Inhibition of B-Catenin Signaling for Treatment of Hepatocellular Carcinoma

描述(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，它们可以破坏Beat-Catenin途径，这是许多(如果不是大多数)肝细胞癌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，但在包括肝癌在内的许多肿瘤类型中也被异常激活。Wnt/b-catenin信号将细胞黏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因子，它与许多辅助抑制因子和辅助激活因子相互作用，调节靶基因的转录。在肝细胞癌中，b-连环蛋白本身或调节β-连环蛋白稳定性的编码蛋白的突变会导致核内b-连环蛋白水平升高，并导致细胞增殖和生存程序的转录激活。针对β-连环蛋白信号的特定方面的新药物提供了以选择性和有效的方式靶向肝癌肿瘤的机会。本申请中提出的研究的目标是利用体外(基于细胞的)和体内(小鼠异种移植)研究来验证一类针对WNT-b-连环蛋白途径的新化合物。在第一个具体目标中，我们目前的先导化合物的544个类似物将在我们的基于HepG2细胞的测试中进行测试。在目标2中，将检查一组人类癌细胞对五种最好的b-连环蛋白抑制剂的敏感性。敏感的细胞系和活性化合物将被选择用于使用肝癌的体内模型进行评估。在第三个特定目标中，将测试这些抑制剂的体内毒性以及在小鼠身上的药代动力学特性。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，使用优化的剂量和给药途径来展示活性化合物的体内疗效。总而言之，这些研究将验证β-连环蛋白抑制剂作为抗肝癌临床前候选药物。这项研究的长期目标是将这类化合物投入人体临床试验。 公共卫生相关性：肝癌是全世界主要的死亡原因。目前治疗肝癌的有效方法很少，因此，这种疾病患者的预后很差。本文概述的这项研究将评估一组化合物作为潜在的抗癌药物，这些化合物可以阻断与肝癌有关的关键途径。如果成功，这些研究将为肝癌的治疗提供新的治疗选择。

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.