Mechanism-based abrogation of BCC pathogenesis

基于机制的 BCC 发病机制的消除

• 批准号: 8296459
• 负责人: DAVID RINSEY BICKERS
• 金额: $ 36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296459
• 关键词: Ablation; Address; Affect; Alleles; American; Animals; Antifungal Agents; Apoptosis; Automobile Driving; Azoles; Basal Cell Nevus Syndrome; Basal cell carcinoma; Cell Line; Cell Survival; Cells; Clinical Trials; Communication; Complex; Data; Defect; Development; Diagnosis; Drug Combinations; Drug Delivery Systems; Embryonic Development; Engineering; Erinaceidae; Event; Exposure to; FDA approved; Genes; Genetic; Germ-Line Mutation; Growth; Health Care Costs; Hereditary Disease; Homeostasis; Human; Human Development; Inborn Genetic Diseases; Incidence; Individual; Induced Mutation; Itraconazole; Knowledge; Laboratories; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Microscopic; Modeling; Molecular; Molecular Target; Mus; Mutation; Newborn Infant; PTCH gene; Pathogenesis; Pathway interactions; Patients; Perifosine; Pharmaceutical Preparations; Phase; Phosphorylation; Prevention; Regimen; Regulatory Pathway; Resistance; Risk; Safety; Secondary to; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Skin; Sonic Hedgehog Pathway; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Tumor Suppressor Proteins; UV induced; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; base; combinatorial; design; human FRAP1 protein; human disease; in vitro Assay; inhibitor/antagonist; innovation; insight; keratinocyte; knock-down; medulloblastoma; mouse model; novel; novel therapeutic intervention; pre-clinical; prevent; small molecule; smoothened signaling pathway; transcription factor; tumor; tumor growth; tumor progression; ultraviolet

DESCRIPTION (provided by applicant): Basal cell carcinomas (BCCs) are the most common type of human malignancy in the United States; more than 1,000,000 Americans are diagnosed with BCCs each year. The management of these tumors is a major contributor to health care costs. BCC risk directly correlates with exposure to environmental solar ultraviolet (UV) radiation and these tumors manifest activated sonic hedgehog (Shh) signaling and Shh is among the most fundamental signal transduction pathways in embryonic development. Activated Shh signaling secondary to inactivating germline mutations in Ptch, the repressor of this pathway, characterizes both human and murine BCCs. This is associated with the rare, dominantly inherited disorder known as Gorlin syndrome. These patients develop large numbers of BCCs in addition to developing various extracutaneous tumors such as medulloblastomas. Knowledge of the importance of Shh signaling in driving BCC pathogenesis has led to the identification of small molecules that target different components of this pathway including Smo, Shh, and Gli-1. However, because the Shh signaling pathway is indispensable for development and tissue homeostasis, the potential toxicity of Shh inhibitors is an important consideration for human use. Moreover, both preclinical and our recently-completed clinical trials indicate that simply targetin the Shh pathway does not totally block the proliferation of BCC cells, suggesting that additional pathway(s) may contribute to BCC pathogenesis. We have generated preliminary data showing efficacious suppression of the growth of UVB-induced BCCs by simultaneously inhibiting the Shh and Akt1 and mTOR pathways thereby implicating Akt1-mTOR signaling in BCC development. Furthermore, we have shown that the Shh pathway directly regulates mTOR expression and that mTOR is a direct transcriptional target of SOX9, a transcription factor regulated by Gli-1. In this proposal we will test the hypothesis that there are cooperative interactions between Akt1 and Shh pathways that converge on mTOR, and that blocking both Shh and Akt1 pathways is necessary to successfully block BCC pathogenesis. Using both in vitro assays and BCC murine models generated in our laboratory to recapitulate Gorlin syndrome (Ptch1+/-/SKH-1 and Akt KO/Ptch1+/-/SKH-1, and Gli-luciferase/Ptch+/-/SKH-1), we will (1) define the importance of Akt1 in the pathogenesis of BCCs, (2) determine the mechanism of the cooperative interactions between Akt1 and Shh pathways in regulating mTOR, and (3) test the use of combinations of therapeutic agents capable of targeting both pathways simultaneously. The studies proposed here have substantial potential to provide important insights into the mechanisms underlying signaling events that drive the pathogenesis of BCCs. By utilizing non-toxic targeted agents in various combinations, it is likely that we can develop novel therapeutic approaches for preventing/treating human BCCs. PUBLIC HEALTH RELEVANCE: Basal cell carcinomas (BCCs) of the skin are the most common type of human cancer in the United States. BCCs are known to have abnormalities in the sonic hedgehog (Shh) signaling pathway, one of the key regulators of animal and human development. Our data show that a pathway crucial for survival of cells, the Akt1-mTOR pathway, cooperates with the Shh pathway, and these pathways together drive the growth of BCCs. The proposed study will investigate two aspects of BCC pathogenesis: 1) the cross-communication between the Shh and Akt1-mTOR pathways in driving BCC development, and 2) the efficacy and safety of simultaneously inhibiting the Shh and Akt1 pathways using a combination of drugs that long have been used to treat other human diseases. The studies to be conducted in this proposal are designed to help identify novel safe and effective drugs to treat BCCs.

描述（由申请人提供）：基底细胞癌（BCC）是美国最常见的人类恶性肿瘤类型；每年有超过 1,000,000 名美国人被诊断患有 BCC。这些肿瘤的治疗是医疗保健费用的主要来源。 BCC 风险与暴露于环境太阳紫外线 (UV) 辐射直接相关 这些肿瘤表现出激活的声波刺猬（Shh）信号传导，而Shh是胚胎发育中最基本的信号转导途径之一。继发于 Ptch 种系突变失活后激活的 Shh 信号传导，Ptch 是该途径的抑制因子，是人类和小鼠 BCC 的特征。这与一种罕见的显性遗传性疾病——戈林综合征有关。这些患者除了出现各种皮外肿瘤（例如髓母细胞瘤）外，还会出现大量基底细胞癌。由于了解了 Shh 信号传导在驱动 BCC 发病机制中的重要性，因此鉴定出了针对该通路不同成分的小分子，包括 Smo、Shh 和 Gli-1。然而，由于Shh信号通路对于发育和组织稳态不可或缺，因此Shh抑制剂的潜在毒性是人类使用的一个重要考虑因素。此外，临床前试验和我们最近完成的临床试验都表明，简单地靶向 Shh 通路并不能完全阻止 BCC 细胞的增殖，这表明其他通路可能有助于 BCC 发病机制。我们生成的初步数据显示，通过同时抑制 Shh、Akt1 和 mTOR 通路，可有效抑制 UVB 诱导的 BCC 生长，从而表明 Akt1-mTOR 信号传导参与 BCC 的发展。此外，我们还表明，Shh 通路直接调节 mTOR 表达，并且 mTOR 是 SOX9（受 Gli-1 调节的转录因子）的直接转录靶标。在本提案中，我们将测试以下假设：Akt1 和 Shh 通路之间存在协同相互作用，并汇聚于 mTOR，并且阻断 Shh 和 Akt1 通路对于成功阻断 BCC 发病机制是必要的。使用我们实验室生成的体外测定和 BCC 小鼠模型来重现 Gorlin 综合征（Ptch1+/-/SKH-1 和 Akt KO/Ptch1+/-/SKH-1 和 Gli-荧光素酶/Ptch+/-/SKH-1） ，我们将（1）定义Akt1在BCC发病机制中的重要性，（2）确定Akt1和Shh通路在调节mTOR方面的协同相互作用的机制， (3) 测试能够同时靶向两种途径的治疗药物组合的使用。这里提出的研究具有巨大的潜力，可以为驱动 BCC 发病机制的信号事件背后的机制提供重要见解。通过利用各种组合的无毒靶向药物，我们有可能开发出预防/治疗人类基底细胞癌的新治疗方法。 公共卫生相关性：皮肤基底细胞癌 (BCC) 是美国最常见的人类癌症类型。已知 BCC 的声波刺猬 (Shh) 信号通路存在异常，该通路是动物和人类发育的关键调节因子之一。我们的数据表明，对细胞生存至关重要的途径 Akt1-mTOR 途径与 Shh 途径协同作用，这些途径共同驱动 BCC 的生长。拟议的研究将调查 BCC 发病机制的两个方面：1) Shh 和 Akt1-mTOR 通路在驱动 BCC 发展中的交叉通讯，2) 使用药物组合同时抑制 Shh 和 Akt1 通路的有效性和安全性长期以来一直被用来治疗其他人类疾病。该提案中进行的研究旨在帮助确定治疗基底细胞癌的安全有效的新型药物。