دورية أكاديمية
A Proof-of-Concept Study of Sequential Treatment with the HDAC Inhibitor Vorinostat following BRAF and MEK Inhibitors in BRAFV600-Mutated Melanoma.
| العنوان: | A Proof-of-Concept Study of Sequential Treatment with the HDAC Inhibitor Vorinostat following BRAF and MEK Inhibitors in BRAFV600-Mutated Melanoma. |
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| المؤلفون: | Embaby A; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Huijberts SCFA; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands., Wang L; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Leite de Oliveira R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.; CEMM, Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands., Rosing H; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Nuijen B; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Sanders J; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Hofland I; Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Steenis C; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Kluin RJC; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Lieftink C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Smith CG; NeoGenomics, Babraham Research Park, Cambridge, United Kingdom., Blank CU; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., van Thienen JV; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Haanen JBAG; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Steeghs N; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Opdam FL; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Beijnen JH; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Faculty of Science, Utrecht University, Utrecht, the Netherlands., Huitema ADR; Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.; Faculty of Science, Utrecht University, Utrecht, the Netherlands., Schellens JHM; Faculty of Science, Utrecht University, Utrecht, the Netherlands., Wilgenhof S; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 01; Vol. 30 (15), pp. 3157-3166. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Melanoma*/drug therapy , Melanoma*/genetics , Melanoma*/pathology , Melanoma*/mortality , Proto-Oncogene Proteins B-raf*/genetics , Proto-Oncogene Proteins B-raf*/antagonists & inhibitors , Vorinostat*/administration & dosage , Vorinostat*/pharmacology , Histone Deacetylase Inhibitors*/administration & dosage , Histone Deacetylase Inhibitors*/therapeutic use , Histone Deacetylase Inhibitors*/adverse effects , Histone Deacetylase Inhibitors*/pharmacology , Histone Deacetylase Inhibitors*/pharmacokinetics , Mutation* , Protein Kinase Inhibitors*/therapeutic use , Protein Kinase Inhibitors*/administration & dosage , Protein Kinase Inhibitors*/adverse effects , Antineoplastic Combined Chemotherapy Protocols*/therapeutic use , Antineoplastic Combined Chemotherapy Protocols*/adverse effects, Humans ; Female ; Male ; Middle Aged ; Aged ; Adult ; Proof of Concept Study ; Drug Resistance, Neoplasm/genetics ; Drug Resistance, Neoplasm/drug effects ; Aged, 80 and over |
| مستخلص: | Purpose: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. Patients and Methods: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. Results: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. Conclusions: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%). (©2024 American Association for Cancer Research.) |
| معلومات مُعتمدة: | N16VOM Oncode Institute |
| المشرفين على المادة: | EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) 58IFB293JI (Vorinostat) EC 2.7.11.1 (BRAF protein, human) 0 (Histone Deacetylase Inhibitors) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240513 Date Completed: 20240801 Latest Revision: 20240801 |
| رمز التحديث: | 20240801 |
| DOI: | 10.1158/1078-0432.CCR-23-3171 |
| PMID: | 38739109 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-23-3171 |