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Focal Adhesion Kinase - Tumor Biology and Therapeutics

粘着斑激酶 - 肿瘤生物学和治疗学

基本信息

批准号：
10561676
负责人：
Timothy A Marlowe
金额：
$ 32.52万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
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/10561676
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 Invaded 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 Clinical Trials Phase II Clinical Trials Phosphotransferases Progress Reports Proliferating Property Protein Tyrosine Kinase Proteins Proteomics Proto-Oncogene Proteins c-akt Ras/Raf Regulation Research Resistance 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 cancer cell cancer subtypes cell motility improved in vivo inhibitor inhibitor therapy kinase inhibitor melanoma migration mouse model mutant myristoylation nanomolar novel overexpression patient derived xenograft model paxillin protein complex response scaffold stapled peptide targeted treatment tumor tumor progression tumor xenograft

项目摘要

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