aPKC function in Hedgehog signaling and basal cell carcinoma

aPKC 在 Hedgehog 信号传导和基底细胞癌中的功能

基本信息

批准号：
8804247
负责人：
Scott Atwood
金额：
$ 11.81万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-11 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8804247
关键词：
Allografting Basal cell carcinoma Binding Sites Biochemistry Biological Models Cell Line Cell Polarity Cessation of life DNA Binding Data Defect Development Drug resistance Environment Epithelial Epithelium Erinaceidae Exhibits Gene Targeting Genes Genetic Goals Growth Hair follicle structure Health Human Laboratories Length Ligand Binding Link Malignant Epithelial Cell Malignant Neoplasms Mediating Molecular Biology Mus Mutation Nature Neoplasm Metastasis Nuclear Oncogenes Organ Organism Pathway interactions Pattern Peptides Phase Phosphorylation Post-Translational Protein Processing Process Proteins Proteomics Reagent Research Resistance Retirement Scaffolding Protein Signal Pathway Signal Transduction Skin Cancer Specificity Stem cells Testing Therapeutic Transcription Coactivator Transducers Tumor Cell Invasion Vertebrates Work Zinc Fingers atypical protein kinase C drug discovery human SMO protein inhibitor/antagonist migration new therapeutic target next generation sequencing novel novel therapeutics overexpression protein kinase C iota receptor smoothened signaling pathway stem cell fate therapeutic target transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most prevalent cancer in the world and nearly half of US citizens are likely to develop this cancer before retirement. BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway, an essential developmental pathway that has been implicated in approximately 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates the impressive proliferative defects in cancers remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained approval for treatment of late advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in naïve tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need for new therapeutic targets. I have recently discovered that a critically important oncogene, atypical Protein Kinase C iota/lambda (aPKC-ι/λ), involved in stem cell fate choice during development of nearly all multicellular organisms is essential for high, sustained Hh pathway activation in BCCs. I have also shown pharmacological inhibition of aPKC suppresses murine BCC tumor growth and the growth of naïve and Smo-resistant BCC cells. The goal of my research is to determine the mechanisms that allow the polarity protein aPKC-ι/λ to promote Hh pathway activation and naïve and Smo-resistant BCC growth. During the K99 phase, I will determine how phosphorylation of Gli by aPKC-ι/λ alters target gene specificity to promote tumor growth, how BCC's regulate aPKC-ι/λ activity, and test the therapeutic potential of additional novel aPKC-ι/λ inhibitors for the treatment of naïve and resistant BCC. During the R00 phase, I will determine how aPKC-ι/λ-dependent Gli1 responsive genes regulate tumor invasion and analyze aPKC-ι/λ function in Smo-resistant BCCs. The results of this study will reveal conserved mechanisms that govern cell polarity and Hh signaling during BCC that will prove invaluable in generating novel therapeutics for the treatment of Hh-dependent cancers.

描述（由申请人提供）：基底细胞癌（BCC）是世界上最常见的癌症，近一半的美国公民可能在退休前患上这种癌症，BCC 是源自刺猬激活突变的侵袭性上皮肿瘤。 Hh) 途径是一种重要的发育途径，约 25% 的人类癌症死亡与 Hh 信号通路有关，尽管 Hh 信号传导具有至关重要的性质，但 Hh 是如何介导令人印象深刻的增殖缺陷的。当 Hh 配体结合并抑制跨膜受体 Patched1 时，Hh 通路激活开始，从而使信号转导器 Smoothened (Smo) 激活 Gli 转录因子并放大 Hh 靶基因的表达，目前对癌症的了解仍知之甚少。Smo 抑制剂最近已获得批准用于治疗晚期晚期癌症。或转移性基底细胞癌并表现出有效的肿瘤消退，虽然这些抑制剂对幼稚肿瘤有效，但侵袭性肿瘤往往会对该药物产生早期耐药性，这说明需要新的治疗靶点。最近发现，一种至关重要的癌基因，非典型蛋白激酶 C iota/lambda (aPKC-ι/λ)，参与几乎所有多细胞生物体发育过程中的干细胞命运选择，对于 BCC I 中 Hh 通路的高度、持续激活至关重要。还显示 aPKC 的药理学抑制作用可抑制小鼠 BCC 肿瘤的生长以及幼稚和 Smo 耐药的 BCC 细胞的生长。确定极性蛋白 aPKC-ι/λ 促进 Hh 通路激活以及幼稚和 Smo 抗性 BCC 生长的机制。在 K99 阶段，我将确定 aPKC-ι/λ 的 Gli 磷酸化如何改变靶基因特异性。促进肿瘤生长、BCC 如何调节 aPKC-ι/λ 活性，并测试其他新型 aPKC-ι/λ 抑制剂治疗初治和在 R00 阶段，我将确定 aPKC-ι/λ 依赖性 Gli1 响应基因如何调节肿瘤侵袭，并分析 Smo 耐药 BCC 中的 aPKC-ι/λ 功能。这项研究的结果将揭示控制肿瘤的保守机制。 BCC 期间的细胞极性和 Hh 信号传导对于产生治疗 Hh 依赖性癌症的治疗小说具有不可估量的价值。