Pharmacogenetic discovery in CALGB (Alliance) 90401 and mechanistic validation of a VAC14 polymorphism that increases risk of docetaxel-induced neuropathy
Authors: D. L. Hertz, K. Owzar, S. Lessans, C. Wing, C. Jiang, W. K. Kelly, J. N. Patel, S. Halabi, Y. Furukawa, H. E. Wheeler, A. Sibley, C. Lassiter, L. S. Weisman, D. Watson, S. D. Krens, F. Mulkey, C. L. Renn, E. J. Small, P. G. Febbo, I. Shterev, D. Kroetz, P. N. Friedman, J. F. Mahoney, M. A. Carducci, M. J. Kelley, Y. Nakamura, M. Kubo, S. G. Dorsey, M. E. Dolan, M. J. Morris, M. J. Ratain, H. L. McLeod
Summary:
Purpose: Discovery of single nucleotide polymorphisms (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: 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. A SNP in VAC14 (rs875858) surpassed genome-wide significance (p=2.12x10-8 adjusted p=5.88x10-7). 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.
Source: Clinical Cancer Research; 2016
Summary:
Purpose: Discovery of single nucleotide polymorphisms (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: 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. A SNP in VAC14 (rs875858) surpassed genome-wide significance (p=2.12x10-8 adjusted p=5.88x10-7). 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.
Source: Clinical Cancer Research; 2016