Mechanism-based abrogation of BCC pathogenesis

基于机制的 BCC 发病机制的消除

基本信息

批准号：
8460080
负责人：
DAVID RINSEY BICKERS
金额：
$ 35.28万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8460080
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 Targeting Embryonic Development Erinaceidae Event Exposure to FDA approved Genes Genetic Genetic Engineering 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

项目摘要

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.

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名美国人被诊断出患有BCC。这些肿瘤的管理是医疗费用的主要贡献者。 BCC风险直接与暴露于环境太阳能紫外线（UV）辐射有关这些肿瘤表现出激活的声音刺猬（SHH）信号传导和SHH是胚胎发育中最基本的信号转导途径之一。该途径的阻遏物PTCH中灭活种系突变继发的激活的SHH信号传导是人类和鼠BCC的特征。这与称为戈林综合征的罕见，主要遗传性疾病有关。这些患者除了开发出多种心外肿瘤（例如髓母细胞瘤）外，还会发展出大量的BCC。了解SHH信号在驱动BCC发病机理中的重要性已导致鉴定针对该途径不同组件的小分子，包括SMO，SHH和GLI-1。但是，由于SHH信号通路对于发育和组织稳态是必不可少的，因此SHH抑制剂的潜在毒性是人类使用的重要考虑因素。此外，临床前和我们最近完成的临床试验均表明，仅针对SHH途径的靶向并不能完全阻止BCC细胞的增殖，这表明其他途径可能有助于BCC发病机理。我们通过同时抑制SHH和AKT1和MTOR途径，从而有效地抑制了UVB诱导的BCC的生长，从而有效地抑制了AKT1-MTOR信号传导，从而有效地抑制了UVB诱导的BCC的生长。此外，我们已经表明，SHH途径直接调节MTOR表达，MTOR是Sox9的直接转录靶标，Sox9是由GLI-1调节的转录因子。在此提案中，我们将测试以下假设：Akt1和SHH途径之间存在合作的相互作用，并且在MTOR上收敛，并且必须成功阻止BCC发病机理，而阻止SHH和AKT1途径是必要的。使用实验室中生成的体外测定和BCC鼠模型，以概括Gorlin综合征（PTCH1+/ - /SKH-1和AKT KO/PTCH1+//SKH-1，以及Gli-Luciferase/PTCH+/ - /SKH-1），我们将（1）确定（1）确定该机制的Akt1 bccs bcc insegence bcc in n y n y akt1 bcc s n y akt1 bcc s n y n y akt1 bcc s of akt1的重要性（在调节MTOR中，Akt1与SHH途径之间的合作相互作用，以及（3）测试能够同时靶向这两种途径的治疗剂组合的使用。此处提出的研究具有重要的潜力，可以提供对驱动BCC发病机理的基本机制的重要见解。通过在各种组合中利用无毒的靶向剂，我们很可能可以开发用于预防/治疗人类BCC的新型治疗方法。