activity by the p53 oncogenic variant R249S and affect its conformation in cells. Our results indicate for the first time that, especially under stress conditions, not only Hsp90 but also Hsp70 is required for the chaperoning of WT and R249S p53.

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“…Blockade of the ATPase activity of Hsp90 have effectively inhibited cell signaling molecules in proliferating cancer cells (43). However, geldanamycin and its derivatives have some significant limited pharmaceutical properties as well as toxicities in clinical trials (14,44). For these reasons, the development of novel Hsp90 inhibitors has been an area of intense research.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

Song

Chaerkady

Tan

et al. 2008

Molecular Cancer Therapeutics

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Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose-and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

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Hsp90 Inhibitors in the Clinic

Cited by 102 publications

References 107 publications

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

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