Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer.
Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer.
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DOI：
10.1158/1078-0432.ccr-16-2245
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Montgomery RB
中科院分区：
文献类型：
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作者：
Mostaghel EA;Cho E;Zhang A;Alyamani M;Kaipainen A;Green S;Marck BT;Sharifi N;Wright JL;Gulati R;True LD;Loda M;Matsumoto AM;Tamae D;Penning TN;Balk SP;Kantoff PW;Nelson PS;Taplin ME;Montgomery RB
溶质载体有机阴离子（SLCO）基因的种系变异影响细胞类固醇摄取并与前列腺癌（PCa）结局相关。我们假设，由于其甾体结构，CYP 17 A抑制剂阿比特龙可能经历SLCO介导的转运，SLCO基因变异可能影响细胞内阿比特龙水平和结果。在前列腺切除术前24周的LHRH激动剂加醋酸阿比特龙加泼尼松的临床试验中，测量了58名患有局限性前列腺癌的男性的血清和组织中的类固醇和阿比特龙水平。对6个SLCO基因的13个单核苷酸多态性（SNPS）进行了基因分型。阿比特龙水平跨越宽范围（血清中位数28 ng/ml，108 nM;组织中位数77 ng/ml，271 nM），并且相关（r=0.355，p=0.001）。水平与CYP 17 A上游的类固醇（双烯醇酮，孕酮）呈正相关，与CYP 17 A下游的类固醇（DHEA，AED，睾酮）呈负相关。在前列腺切除术时，与可检测的组织阿比特龙相比，不可检测的组织阿比特龙男性的血清PSA和肿瘤体积较高（中位数分别为0.10 vs 0.03ng/dl，p=0.02; 1.28 vs 0.44cc，p=0.09）。SLCO 2B 1中的SNP与组织阿比特龙的显著差异（rs 1789693，p=0.0008; rs 12422149，p=0.03）和较高的微小残留病变率（肿瘤体积<0.5 cc; rs 1789693，67% vs 27%，p=0.009; rs 1077858，46% vs 0%，p=0.03）相关。表达SLC 0 2B 1的LNCaP细胞显示与载体对照相比高2-4倍的阿比特龙水平（p<0.05）。前列腺内阿比特龙水平和SLCO基因的遗传变异与高危局限性PCa的病理反应相关SLCO基因的变异可以作为阿比特龙治疗反应的预测因子。
Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer (PCa) outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo SLCO-mediated transport and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized PCa in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 single nucleotide polymorphisms (SNPS) in 6 SLCO genes. Abiraterone levels spanned a broad range (serum median 28ng/ml, 108nM; tissue median 77ng/ml, 271nM) and were correlated (r=0.355, p=0.001). Levels correlated positivey with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable vs detectable tissue abiraterone at prostatectomy (median 0.10 vs 0.03ng/dl, p=0.02; 1.28 vs 0.44cc, p=0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, p=0.0008; rs12422149, p=0.03) and higher rates of minimal residual disease (tumor volume <0.5cc; rs1789693, 67% vs 27%, p=0.009; rs1077858, 46% vs 0%, p=0.03). LNCaP cells expressing SLCO2B1 showed 2–4 fold higher abiraterone levels compared to vector controls (p<0.05). Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized PCa. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.