Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer—results of a first-in-man dose-escalation study with a fixed-dose extension phase

Isambert, Nicolás; Delord, Jean‐Pierre; Soria, Jean‐Charles; Hollebecque, Antoine; Gomez‐Roca, Carlos; Purcea, Daniela; Rouits, Elisabeth; Belli, Riccardo; Fumoleau, P.

doi:10.1093/annonc/mdv031

Cited by 28 publications

(28 citation statements)

References 22 publications

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“…Consistent with this, an acetylome analysis that compared protein acetylation by entinostat versus vorinostat directly demonstrated that a subset of lysine residues on Hsp90 are acetylated by vorinostat but not by entinostat treatment (38). To confirm that vorinostat inhibits Hsp90 activity in HIV-infected HSPCs and PBMCs, we assessed Hsp70 levels, which are induced upon inhibition of Hsp90 activity in a heat shock factor-1-dependent pathway (39)(40)(41). As a positive control, we treated HSPCs and PBMCs with a specific Hsp90 inhibitor (17-AAG), which induced a dramatic increase in Hsp70, compared to the solvent control ( Fig.…”

Section: Resultsmentioning

confidence: 78%

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Zaikos

Painter

Kettinger

et al. 2018

J Virol

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Combinations of drugs that affect distinct mechanisms of HIV latency aim to induce robust latency reversal leading to cytopathicity and elimination of the persistent HIV reservoir. Thus far, attempts have focused on combinations of protein kinase C (PKC) agonists and pan-histone deacetylase inhibitors (HDIs) despite the knowledge that HIV gene expression is regulated by class 1 histone deacetylases. We hypothesized that class 1-selective HDIs would promote more robust HIV latency reversal in combination with a PKC agonist than pan-HDIs because they preserve the activity of proviral factors regulated by non-class 1 histone deacetylases. Here, we show that class 1-selective agents used alone or with the PKC agonist bryostatin-1 induced more HIV protein expression per infected cell. In addition, the combination of entinostat and bryostatin-1 induced viral outgrowth, whereas bryostatin-1 combinations with pan-HDIs did not. When class 1-selective HDIs were used in combination with pan-HDIs, the amount of viral protein expression and virus outgrowth resembled that of pan-HDIs alone, suggesting that pan-HDIs inhibit robust gene expression induced by class 1-selective HDIs. Consistent with this, pan-HDI-containing combinations reduced the activity of NF-κB and Hsp90, two cellular factors necessary for potent HIV protein expression, but did not significantly reduce overall cell viability. An assessment of viral clearance from cultures indicated that maximal protein expression induced by class 1-selective HDI treatment was crucial for reservoir clearance. These findings elucidate the limitations of current approaches and provide a path toward more effective strategies to eliminate the HIV reservoir. Despite effective antiretroviral therapy, HIV evades eradication in a latent form that is not affected by currently available drug regimens. Pharmacologic latency reversal that leads to death of cellular reservoirs has been proposed as a strategy for reservoir elimination. Because histone deacetylases (HDACs) promote HIV latency, HDAC inhibitors have been a focus of HIV cure research. However, many of these inhibitors broadly affect multiple classes of HDACs, including those that promote HIV gene expression (class 1 HDACs). Here, we demonstrate that targeted treatment with class 1-selective HDAC inhibitors induced more potent HIV latency reversal than broadly acting agents. Additionally, we provide evidence that broadly acting HDIs are limited by inhibitory effects on non-class 1 HDACs that support the activity of proviral factors. Thus, our work demonstrates that the use of targeted approaches to induce maximum latency reversal affords the greatest likelihood of reservoir elimination.

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Section: Resultsmentioning

confidence: 78%

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Zaikos

Painter

Kettinger

et al. 2018

J Virol

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“…Only Debio0932 has been evaluated in a phase I trial. Toxicity was manageable, but with limited clinical activity [26]. No data are available for this compound in ALK-rearranged patients.…”

Section: Expert Opinionmentioning

confidence: 99%

“…The extension cohort consisted of another 30 patients (15 NSCLC), these patients were treated with 1000 mg once daily. Approximately half of the NSCLC patients showed SD (one metabolic PR) [26]. The subsequent phase I/II trial in molecularly unselected NSCLC patients that combined debio0932 with standard of care chemotherapy has been terminated (NCT 01714037) for unknown reasons.…”

Section: Debio0932mentioning

confidence: 99%

Heat shock protein antagonists in early stage clinical trials for NSCLC

Hendriks

Dingemans

2017

Expert Opinion on Investigational Drugs

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Cancer cells have a higher need of chaperones than normal cells to prevent the toxic effects of intracellular protein misfolding and aggregation. Heat shock proteins (Hsps) belong to these chaperones; they are classified into families according to molecular size. Hsps are upregulated in many cancers and inhibition can inhibit tumor growth by destabilizing proteins necessary for tumor survival. In non-small cell lung cancer (NSCLC), there are three different Hsp antagonist classes that are in (early) clinical trials: Hsp90, Hsp70 and Hsp27 inhibitors. Areas covered: The rationale to use Hsp inhibitors in NSCLC will be summarized and phase I-III trials will be reviewed. Expert opinion: Several Hsp90 inhibitors have been tested in phase I-III trials, until now none was positive in unselected NSCLC; therefore development of AUY922, ganetespib and retaspimycin was halted. Results seem more promising in molecularly selected patients, especially in ALK-rearranged NSCLC. Hsp27 is overexpressed in squamous NSCLC and is a mechanism of chemotherapy resistance. The Hsp27 inhibitor apatorsen is now tested in squamous NSCLC. No phase II/III data are known for Hsp70 inhibitors. Combination of Hsp inhibitors with heat shock transcription factor 1 inhibitors or focal adhesion kinase inhibitors might be of interest for future trials.

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“…Recently, several novel smallmolecule Hsp90 inhibitors have been developed, some of which have been demonstrated to induce brain Hsps in murine models of Alzheimer's disease and Parkinson's disease (66,67). Furthermore, although some of these compounds have failed in clinical trials for various malignancies or cancers due to limited clinical activity, the adverse effects of the drugs were manageable (68). These compounds may be of utility as therapeutic agents against SCA14.…”

Section: Hsp Cytoprotection In Sca14mentioning

confidence: 99%

Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14

Nakazono

Adachi

Takahashi

et al. 2018

Journal of Biological Chemistry

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Amyloid and amyloid-like protein aggregations are hallmarks of multiple, varied neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. We previously reported that spinocerebellar ataxia type 14 (SCA14), a dominant-inherited neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cγ (PKCγ). A number of protein chaperones, including heat shock protein 70 (Hsp70), promote the degradation and/or refolding of misfolded proteins and thereby prevent their aggregation. Here, we report that, in various SCA14-associated, aggregating PKCγ variants, endogenous Hsp70 is incorporated into aggregates and that expression of these PKCγ mutants up-regulates Hsp70 expression. We observed that PKCγ binds Hsp70 and that this interaction is enhanced in the SCA14-associated variants, mediated by the kinase domain that is involved in amyloid-like fibril formation as well as the C2 domain of PKCγ. Pharmacological up-regulation of Hsp70 by the Hsp90 inhibitors celastrol and herbimycin A attenuated the aggregation of mutant PKCγ in primary cultured Purkinje cells. Up-regulation of Hsp70 diminished net PKCγ aggregation by preventing aggregate formation, resulting in decreased levels of apoptotic cell death among primary cultured Purkinje cells expressing the PKCγ variant. Of note, herbimycin A also ameliorated abnormal dendritic development. Extending our observations, administration of celastrol to mice up-regulated cerebellar Hsp70. Our findings identify heat shock proteins as important endogenous regulators of pathophysiological PKCγ aggregation and point to Hsp90 inhibition as a potential therapeutic strategy in the treatment of SCA14.

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Debio0932, a second-generation oral heat shock protein (HSP) inhibitor, in patients with advanced cancer—results of a first-in-man dose-escalation study with a fixed-dose extension phase

Abstract: NCT01168752.

Cited by 28 publications

References 22 publications

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Class 1-Selective Histone Deacetylase (HDAC) Inhibitors Enhance HIV Latency Reversal while Preserving the Activity of HDAC Isoforms Necessary for Maximal HIV Gene Expression

Heat shock protein antagonists in early stage clinical trials for NSCLC

Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14

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