ArticleBritish journal of cancer2015
A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies.
Article in British journal of cancer, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Combination therapy with HSP90 inhibitors and NanoPulse stimulation synergistically impedes hepatocellular carcinoma and breast cancer growth in mice.Scientific reports · 2026Article
- A small-molecule HSP90 inhibitor, NVP-HSP990, alleviates rotavirus infection.Journal of virology · 2026Article
- Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma.Research square · 2025Article
- In Vivo Visualization and Quantification of Brain Heat Shock Protein 90 with [Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2025Article
- Advances in the structures, mechanisms and targeting of molecular chaperones.Signal transduction and targeted therapy · 2025Review
- Radius additivity score: a novel combination index for tumour growth inhibition in fixed-dose xenograft studies.Frontiers in pharmacology · 2023Article
- Chaperone-assisted E3 ligase CHIP: A double agent in cancer.Genes & diseases · 2022Review
- A quantitative high-throughput screen identifies compounds that lower expression of the SCA2-and ALS-associated gene ATXN2.The Journal of biological chemistry · 2022Article
- TRAP1 in Oxidative Stress and Neurodegeneration.Antioxidants (Basel, Switzerland) · 2021Review
- Resilience in Long-Term Viral Infection: Genetic Determinants and Interactions.International journal of molecular sciences · 2021Article
- The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition.Acta pharmaceutica Sinica. B · 2021Review
- Priming with HDAC Inhibitors Sensitizes Ovarian Cancer Cells to Treatment with Cisplatin and HSP90 Inhibitors.International journal of molecular sciences · 2020Article
- Proteostasis and Proteotoxicity in the Network Medicine Era.International journal of molecular sciences · 2020Review
- Approaches to develop therapeutics to treat frontotemporal dementia.Neuropharmacology · 2020Review
- Suppression of Esophageal Cancer Stem-like Cells by SNX-2112 Is Enhanced by STAT3 Silencing.Frontiers in pharmacology · 2020Article
- Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity.Theranostics · 2020Article
- Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- The proteostasis network provides targets for neurodegeneration.British journal of pharmacology · 2019Review
- Traditional and Novel Mechanisms of Heat Shock Protein 90 (HSP90) Inhibition in Cancer Chemotherapy Including HSP90 Cleavage.Biomolecules & therapeutics · 2019Article
- Mild hyperthermia as a localized radiosensitizer for deep-seated tumors: investigation in an orthotopic prostate cancer model in mice.The British journal of radiology · 2019Article
Corrections and comments
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundHeat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs).
methodsHeat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control.
resultsA total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease.
conclusionsHeat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly.
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