1. Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy
- Author
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Kouros Owzar, M. Eileen Dolan, Ivo D. Shterev, Michael A. Carducci, Susan G. Dorsey, Paula N. Friedman, Yoichi Furukawa, Dorothy Watson, Michael J. Kelley, Yusuke Nakamura, Flora Mulkey, Stefanie D. Krens, Alexander B. Sibley, Jai N. Patel, Chen Jiang, Deanna L. Kroetz, Phillip G. Febbo, Michiaki Kubo, Lois S. Weisman, Claudia Wing, Mark J. Ratain, Sherrie Lessans, Susan Halabi, John Francis Mahoney, Daniel L. Hertz, William Kevin Kelly, Heather E. Wheeler, Cynthia L. Renn, Eric J. Small, Michael J. Morris, Howard L. McLeod, and Cameron B Lassiter
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Genome-wide association study ,Docetaxel ,Bioinformatics ,Inbred C57BL ,Castration-Resistant ,Prostate cancer ,Mice ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Aged, 80 and over ,Mice, Knockout ,Intracellular Signaling Peptides and Proteins ,Single Nucleotide ,Middle Aged ,Bevacizumab ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,Chemotherapy-induced peripheral neuropathy ,030220 oncology & carcinogenesis ,Taxoids ,medicine.drug ,Adult ,Genotype ,Knockout ,Oncology and Carcinogenesis ,Single-nucleotide polymorphism ,and over ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Polyneuropathies ,Double-Blind Method ,medicine ,SNP ,Animals ,Humans ,Genetic Predisposition to Disease ,Oncology & Carcinogenesis ,Polymorphism ,Aged ,business.industry ,Membrane Proteins ,Prostatic Neoplasms ,medicine.disease ,Pharmacogenomic Testing ,Mice, Inbred C57BL ,030104 developmental biology ,Prednisone ,business ,Pharmacogenetics ,Genome-Wide Association Study - Abstract
Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.
- Published
- 2016