Inhibition of B-Catenin Signaling for Treatment of Hepatocellular Carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是一个主要的公共卫生问题，几乎没有有效的治疗选择。为了开发新的治疗方式，我们已经确定了一类小分子药物，可以破坏β -连环蛋白通路，这是许多（如果不是大多数的话）HCC肿瘤的主要信号通路之一。wnt（无翼和int-1）/b-catenin信号通路对脊椎动物的发育至关重要，但在包括HCC在内的许多肿瘤类型中也被异常激活。Wnt/b-catenin信号将细胞粘附和运动信号与生长、增殖和存活结合在一起。在分子方面，β -连环蛋白是一种转录调节剂，与许多共抑制因子和共激活因子相互作用，调节靶基因的转录。在HCC中，b-连环蛋白本身或编码调节-连环蛋白稳定性的蛋白质的基因突变导致核b-连环蛋白水平升高和细胞增殖和生存程序的转录激活。靶向β -连环蛋白信号传导特定方面的新药物提供了以选择性和有效的方式靶向HCC肿瘤的机会。本申请中提出的研究目标是通过体外（基于细胞的）和体内（小鼠异种移植）研究验证一类针对wnt-b-catenin途径的新化合物。在第一个特异性Aim中，我们目前先导化合物的544个类似物将在我们基于HepG2细胞的实验中进行测试。在Aim 2中，一组人类癌细胞系将被检查对五种最佳b-连环蛋白抑制剂的敏感性。将选择敏感细胞系和活性化合物用于HCC体内模型的评估。在第三个特定目标中，将测试这些抑制剂的体内毒性以及小鼠的药代动力学特性。最后，在第四个特定目标中，敏感细胞系将用于小鼠异种移植模型，通过优化活性化合物的剂量和给药途径来证明体内疗效。总之，这些研究将验证β -连环蛋白抑制剂作为抗HCC的临床前候选药物。这项研究的长期目标是使这类化合物进入人体临床试验。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a major public health problem with few effective treatment options. In an effort to develop new treatment modalities, we have identified a class of small molecule agents that disrupt the beat-catenin pathway, one of the major signaling pathways in many, if not most, HCC tumors. The wnt (wingless and int-1)/b-catenin signaling pathway is critical for vertebrate development but is also aberrantly activated in a number of tumor types including HCC. Wnt/b-catenin signaling integrates cell-adhesion and motility signals with growth, proliferation and survival. In molecular terms, beta-catenin is a transcriptional regulator that interacts with a number of co-repressors and co-activators to regulate the transcription of target genes. In HCC mutations in b-catenin itself or in genes encoding proteins that regulate beta-catenin stability lead to elevated levels of nuclear b-catenin and transcriptional activation of cellular proliferation and survival programs. New agents that target specific aspects of beta-catenin signaling present the opportunity to target HCC tumors in a selective and efficacious manner. The goal of the research proposed in this application is to validate a new class of compounds directed against the wnt-b-catenin pathway using in vitro (cell-based) and in vivo (mouse xenograft) studies. In the first Specific Aim, 544 analogues of our current lead compound will be tested in our HepG2 cell-based assay. In Aim 2, a panel of human cancer cell lines will be examined for sensitivity to a five best b-catenin inhibitors. Sensitive cell lines and active compounds will be selected for evaluation using in vivo models of HCC. The inhibitors will be tested for in vivo toxicity as well as pharmacokinetic properties in mice in the third Specific Aim. Finally, in the fourth Specific Aim, sensitive cell lines will be used in mouse xenograft models using optimized dose and route of administration of active compounds to demonstrate in vivo efficacy. Together these studies will validate beta-catenin inhibitors as anti- HCC pre-clinical candidates. The long-term goal of this research is to move this class of compounds into human clinical trials. PUBLIC HEALTH RELEVANCE: Liver cancer is a major cause of death throughout the world. There are very few effective treatments for liver cancer and consequently, the prognosis for patients with this disease is poor. The research outlined here will evaluate a group of compounds that block a key pathway involved in liver cancer as potential anticancer drugs. If successful, these studies will provide a new therapeutic option for the treatment of liver cancer.