PO.PR02.01 · 预防研究

雄激素受体抑制剂Apalutamide在BBN诱导的大鼠膀胱肿瘤模型中阻断膀胱癌的疗效

Efficacy of androgen receptor inhibitor, Apalutamide, in intercepting bladder cancer in a BBN-induced rat bladder tumor model

编号 950 展板 9 时间 4/19 02:00–05:00 区域 Section 37 主讲 Venkateshwar Madka, PhD

分会场 Experimental Chemoprevention and Interception: Data and Tools

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作者与单位 Authors & Affiliations

Venkateshwar Madka¹, Gopal Pathuri¹, Anil Singh¹, Surya P. Singh¹, Anh Bao¹, Nicole Stratton¹, Shizuko Sei², John Clifford², Chinthalapally V. Rao¹

¹Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, University of Oklahoma HSC, Oklahoma City, OK,²Division of Cancer Prevention, National Cancer Institute, Rockville, MD

摘要 Abstract

中文摘要

膀胱癌（BC）是第二常见的泌尿生殖系统癌症。大多数肿瘤在非肌层浸润（NMIBC）阶段被检出并接受治疗；然而，高复发率、治疗耐药、肿瘤进展和转移每年造成显著死亡。许多研究表明，BC在男性中的发病率显著更高且进展更为主要。实验数据还显示BC肿瘤发生与雄激素受体（AR）信号传导密切相关，使AR成为癌症阻断的有前景靶点。在本研究中，评估了AR拮抗剂apalutamide（APA）在N-丁基-N-(4-羟基)-亚硝胺（BBN）大鼠BC模型中的BC预防疗效。雄性和雌性Fischer大鼠被随机分为安慰剂组和干预组（每组每性别30只：24只BBN+6只生理盐水）。在8周龄时，致癌物组的大鼠经口灌胃给予BBN（150 mg/剂量；每周2次，持续8周）以诱导BC。干预组的大鼠经口灌胃给予7.5、15或30 mg/kg体重的APA（每周5次）直至终止。APA的早期干预始于致癌阶段，即最后一次BBN后一周，而延迟干预始于乳头状瘤阶段，即最后一次BBN后约10周。分别在雄性和雌性大鼠40周龄和50周龄时评估膀胱肿瘤。APA未引起任何明显毒性。BBN处理在所有大鼠中诱导膀胱肿瘤，导致安慰剂组的膀胱明显大于生理盐水组的正常膀胱。重要的是，与安慰剂相比，APA显著降低了膀胱重量，提示干预组的肿瘤生长受到抑制。在早期干预下，与安慰剂组相比，雄性大鼠的膀胱重量降低了60%-65%（p<0.05），雌性大鼠降低了54%-63%（p<0.05）。APA处理还以剂量依赖方式显著降低了大膀胱肿瘤的发生率，雄性降低30%-47%（p<0.05-p<0.01），雌性降低32%-50%（p<0.05）。延迟干预也仅在雄性大鼠中使膀胱重量降低21%-53%（p<0.01），大肿瘤发生率减少28%-66%。肿瘤切片的组织病理学分析表明，与安慰剂相比，APA处理的大鼠中乳头状瘤、NMIBC和MIBC的多发性显著减少，提示肿瘤进展受到抑制。生物标志物和基因表达分析提示APA处理调节了关键的促肿瘤通路。总之，这项临床前研究证实，AR拮抗剂apalutamide可阻断膀胱肿瘤的生长和进展，值得在临床试验中进一步研究。（本项目由NCI-NIH、DHHS的联邦资金全额资助，合同号75N91019D00020-75N91022F00002）

查看英文原文 English abstract

Bladder cancer (BC) is the second-most diagnosed genitourinary cancer. Most tumors are detected at the non-muscle invasive (NMIBC) stage and treated; however high recurrence rate, treatment resistance, tumor progression and metastasis contribute to significant mortality annually. Many studies have indicated significantly higher incidence rates and BC progression to be more predominant in men. Experimental data have also showed strong association of BC tumorigenesis with androgen receptor (AR) signaling , making AR a promising target for cancer interception. In this study, AR antagonist, apalutamide (APA) was evaluated for BC preventive efficacy in a N-butyl-N-(4-hydroxyl)-nitrosamine (BBN)-rat BC model. Male and female Fischer rats were randomized into placebo and intervention groups (30 rats/group/sex: 24 BBN+6 Saline). At 8 weeks of age, rats in carcinogen groups received BBN by oral gavage (150mg/dose; 2x/week for 8 weeks) to induce BC. APA was given to rats in intervention groups at 7.5, 15, or 30mg/kg body weight by oral gavage (5x/week) until termination. Early intervention with APA started at carcinogenesis stage i.e., a week after last BBN, while delayed intervention began at papilloma stage i.e., ~10 weeks after last BBN. Bladder tumors were assessed at 40 and 50 weeks of age in male and female rats respectively. APA did not cause any overt-toxicities. BBN treatment induced bladder tumors in all rats, resulting in significantly larger bladders in placebo group compared to normal bladders in saline group. Importantly, APA significantly reduced bladder weights suggesting tumor growth inhibition in intervention groups compared to placebo. With early intervention, bladder weights were reduced by 60%-65% in male rats (p<0.05) and by 54%-63% in female rats (p<0.05) when compared to the placebo group. Incidence of large bladder tumors was also significantly decreased with APA treatment by 30%-47% in males (p<0.05-p<0.01) and by 32%-50% in females (p<0.05) in a dose dependent manner. Delayed intervention also resulted in 21%-53% (p<0.01) reduction of bladder weights and 28%-66% less incidence of large tumors in male rats only. Histopathological analysis of the tumor sections demonstrated suppression of tumor progression in APA treated rats as indicated by the significant decrease in multiplicity of papillomas, NMIBC, and MIBC when compared to placebo. Biomarker and gene expression analysis suggested modulation of critical tumor promoting pathways with APA treatment. In summary, this preclinical study demonstrated that an AR antagonist, apalutamide, can intercept bladder tumor growth and progression and warrants further investigation in clinical trials. (Project funded in whole with Federal funds from the NCI-NIH, DHHS, under Contract No. 75N91019D00020 - 75N91022F00002).

利益披露 Disclosure

V. Madka, None.. G. Pathuri, None.. A. Singh, None.. S. P. Singh, None.. A. Bao, None.. N. Stratton, None.. S. Sei, None.. J. Clifford, None.. C. V. Rao, None.

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