Armstrong Andrew J, Netto George J, Rudek Michelle A, Halabi Susan, Wood David P, Creel Patricia A, Mundy Kelly, Davis S Lindsay, Wang Ting, Albadine Roula, Schultz Luciana, Partin Alan W, Jimeno Antonio, Fedor Helen, Febbo Phillip G, George Daniel J, Gurganus Robin, De Marzo Angelo M, Carducci Michael A
Duke Comprehensive Cancer Center and Duke Prostate Center, Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27710, USA.
Clin Cancer Res. 2010 Jun 1;16(11):3057-66. doi: 10.1158/1078-0432.CCR-10-0124. Epub 2010 May 25.
Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy.
Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum > or =7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy.
Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood.
At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed.
鉴于在前列腺癌中雷帕霉素哺乳动物靶点（mTOR）抑制的临床前和临床观察结果存在差异，我们试图确定mTOR/TORC1抑制剂雷帕霉素对接受根治性前列腺切除术的中高危前列腺癌男性患者的药效学作用。
对于多灶性Gleason评分≥7的前列腺癌男性患者，在根治性前列腺切除术前行14天口服3或6mg雷帕霉素治疗；纳入10名未接受治疗的对照受试者。主要结局是比较治疗后根治性前列腺切除术中肿瘤组织与治疗前活检肿瘤组织中核糖体S6磷酸化的抑制情况，采用Simon两阶段设计评估药效学疗效。
共纳入32名受试者：20名服用3mg，2名服用6mg，10名作为对照。3mg剂量组未观察到剂量限制性毒性；然而，服用6mg的两名男性均出现剂量限制性毒性，包括血小板减少和发热伴3级口腔炎。3mg剂量组观察到的不良事件包括口腔炎、皮疹、肠梗阻和中性粒细胞减少。药效学研究显示，在10名可评估的接受雷帕霉素治疗且有足够配对组织的男性中，50%的患者肿瘤S6磷酸化受到抑制[中位抑制率58%（P = 0.049），而对照组为2%（P = 0.75）]，对AKT活性无显著影响。我们观察到Ki-67或caspase-3裂解无变化，但注意到雷帕霉素治疗后细胞质p27染色减少，核定位增加。前列腺组织中雷帕霉素浓度比血液中高3至4倍。
每日3mg剂量时，雷帕霉素成功且安全地抑制了前列腺癌S6磷酸化，并在前列腺组织中达到了相对较高的浓度。未观察到对AKT磷酸化、肿瘤增殖或凋亡的影响。
