Journal
CLINICAL CANCER RESEARCH
Volume 22, Issue 19, Pages 4890-4900Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-15-2823
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Funding
- NIH National Institute of General Medical Sciences Grant [U01 GM61390]
- NIH/National Institute of General Medical Sciences (NIGMS) Pharmacogenomics of Anticancer Agents [U01GM61393]
- NIH/National Institute of Nursing Research (NINR) [P30NR014129]
- ALLIANCE grants [CA31946, CA33601]
- ECOG-ACRIN grants [CA21115, CA16116]
- Genentech
- [U10CA031983]
- [U10CA060138]
- [U10CA047577]
- [U10CA180838]
- [U10CA180857]
- Grants-in-Aid for Scientific Research [16H01569] Funding Source: KAKEN
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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 x 10(-8), adjusted P = 5.88 x 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. (C) 2016 AACR.
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