Focal Adhesion Kinase - Tumor Biology and Therapeutics

粘着斑激酶 - 肿瘤生物学和治疗学

• 批准号: 10366214
• 负责人: Timothy A Marlowe
• 金额: $ 33.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366214
• 关键词: 3-Dimensional; Adhesions; Aftercare; Antineoplastic Agents; Apoptosis; BRAF gene; Binding; Biological; Biological Assay; Cell Line; Cell Survival; Cell model; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Crystallization; Crystallography; Data; Dependence; Development; Drug Kinetics; Drug Targeting; Engineering; Enzymes; Evaluation; Extracellular Matrix; Focal Adhesion Kinase 1; Focal Adhesions; Funding; Genes; Genetic; Immune Cell Suppression; In Vitro; Lead; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Melanoma Cell; Molecular; Monitor; Mutation; Neoplasm Metastasis; Normal tissue morphology; Oncology; Outcome; Pathway interactions; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phase I/II Clinical Trial; Phosphotransferases; Progress Reports; Property; Protein Tyrosine Kinase; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Ras/Raf; Regulation; Research; Resistance; Rivers; Roentgen Rays; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Skin Cancer; Solid Neoplasm; Talin; Techniques; Tertiary Protein Structure; Testing; Therapeutic; Tumor Biology; angiogenesis; anti-cancer; base; cancer cell; cancer subtypes; cell motility; improved; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; melanoma; migration; mouse model; mutant; nanomolar; novel; overexpression; patient derived xenograft model; paxillin; protein complex; response; scaffold; stapled peptide; targeted treatment; tumor; tumor progression; tumor xenograft

PROJECT ABSTRACT Focal Adhesion Kinase (FAK) is a multifunctional non-receptor tyrosine kinase and scaffolding protein that is overexpressed in numerous solid tumors including melanoma, while minimally expressed in normal tissue. FAK has been widely investigated as a cancer drug target due its contribution in multiple aspects of tumor progression, including adhesion, invasion, proliferation, survival, metastasis, angiogenesis, and immune cell suppression. However, development of FAK inhibitors has largely focused on inhibition of the kinase enzyme of FAK opposed to inhibition of key scaffolding interactions. Particularly, limited efforts have been made at the discovery and biological evaluation of inhibitors of the focal adhesion targeting (FAT) scaffolding domain of FAK, the domain required for FAK localization to focal adhesions. During this period of support, we have identified the first discovered stapled peptide-based FAK inhibitor (UA-1907) that binds to and co-crystallizes with the FAT domain, and competitively inhibits FAK-paxillin binding. We have identified a myristoylated derivative (UA-2012) with improved cellular potency, favorable drug-like properties, and in vivo efficacy; and developed a bivalent peptide (UA-2023) with low nanomolar binding to FAT. However, the mechanistic differences between these novel FAT domain peptides and traditional FAK-kinase inhibitors on perturbation of focal adhesion complexes and the FAK interactome have yet to be elucidated. Furthermore, we have preliminary data showing that FAT inhibition provides selective anti-cancer effects in NRAS mutant melanoma cells. Melanoma is the deadliest form of skin cancer and there are no current effective targeted therapies against NRAS mutant melanoma, which represents ~30% of all patients. We hypothesize that FAK FAT domain inhibitors have distinct biological effects on the focal adhesion complex in cancer cells compared to FAK kinase inhibitors; and cancer cells with alterations in NRAS signaling pathways have a molecular dependence on FAK FAT scaffolding for survival, thus promoting selective anti-cancer efficacy. In specific aim 1, we will identify the unique differences between FAK FAT scaffold inhibitors and FAK kinase inhibitors on modulation of the focal adhesion complex and the FAK interactome. In specific aim 2, we will define the molecular mechanisms of sensitivity/resistance to FAK FAT inhibition in melanoma cells with activating mutations in NRAS and BRAF pathways. In specific aim 3, we will evaluate in vivo efficacy of novel FAK FAT domain inhibitors in mouse models of NRAS and BRAF driven cancer. Overall, in this project we will utilize FAT stapled peptides to validate that FAT domain targeting provides additional biological efficacy on the focal adhesion complex compared to FAK- kinase inhibitors and that NRAS mutant melanoma has a unique sensitivity to FAK FAT inhibition. .

项目摘要 粘着斑激酶(FAK)是一种多功能的非受体酪氨酸激酶和支架蛋白，是 在包括黑色素瘤在内的许多实体肿瘤中高表达，而在正常组织中低水平表达。FAK 由于其在肿瘤进展的多个方面的贡献，已被广泛研究为抗癌药物靶点， 包括黏附、侵袭、增殖、存活、转移、血管生成和免疫细胞抑制。 然而，FAK抑制剂的发展主要集中在抑制FAK的激酶上，而不是 到抑制关键的支架相互作用。特别是，在发现和发现方面所做的努力有限 粘着斑靶向(FAT)支架结构域抑制剂的生物学评价 FAK定位到灶性粘连所必需的。在这段支持期间，我们已经确定了第一个 发现了与脂肪结构域结合并与其共结晶的基于装订的多肽的FAK抑制剂(UA-1907)， 并竞争性地抑制FAK-帕西林结合。我们已经确定了一种肉豆蔻酰化的衍生物(UA-2012) 提高了细胞效力、良好的类药物特性和体内疗效；并开发了一种二价肽 (UA-2023)，与脂肪的纳摩尔结合量低。然而，这些新型脂肪之间的机制差异 结构域肽和传统的FAK-激酶抑制剂对局灶性黏附复合体和FAK的扰动 相互作用组还没有被阐明。此外，我们有初步数据显示，脂肪抑制 在NRAS突变黑色素瘤细胞中提供选择性抗癌作用。黑色素瘤是最致命的皮肤类型 癌症，目前还没有针对NRAS突变黑色素瘤的有效靶向治疗，它代表着 约占所有患者的30%。我们假设FAK脂肪结构域抑制剂对 与FAK激酶抑制剂相比，癌细胞中的焦点黏附复合体； NRAS信号通路的改变依赖于FAK脂肪支架 存活，从而提高选择性抗癌疗效。在具体目标1中，我们将确定唯一的 FAK脂肪支架抑制剂和FAK激酶抑制剂对局灶性黏附调控的差异 Complex和FAK互动组。在具体目标2中，我们将定义 激活NRAS和BRAF突变的黑色素瘤细胞对FAK脂肪抑制的敏感性/抵抗力 小路。在具体目标3中，我们将评估新型FAK脂肪结构域抑制剂在小鼠模型中的体内疗效 NRAS和BRAF导致的癌症。总之，在这个项目中，我们将使用脂肪装订的多肽来验证这一点 与FAK相比，脂肪结构域靶向在焦点黏附复合体上提供了额外的生物学效果- 激酶抑制剂和NRAS突变黑色素瘤对FAK脂肪抑制具有独特的敏感性。 。