Phase 1/1<scp>B</scp> trial of the heat shock protein 90 inhibitor <scp>NVP</scp>‐<scp>AUY</scp>922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma

Seggewiss‐Bernhardt, Ruth; Bargou, Ralf C.; Goh, Yeow Tee; Stewart, A. Keith; Spencer, Andrew; Alegre, Adrián; Bladé, Joan; Ottmann, Oliver G.; Fernandez-Ibarra, Cristina; Lü, Hong; Pain, Scott; Akimov, Mikhail; Iyer, Swaminathan P.

doi:10.1002/cncr.29339

Cited by 55 publications

(28 citation statements)

References 22 publications

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“…Strategies to downregulate the HSR in myeloma have not been successful in clinical trials. For example, HSP90 inhibitors have been tested in clinical trials but have not been effective in myeloma [ 16 , 17 , 41 ]. Interestingly, our data show that bortezomib treatment did not lead to HSP90 induction in any of the four cell lines tested (Figure 1B ).…”

Section: Discussionmentioning

confidence: 99%

“…HSPs serve a wide variety of functions, but are primarily involved in protein folding and protein homeostasis regulation [ 14 , 15 ]. HSP inhibitors have been tested in myeloma clinical studies both as single agents and in combination with bortezomib [ 16 , 17 ]. However, none have been FDA-approved because HSP inhibitors suffer from low potency at clinically relevant levels and an induction in compensatory HSPs [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation

et al. 2016

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Proteasome inhibitors such as bortezomib are highly active in multiple myeloma by affecting signaling cascades and leading to a toxic buildup of misfolded proteins. Bortezomib-treated cells activate the cytoprotective heat shock response (HSR), including upregulation of heat shock proteins (HSPs). Here we inhibited the bortezomib-induced HSR by silencing its master regulator, Heat Shock Factor 1 (HSF1). HSF1 silencing led to bortezomib sensitization. In contrast, silencing of individual and combination HSPs, except HSP40β, did not result in significant bortezomib sensitization. However, HSP40β did not entirely account for increased bortezomib sensitivity upon HSF1 silencing. To determine the mechanism of HSF1 activation, we assessed phosphorylation and observed bortezomib-inducible phosphorylation in cell lines and patient samples. We determined that this bortezomib-inducible event is phosphorylation at serine 326. Prior clinical use of HSP inhibitors in combination with bortezomib has been disappointing in multiple myeloma therapy. Our results provide a rationale for targeting HSF1 activation in combination with bortezomib to enhance multiple myeloma treatment efficacy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation

et al. 2016

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“…Unfortunately, these inhibitors showed limited efficacy as a single agent, however, they are still in various stages of clinical trials as a component for combination therapies (16,29). Luminespib used as a single agent in a phase II study in lung cancer patients showed poor effectiveness (16,29).…”

Section: Introductionmentioning

confidence: 99%

Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines

Codony-Servat

Viteri

Codony-Servat

et al. 2019

Transl. Lung Cancer Res.

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Background: Osimertinib improve therapy for non-small cell lung cancer (NSCLC). However, invariable acquired resistance appears. Methods: MTT assay was used to analyze cell viability. Protein expression and activation was detected by Western blotting. In addition, the effects of heat shock protein 90 (Hsp90) inhibitors and osimertinib were studied in colony formation assays. Results: Our laboratory generated osimertinib resistant cell lines from PC9 cell line and overexpression or activation of several proteins was detected. Hsp90 inhibitors, ganetespib and luminespib, inhibited cell viability and colony formation in H1975, PC9 and PC9-derived osimertinib-resistant cell lines and combination of these inhibitors with osimertinib achieved to enhance this cell viability and colony formation inhibition. Luminespib downregulated the expression of the several proteins involved in osimertinibresistance and the combination of this compound plus osimertinib caused an important decrease of expression of several of these proteins, such as Stat3, Yap, Akt, EGFR and Met. Osimertinib activated the phosphorylation of several membrane receptors and downstream molecules that was partially inhibited by luminespib. In addition, a lung cancer patient with an EGFR eon 20 mutation had a partial radiographic response to ganetespib. Conclusions: Hsp90 inhibitors and osimertinib exhibits a good efficiency to inhibit cell viability, colony formation and inhibits expression and activation of proteins involved in osimertinib-resistance and may represent an effective strategy for NSCLC with intrinsic resistance to osimertinib inhibition.

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“…Heat shock proteins (Hsps) are a family of molecular chaperones that consist of Hsp100, Hsp90, Hsp70, Hsp60 and many other smaller Hsps (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…It also has good pharmacokinetic properties and showed significant tumor growth inhibition in a human colon cancer xenograft model. Compound 3 (AUY922) has been under a number of clinical trials for years either as monotherapy or in combination with other therapeutical agents [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

Zhang

Wang

Liu

et al. 2017

European Journal of Medicinal Chemistry

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A structure-based medicinal chemistry optimization was conducted on the clinical Hsp90 inhibitor diarylisoxazole 3. Several series of new compounds were designed and synthesized by incorporating diversified amino acid derivatives with various lengths to the 3-amido motif of the isoxazole scaffold. Compound 14j was identified to have high Hsp90 binding potency (14 nM) and antiproliferative activity against H3122 human lung cancer and BT-474 breast cancer cells. Treatment of 14j with H3122 cell led to degradation of client protein ALK, reduction of downstream phosphorylation of AKT and ERK, and up-regulation of Hsp70. Molecular docking suggested that the terminal valine moiety and the ethyleneglycol linker in compound 14j formed additional apolar and polar interaction network with a number of amino acid residues.

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Phase 1/1B trial of the heat shock protein 90 inhibitor NVP‐AUY922 as monotherapy or in combination with bortezomib in patients with relapsed or refractory multiple myeloma

Cited by 55 publications

References 22 publications

Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation

Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation

Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines

Design, synthesis and pharmacological evaluation of 4,5-diarylisoxazols bearing amino acid residues within the 3-amido motif as potent heat shock protein 90 (Hsp90) inhibitors

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