PO.PR02.01 · 预防研究

STAT3抑制剂TTI-101在致癌物诱导的大鼠膀胱肿瘤模型中有效阻断膀胱癌

STAT3 inhibitor TTI-101 effectively intercepts bladder cancer in a carcinogen-induced rat bladder tumor model

编号 951 展板 10 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, Nicole Stratton¹, Anh Bao¹, David J. Tweardy², Shizuko Sei³, Vignesh Gunasekharan³, 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 Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,³Division of Cancer Prevention, National Cancer Institute, Rockville, MD

摘要 Abstract

中文摘要

膀胱癌（BC）是全球第9大常见癌症。大多数膀胱肿瘤在非肌层浸润（NMIBC）阶段被检出并治疗。然而，肿瘤频繁复发，许多进展为MIBC并转移，造成显著死亡。BC发病率和死亡率的上升凸显了开发新的管理方案的必要性。转录因子信号转导及转录激活因子3（STAT3）通过炎症和免疫应答调控细胞增殖。其激活在正常细胞中受到高度调控，但在包括BC在内的癌症中呈组成性激活。研究显示，显性负性STAT3的表达可抑制裸鼠中的肿瘤形成。我们及其他研究者此前报道，STAT3抑制剂可降低BC细胞的存活和增殖。在本研究中，我们测定了STAT3抑制小分子（GLG-302、SH5-07、TTI-101）在体外BC细胞和体内大鼠肿瘤中的药效学pSTAT3抑制作用。进一步评估了TTI-101在N-丁基-N-(4-羟基)-亚硝胺（BBN）大鼠BC模型中阻断BC的潜力。雌性F344大鼠被随机分为安慰剂组、STAT3组（n=24）和舒林酸（Sulindac）组（n=18）干预组。8周龄时，大鼠经口灌胃给予BBN（150 mg/剂量；每周2次，持续8周）。药物治疗在乳头状瘤阶段开始，即最后一次BBN后约10周。干预组大鼠经口灌胃给予25或75 mg/kg体重的TTI-101（每周5次），持续20周。舒林酸以10 mg/kg体重给药作为对照药。所有药物均使用60% labrasol:40% PEG400配制。在约45周龄时评估膀胱肿瘤。TTI-101未引起任何明显毒性。BBN在所有大鼠中诱导膀胱肿瘤，导致安慰剂组的膀胱较大（0.31±0.06 g；均值±SEM）。重要的是，与安慰剂相比，TTI-101 25 mg/kg和75 mg/kg组的膀胱重量分别为0.21±0.06 mg（抑制32%；p>0.05）和0.13±0.01 g（抑制58%；p<0.01）。舒林酸处理具有非显著的46%抑制（0.17±0.02 g；p=0.07）。在安慰剂组中，约半数大鼠发生大膀胱肿瘤（>200 mg；发生率50%）。有趣的是，TTI-101 25 mg/kg（发生率17%；p<0.05）和75 mg/kg体重剂量（发生率8%；p<0.005）以剂量依赖方式使发生此类肿瘤的大鼠显著减少（分别减少67%-83%）。因此，使用TTI-101抑制STAT3可剂量依赖性地抑制膀胱肿瘤生长。生物标志物和基因表达分析提示，随着pSTAT3表达降低，关键促肿瘤通路受到调节。总之，我们的研究证实，使用TTI-101抑制STAT3可阻断膀胱肿瘤生长，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75N91019D00020-75N91020F00005）

查看英文原文 English abstract

Bladder cancer (BC) is the 9th most common cancer worldwide. Most bladder tumors are detected and treated at the non-muscle invasive (NMIBC) stage. However, tumors recur frequently, many progress to MIBC and metastasize contributing to significant mortality. Rising incidence and mortality in BC underscore the need to develop new regimen for its management. Transcriptional factor Signal transducer and activator of transcription 3 (STAT3) regulates cell proliferation through inflammation and immune responses. Its activation is highly regulated in normal cells but in cancers including BC, it is constitutively active. Expression of dominant-negative STAT3 was shown to inhibit tumor formation in nude mice. Earlier we and others reported that STAT3 inhibitors reduces BC cell survival and proliferation. In the present study, we determined pharmacodynamic pSTAT3 inhibitory effect of STAT3 inhibiting small molecules (GLG-302, SH5-07, TTI-101) in-vitro BC cells and in-vivo rat tumors. TTI-101 was further evaluated for its potential to intercept BC in a N-butyl-N-(4-hydroxyl)-nitrosamine (BBN)-rat BC model. Female F344 rats were randomized into a placebo, STAT3 (n=24) and Sulindac (n=18) intervention groups. Eight-weeks of age, rats were given BBN by oral gavage (150mg/dose; 2x/week for 8 weeks). Drug treatment was initiated at papilloma stage i.e., ~10 weeks after last BBN. Rats in intervention groups received TTI-101 at 25 or 75mg/kg body weight by oral gavage (5x/week) for 20 weeks. Sulindac was administered at 10mg/kg BW as a comparator. All drugs were formulated using 60% labrasol:40% PEG400. Bladder tumors were assessed at ~45 weeks of age. TTI-101 did not cause any overt-toxicities. BBN-induced bladder tumors in all rats, resulting in larger bladders in placebo group (0.31±0.06g; Mean±SEM). Importantly, bladder weights in TT1-101 25mg/kg and 75mg/kg groups were 0.21±0.06mg (32% inhibition; p>0.05) and 0.13±0.01g (58% inhibition; p<0.01) when compared to the placebo. Sulindac treatment had non-significant 46% inhibition (0.17±0.02g; p=0.07). In the placebo group, about half of all rats developed large bladder tumors (>200mg; 50% incidence). Interestingly, significantly fewer rats developed such tumors with TTI-101 25-mg/kg (17% incidence; p<0.05) and at 75mg/kg BW dose (8% incidence; p<0.005) in a dose dependent manner (67%-83% less respectively). Thus, STAT3 inhibition with TTI-101 resulted in a dose dependent inhibition of bladder tumors growth. Biomarker and gene expression analysis suggested modulation of critical tumor promoting pathways with decrease in pSTAT3 expression. Collectively, our study demonstrated that STAT3 inhibition using TTI-101 can intercept bladder tumor growth and warrants further investigation in clinical trials. (Project funded in whole with Federal funds from the NCI-NIH, DHHS, under Contract No. 75N91019D00020-75N91020F00005).

利益披露 Disclosure

V. Madka, None.. G. Pathuri, None.. A. Singh, None.. N. Stratton, None.. A. Bao, None.. D. J. Tweardy, None.. S. Sei, None.. V. Gunasekharan, None.. C. V. Rao, None.

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