Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

Lang, Sven A.; Moser, Christian; Fichnter-Feigl, Stefan; Schachtschneider, Philipp; Hellerbrand, Claus; Schmitz, Volker; Schlitt, Hans J.; Geissler, Edward K.; Stoeltzing, Oliver

doi:10.1002/hep.22685

Cited by 56 publications

(64 citation statements)

References 35 publications

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“…Additionally, 17-DMAG downregulated VEGF-R2 protein expression on endothelial cells, inhibited VEGF-A-induced Erk and Akt activation, and downregulated total Akt expression (24). Furthermore, treatment with 17-DMAG decreased platelet-derived growth factor-Rb expression and function on vascular smooth muscle cells (24). All these results signify the antiangiogenic effect of HSP90 inhibition in cancer.…”

Section: Discussionmentioning

confidence: 89%

“…Treatment with 17-AAG and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, or alvespimycin), a water-soluble geldanamycin analog, decreased MVD in gastric, colon, and hepatocellular carcinoma xenograft models (7,11,22,23). Additionally, 17-DMAG downregulated VEGF-R2 protein expression on endothelial cells, inhibited VEGF-A-induced Erk and Akt activation, and downregulated total Akt expression (24). Furthermore, treatment with 17-DMAG decreased platelet-derived growth factor-Rb expression and function on vascular smooth muscle cells (24).…”

Section: Discussionmentioning

confidence: 99%

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⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Nagengast¹,

Korte²,

Munnink³

et al. 2010

J Nucl Med

106

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Angiogenesis is a critical step in tumor development, in which vascular endothelial growth factor (VEGF) is a key growth aspect. Heat shock protein 90 (HSP90), a molecular chaperone, is essential for the activity of key proteins involved in VEGF transcription. Currently, no biomarkers to predict the effect of, or monitor, HSP90 inhibition therapy in individual patients exist. 89 Zr-bevacizumab PET provides a noninvasive tool to monitor tumor VEGF levels. The aim of this study was to investigate 89 Zr-bevacizumab PET for early antiangiogenic tumor response evaluation of treatment with the new HSP90 inhibitor NVP-AUY922. In xenografts of A2780 and its cisplatin-resistant CP70 human ovarian cancer subline, 89 Zr-bevacizumab smallanimal PET was performed before and after NVP-AUY922 treatment and verified with histologic response and ex vivo tumor VEGF levels. Compared with pretreatment values, 2 wk of NVP-AUY922 treatment decreased 89 Zr-bevacizumab uptake by 44.4% (P 5 0.0003) in A2780 xenografts, whereas tumor uptake was not affected in CP70 xenografts. The same pattern was observed in A2780 and CP70 tumor VEGF levels, measured with enzyme-linked immunosorbent assay, and mean vessel density after NVP-AUY922 treatment. These findings coincided with reduction in the proliferation rate, assessed by Ki67 staining, in A2780 tumor tissue only. Conclusion: 89 Zr-bevacizumab PET was in line with the antiangiogenic response and direct antitumor effects after NVP-AUY922 treatment, supporting the specificity of 89 Zr-bevacizumab PET as a sensitive technique to monitor the antiangiogenic response of HSP90 inhibition in vivo.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Nagengast¹,

Korte²,

Munnink³

et al. 2010

J Nucl Med

106

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“…Newly developed HSP90 inhibitor showed a lack of significant hepatotoxicity and is more tolerated, which become more practical in therapeutic treatment (Breinig et al, 2009). HSP90 inhibition further prevents tumor growth by disruption of tumor angiogenesis, as demonstrated by blocking PDGFR-expression in vascular smooth muscle cells and VEGF2 expression on endothelial cells (Lang et al, 2009). Moreover, the combinatory use of HSP90 inhibitor and other anticancer agents is proved to be beneficial.…”

Section: Heat Shock Protein 90mentioning

confidence: 99%

“…Moreover, the combinatory use of HSP90 inhibitor and other anticancer agents is proved to be beneficial. Blockage of HSP90 is able to enhance the antitumor effect of mTOR inhibitor rapamycin by blocking the alternative AKT signaling induced by rapamycin (Lang et al, 2009). Inhibition of HSP90 can be invaluable clinically during HCC treatment, either by targeting HSP90 alone or in combination with other anticancer agent.…”

Section: Heat Shock Protein 90mentioning

confidence: 99%

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

Chen¹,

Li²

2012

Hepatocellular Carcinoma - Basic Research

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“…63 The use of an inhibitor of PI3K/ Akt/mTOR (mammalian target of rapamycin: ser/thr kinase signaling pathway), such as NVP-BEZ235, and targeting Hsp90 chaperone improves the efficacy of rapamycin against hepatocellular carcinoma. 64,65 Hsp90 inhibitors target Raf-1. The disruption of the Raf-1/Hsp90 complex by GA results in the loss of Raf-1-Ras associations.…”

Section: Actions Ofmentioning

confidence: 99%

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

et al. 2011

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Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase-1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in RbÀ/À cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized.

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Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

Cited by 56 publications

References 35 publications

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

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Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice #

Cited by 56 publications

References 35 publications

89Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

89Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

Molecular basis for the actions of Hsp90 inhibitors and cancer therapy

Contact Info

Product

Resources

About

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922

⁸⁹Zr-Bevacizumab PET of Early Antiangiogenic Tumor Response to Treatment with HSP90 Inhibitor NVP-AUY922