Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism That Increases Risk of Docetaxel-Induced Neuropathy

Purpose Discovery of single nucleotide polymorphisms (SNPs) that predict a patient\u27s 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=2.12×10-8 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\u3c0.0001). 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

Brain -derived neurotrophic factor modulates paclitaxel-induced allodynia in the mouse

Paclitaxel is one of the most commonly and widely prescribed chemotherapy agents used to treat cancers of the breast, ovaries, and lung. As many as 95% of paclitaxel treated patients, depending on their treatment protocol, develop painful and often disabling peripheral sensory complaints, which are generally resistant to both prevention and conventional approaches to symptom management. One in five patients survives paclitaxel treatment with persistent pain that limits quality of life. Brain-derived neurotrophic factor (BDNF), a growth factor critical to neuron development and survival, is implicated in the development of several neuropathic pain states but has not been examined as a potential mechanism responsible for the pain and sensory complaints that follow paclitaxel treatment. This study explored the potential nociceptive role of BDNF in a mouse model of paclitaxel-induced painful peripheral neuropathy, with a focus on the expression of BDNF and its receptor trkB in mechanical allodynia in the spinal cord. Serial doses of 1 mg/kg paclitaxel in a cremophor base (4 mg/kg cumulative dose) produced a mechanical allodynia in mice that persisted nearly 3 months after paclitaxel dosing ends. Allodynia was attenuated through experimental manipulation of the levels of BDNF ligand as well as through experimental manipulation of trkB isoform expression. Using mice producing less endogenous systemic BDNF we demonstrated that a reduction in paclitaxel-induced allodynia was associated with a reduction in BDNF expression, although the trajectory of symptom development following paclitaxel treatment remained unaltered. However, targeted reductions of spinal BDNF using an intrathecal BDNF scavenging protein reduced both allodynia development and the trajectory of symptom development, suggesting that BDNF modulates allodynia in a time and dose dependent manner. Moreover, genetic deletion of the truncated trkB.T1 receptor resulted in almost complete attenuation of paclitaxel-induced mechanical allodynia, while blockade of full-length trkB signaling blunted both the induction and the persistence of paclitaxel-induced nociception, suggesting that the truncated trkB isoform plays a critical role in paclitaxel-induced allodynia separate from the full length trkB receptor. Findings from this study have important implications for understanding both the neuropathic symptoms of mechanical allodynia as well as the specific mechanical hypersensitivity that follows paclitaxel administration. Results suggest that reducing levels of spinal BDNF early in the course of treatment many blunt both the severity and persistence of painful sensory symptoms, while therapies targeted at the truncated T1 isoform of the trkB receptor may reduce or prevent symptom onset