ABSTRACT
PURPOSE: Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. PATIENTS AND METHODS: Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. RESULTS: Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%). CONCLUSION: Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Neoplasm Proteins/genetics , Neovascularization, Physiologic/genetics , Polymorphism, Single Nucleotide , Pyrimidines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Sulfonamides/therapeutic use , Angiogenesis Inhibitors/pharmacology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Clinical Trials, Phase II as Topic/statistics & numerical data , Cross-Over Studies , DNA Mutational Analysis , Disease-Free Survival , Genetic Markers , Genotype , Germ-Line Mutation , Humans , Indazoles , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Multicenter Studies as Topic/statistics & numerical data , Proportional Hazards Models , Pyrimidines/pharmacology , Randomized Controlled Trials as Topic/statistics & numerical data , Sulfonamides/pharmacologyABSTRACT
Initial rates of uptake of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D; 20 microM) were measured in intact lateral choroid plexus from rat. Although inhibition of uptake by millimolar concentrations of estrone sulfate (ES) and unlabeled 2,4-D was maximal at 85%, inhibition by p-aminohippurate (PAH) saturated at about 50%. Inhibition by ES plus PAH was no greater than by ES or 2,4-D alone. Thus, inhibition studies indicated three distinct components of uptake; two mediated and one not. The sodium-dependent component of 2,4-D uptake coincided with the PAH-sensitive component, indicating uptake mediated by organic anion transporter subtype (Oat) 3. Consistent with this, efflux of 2,4-D from preloaded tissue was accelerated by all Oat3 substrates tested, and 2,4-D increased the efflux of the Oat3 substrate, PAH. Consistent with the inhibition data, kinetic analysis showed three components of 2,4-D uptake: a nonmediated component (linear kinetics), a high-affinity component, and a low-affinity component. The high-affinity component appeared to coincide with the PAH-sensitive and sodium-dependent component characterized in inhibition studies. The PAH-insensitive, low-affinity component was inhibited by ES, dehydroepiandrosterone sulfate, and taurocholate but not by 5-hydroxyindole acetic acid. Thus, the first step in transport of 2,4-D from cerebrospinal fluid to blood involves two transporters: Oat3 and a PAH-insensitive, sodium-independent transporter. Based on inhibitor profile, the latter may be Oatp3.
