AUY922, a novel HSP90 inhibitor: Final results of a first-in-human study in patients with advanced solid malignancies.

Samuel, Thomas A.; Sessa, Cristiana; Britten, Carolyn D.; Milligan, Karen; Mita, Monica; Banerji, Udai; Pluard, TJ; Stiegler, P.; Quadt, Cornelia; Shapiro, Geoffrey I.

doi:10.1200/jco.2010.28.15_suppl.2528

Cited by 34 publications

(24 citation statements)

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“…Importantly, our safety studies were carried out to maximally tolerated doses and no other adverse events were seen to indicate that ganetespib manifests any additional toxicities. Notably, ocular toxicities have recently emerged as an undesirable sideeffect for the newer synthetic Hsp90 inhibitors (40). To date, more than 400 patients have been treated with ganetespib, and an absence of ocular toxicity is evident (<3%; W. Ying, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Ying

Sun

et al. 2012

Molecular Cancer Therapeutics

200

194

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Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 mm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first-and second-generation Hsp90 inhibitors. Mol Cancer Ther; 11(2); 475-84. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Ying

Sun

et al. 2012

Molecular Cancer Therapeutics

200

194

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“…Therefore, inhibition of Hsp90 might lead to irreversible retinal damage. Some Hsp90 inhibitors, including NVP-AUY922 (resorcinol-isoxazole type), IPI-504 (ansamycin type), PF-04929113 (SNX-5422) (indazol-4-one type), and AT13387 (resorcinol-isoindoline type), induced visual disorders such as blurred vision, flashing, delayed dark/ light accommodation, and darkening of vision in humans (Samuel et al, 2010;Sequist et al, 2010;Rajan et al, 2011). In particular, the development of PF-04929113 (SNX-5422) was discontinued due Vol.…”

Section: Discussionmentioning

confidence: 99%

“…Several of these, such as NVP-AUY922, IPI-504, PF-04929113 (SNX-5422), and AT13387, are reported to cause visual disorders, including blurred vision, flashing, delayed dark/light accommodation and darkening of vision (Samuel et al, 2010;Sequist et al, 2010;Shapiro et al, 2010;Rajan et al, 2011). Especially, the development of PF-04929113 (SNX-5422) was discontinued due to ocular toxicity.…”

Section: Introductionmentioning

confidence: 99%

Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs

et al. 2014

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-Heat shock protein 90 (Hsp90) is a constitutively expressed molecular chaperone and plays an important role in the folding of client proteins with key regulatory roles in growth, survival, differentiation and metastasis. Because inhibition of Hsp90 degrades multiple oncogenic client proteins, it is considered to be an attractive anticancer therapy, and clinical trials of several Hsp90 inhibitors have been carried out. In the present study, two structurally distinct Hsp90 inhibitors, CH5164840 and CH5449302, were orally administered to beagle dogs to evaluate systemic toxicity. CH5164840 induced symptoms that suggest visual disorder, and ophthalmological observation and electroretinography (ERG) revealed loss of pupillary light reflex and abnormal waveforms, respectively. Histopathological examination showed changes in the photoreceptor cell layer and the outer nuclear layer of retina. On the other hand, while there were no clinical symptoms related to visual disorder, animals treated with CH5449302 showed similar abnormalities of ERG responses and histopathological changes in the photoreceptor cell layer and the outer nuclear layer of retina. The visual symptoms and abnormalities of ERG responses were noted at an earlier stage or lower dose than other toxicities in both compounds. Considering that two structurally distinct Hsp90 inhibitors induced a retinal toxicity in dogs after repeated administration, and that visual disorders were also reported in some clinical trials of Hsp90 inhibitors, it would seem highly likely that Hsp90 inhibition induces retinal toxicity. Also, our study indicated that a detailed ocular examination to evaluate the safety of Hsp90 inhibitors would be useful in both preclinical and clinical studies.

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“…Unfortunately, 17-AAG did not show its predicted clinical efficacy as a single agent in CRPC, due to toxicity and poor pharmacodynamic properties that prevented therapeutic doses being achieved (Banerji et al 2005, Heath et al 2008, Ramanathan et al 2010. While more potent inhibitors such as AUY922 are currently being developed and show promise as single agents (Samuel et al 2010, Centenera et al 2012, recent evidence of additive or synergistic activity between 17-AAG and cytotoxic agents or specific molecular therapeutics provides a promising new avenue of clinical development for this drug . In preclinical prostate cancer studies, 17-AAG or AUY922 combined with ionizing radiation has demonstrated supra-additive reductions in tumor growth and clonogenicity (Enmon et al 2003, Ochel & Gademann 2006, Gandhi et al 2013.…”

Section: Introductionmentioning

confidence: 99%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspasedependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

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AUY922, a novel HSP90 inhibitor: Final results of a first-in-human study in patients with advanced solid malignancies.

Cited by 34 publications

References 0 publications

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Ganetespib, a Unique Triazolone-Containing Hsp90 Inhibitor, Exhibits Potent Antitumor Activity and a Superior Safety Profile for Cancer Therapy

Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

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