Chemoprevention of tobacco carcinogen-induced bladder cancer

描述（由申请人提供）： 膀胱癌是第五大流行癌症;原发性/二手烟草暴露是主要病因。约80%的患者存在局限于粘膜的浅表疾病。复发是常见的侵犯到肌肉，甚至远处转移，致命的后果。膀胱癌进展涉及通过突变或表观遗传机制激活特定癌基因和生长因子/趋化因子，如CXCL-1和/或灭活肿瘤抑制基因（p53、视网膜母细胞瘤、BIM、p21、RASSF 1A、RUNX 3和p16 INK 4）。基因沉默的表观遗传机制在烟草致癌物介导的膀胱癌进展中占主导地位;据报道至少有50个基因经历了表观遗传修饰。这种基因沉默机制涉及组蛋白，特别是组蛋白H3和H4的特异性翻译后修饰。组蛋白H3、K9和K27三甲基化的增加以及组蛋白H4、K20三甲基化的丧失是癌症中常见的异常。因此，可以逆转癌症富集的组蛋白修饰的药物不仅可以有效治疗浸润性膀胱癌，而且可以预防从浅表病变进展为浸润性病变。我们开发了一种名为LC-1的化合物，它可以在体内和体外抑制膀胱癌细胞的生长。这种药物最初是作为转录因子NF-？B能抑制NF-？膀胱癌细胞中CXCL-1的B依赖性表达。此外，LC-1降低了“坏”表观遗传调节因子的水平，如polycomb蛋白EZH 2、组蛋白脱乙酰酶HADC 1和CtBP-1。此外，它降低了组蛋白H3 K9和K27三甲基化的水平，但增加了组蛋白H4 K20三甲基化的水平。这些LC-1诱导的组蛋白修饰与LC-1处理的细胞中组蛋白H3 K9三甲基化酶SUV 39 h1的表达减少和肿瘤抑制因子RUNX 3、BIM和p21的表达增加相关。假设：LC-1是一种独特的药物，可以通过抑制NF-？B以及逆转癌症相关的表观遗传变化。具体目标：在建立的ICR小鼠和Wister大鼠模型中研究LC-1在烟草致癌物诱导的膀胱癌中的化学预防活性，并将化学预防活性与p21、BIM（LC-1诱导型）、EZH 2、VEGF和SUV 39 h1（LC-1抑制型）的表达水平相关联。重要性：我们的研究具有立即转化的潜力，因为LC-1已经经历了几次毒性和药代动力学研究，目前正在进行白血病的I期临床试验。一项成功的白血病试验可以立即转化为浅表性膀胱病变患者的膀胱癌化学预防试验。

DESCRIPTION (provided by applicant): Bladder cancer is the fifth most prevalent cancer; primary/second-hand tobacco exposure is the major etiologic factor. ~80% of patients present with superficial disease confined to the mucosa. Recurrence is common with invasion into muscle or even distant metastasis with fatal consequences. Bladder cancer progression involves activation of specific oncogenes and growth factors/chemokines such as CXCL-1 and/or inactivation of tumor suppressor genes (p53, retinoblastoma, BIM, p21, RASSF1A, RUNX3, and p16INK4) through mutations or epigenetic mechanisms. Epigenetic mechanism of gene silencing is dominant during tobacco carcinogen mediated bladder cancer progression; at least 50 genes are reported to undergo epigenetic modification. This mechanism of gene silencing involves specific post-translational modifications of histones, particularly histones H3 and H4. Increased histone H3 K9 and K27 trimethylation and loss of histone H4 K20 trimethylation are common abnormalities in cancers. Therefore, drugs that can reverse cancer-enriched histone modifications should be effective in not only treating invasive bladder cancer but also in preventing progression from superficial to invasive lesion. We have developed a compound called LC-1, which inhibits bladder cancer cell growth both in vivo and in vitro. This drug was originally developed as an inhibitor of the transcription factor NF-?B and it inhibited NF-?B-dependent expression of CXCL-1 in bladder cancer cells. Additionally, LC-1 reduced the levels of "bad" epigenetic regulators such as polycomb protein EZH2, histone deacetylase HADC1, and CtBP-1. Furthermore, it reduced the levels of histone H3 K9 and K27 trimethylation but increased the levels of histone H4 K20 trimethylation. These LC-1 induced histone modifications correlated with reduced expression of the histone H3 K9 trimethylase SUV39h1 and increased expression of tumor suppressors RUNX3, BIM, and p21 in LC-1 treated cells. Hypothesis: LC-1 is a unique drug that can prevent bladder cancer progression by inhibiting NF-?B as well as reversing cancer-associated epigenetic changes. Specific aim: Investigate the chemopreventive activity of LC-1 in tobacco carcinogen-induced bladder cancer in established ICR mice and Wister rat models and relate chemopreventive activity with the expression levels of p21, BIM (LC-1 inducible), EZH2, VEGF, and SUV39h1 (LC-1 repressed). Significance: Our study has immediate translational potential because LC-1 has already gone through several toxicity and pharmacokinetic studies and is currently in phase I clinical trial for leukemia. A successful leukemia trial can be translated immediately to bladder cancer chemoprevention trial for patients with superficial bladder lesions.