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。这些肿瘤的管理是医疗保健费用的主要贡献者。BCC风险与暴露于环境太阳紫外线（UV）辐射直接相关 并且这些肿瘤表现出激活的音刺猬（Shh）信号传导，Shh是胚胎发育中最基本的信号传导途径之一。活化的Shh信号传导继发于Ptch中的失活种系突变，Ptch是该途径的阻遏物，其表征人和鼠BCC。这与一种罕见的显性遗传性疾病Gorlin综合征有关。这些患者除了发生各种皮外肿瘤如髓母细胞瘤外，还发生大量的基底细胞癌。Shh信号传导在驱动BCC发病机制中的重要性的知识已经导致鉴定靶向该途径的不同组分的小分子，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是不可或缺的，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都表明，简单地靶向Shh通路并不能完全阻断BCC细胞的增殖，这表明另外的通路可能有助于BCC发病机制。我们已经产生了初步的数据显示，通过同时抑制Shh和Akt 1和mTOR通路，从而暗示Akt 1-mTOR信号转导在BCC发展中有效抑制UVB诱导的BCC的生长。此外，我们已经表明Shh通路直接调节mTOR表达，并且mTOR是Gli-1调节的转录因子SOX 9的直接转录靶点。在这项提案中，我们将测试的假设，Akt 1和Shh途径之间有合作的相互作用，收敛于mTOR，并阻止Shh和Akt 1途径是必要的，成功地阻止BCC的发病机制。使用体外试验和我们实验室产生的BCC小鼠模型来重现Gorlin综合征（Ptch 1 +/-/SKH-1和Akt KO/Ptch 1 +/-/SKH-1，和Gli-luciferase/Ptch+/-/SKH-1），我们将（1）确定Akt 1在BCC发病机制中的重要性，（2）确定Akt 1和Shh通路在调节mTOR中的协同相互作用的机制，和（3）测试能够同时靶向两种途径的治疗剂的组合的使用。这里提出的研究有很大的潜力，提供重要的见解，潜在的信号事件，驱动BCC的发病机制。通过利用各种组合的无毒靶向剂，我们可能开发用于预防/治疗人类BCC的新的治疗方法。 皮肤基底细胞癌（BCC）是美国最常见的人类癌症类型。已知BCC在声音刺猬（Shh）信号通路中存在异常，该信号通路是动物和人类发育的关键调节器之一。我们的数据表明，对细胞存活至关重要的途径Akt 1-mTOR途径与Shh途径合作，这些途径共同驱动BCC的生长。该研究将研究BCC发病机制的两个方面：1）Shh和Akt 1-mTOR通路在驱动BCC发展中的交叉通信，以及2）使用长期用于治疗其他人类疾病的药物组合同时抑制Shh和Akt 1通路的有效性和安全性。本提案中进行的研究旨在帮助确定治疗基底细胞癌的新型安全有效药物。