Phase I/II Trial of Vemurafenib in Dogs with Naturally Occurring, BRAF -mutated Urothelial Carcinoma.

Autor:	Rossman P; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana., Zabka TS; Development Sciences, Genentech Inc., South San Francisco, California., Ruple A; Department of Public Health, College of Health and Human Sciences, Purdue University, West Lafayette, Indiana.; Purdue University Center for Cancer Research, West Lafayette, Indiana., Tuerck D; Department Pharmaceutical Sciences, Roche, Basel, Switzerland., Ramos-Vara JA; Purdue University Center for Cancer Research, West Lafayette, Indiana.; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana., Liu L; Drug Metabolism & Pharmacokinetics, Genentech Inc., South San Francisco, California., Mohallem R; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.; Bindley Bioscience Center, Purdue University, West Lafayette, Indiana., Merchant M; Translational Oncology, Genentech Inc., South San Francisco, California., Franco J; Bindley Bioscience Center, Purdue University, West Lafayette, Indiana., Fulkerson CM; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.; Purdue University Center for Cancer Research, West Lafayette, Indiana., Bhide KP; Bioinformatics Core, College of Agriculture, Purdue University, West Lafayette, Indiana., Breen M; Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina., Aryal UK; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.; Bindley Bioscience Center, Purdue University, West Lafayette, Indiana., Murray E; Global Safety Risk Management, Genentech Inc., South San Francisco, California., Dybdal N; Development Sciences, Genentech Inc., South San Francisco, California., Utturkar SM; Purdue University Center for Cancer Research, West Lafayette, Indiana., Fourez LM; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana., Enstrom AW; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana., Dhawan D; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana., Knapp DW; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana. knappd@purdue.edu.; Purdue University Center for Cancer Research, West Lafayette, Indiana.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Nov; Vol. 20 (11), pp. 2177-2188. Date of Electronic Publication: 2021 Aug 25.
DOI:	10.1158/1535-7163.MCT-20-0893
Abstrakt:	BRAF-targeted therapies including vemurafenib (Zelboraf) induce dramatic cancer remission; however, drug resistance commonly emerges. The purpose was to characterize a naturally occurring canine cancer model harboring complex features of human cancer, to complement experimental models to improve BRAF-targeted therapy. A phase I/II clinical trial of vemurafenib was performed in pet dogs with naturally occurring invasive urothelial carcinoma (InvUC) harboring the canine homologue of human BRAF V600E The safety, MTD, pharmacokinetics, and antitumor activity were determined. Changes in signaling and immune gene expression were assessed by RNA sequencing and phosphoproteomic analyses of cystoscopic biopsies obtained before and during treatment, and at progression. The vemurafenib MTD was 37.5 mg/kg twice daily. Anorexia was the most common adverse event. At the MTD, partial remission occurred in 9 of 24 dogs (38%), with a median progression-free interval of 181 days (range, 53-608 days). In 18% of the dogs, new cutaneous squamous cell carcinoma and papillomas occurred, a known pharmacodynamic effect of vemurafenib in humans. Upregulation of genes in the classical and alternative MAPK-related pathways occurred in subsets of dogs at cancer progression. The most consistent transcriptomic changes were the increase in patterns of T lymphocyte infiltration during the first month of vemurafenib, and of immune failure accompanying cancer progression. In conclusion, the safety, antitumor activity, and cutaneous pharmacodynamic effects of vemurafenib, and the development of drug resistance in dogs closely mimic those reported in humans. This suggests BRAF -mutated canine InvUC offers an important complementary animal model to improve BRAF-targeted therapies in humans. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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