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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：
9761994
负责人：
Timothy A Marlowe
金额：
$ 30.15万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761994
关键词：
ABCB1 gene Area Binding Biochemical Biological Markers Breast C10 CD44 gene Cell model Cellular Structures Clinical Trials Combined Modality Therapy Data Databases Development ERBB2 gene Enzyme Inhibitor Drugs Focal Adhesion Kinase 1 Human Individual Malignant Neoplasms Mediating Molecular Neoplasm Metastasis Outcome Patients Phenotype Phosphorylation Phosphotransferases Predictive Value Prognostic Marker Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Research Resistance Roswell Park Cancer Institute Sampling Signal Transduction Site Stratification Testing Therapeutic Tissue Microarray Treatment Efficacy Tumor Biology Tumor Markers Tyrosine Vascular Endothelial Growth Factor Receptor-3 Xenograft Model Xenograft procedure biobank cancer stem cell in vivo Model inhibitor/antagonist kinase inhibitor malignant breast neoplasm novel novel strategies novel therapeutic intervention patient subsets predicting response predictive marker prototype public health relevance resistance mechanism response scaffold small molecule inhibitor synergism targeted treatment therapeutic target treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Focal Adhesion Kinase (FAK) is a critical survival signal in cancer and a promising therapeutic target that is being evaluated in several clinical trials using kinase enzyme inhibitors. The FAK scaffold provides a new area for developing highly specific therapeutics against its interactome and can be personalized to an individual tumor phenotype. During this period of support, we have demonstrated that we can successfully target the FAK scaffold with small molecule inhibitors, block FAK Y397 autophosphorylation, inhibit FAK- dependent downstream signaling, and develop effective therapeutic approaches. We hypothesize that there are distinct FAK-driven cellular scenarios which require the need for FAK scaffold and/or kinase inhibitors in order to achieve an optimal tumor response. We also hypothesize there are distinct tumor phenotypes that will cause resistance to FAK inhibitors, and by identifying these molecular mechanisms we will develop novel therapeutic approaches to overcome resistance. The first specific aim will define the molecular mechanisms of sensitivity to FAK scaffold inhibitors compared to FAK kinase inhibitors. We will determine the direct effects of FAK scaffolding partners HER-2 and VEGFR-3 on FAK trans- phosphorylation and downstream signaling in the absence of FAK kinase activity. We will analyze our prototype FAK scaffold inhibitors for blocking FAK trans-phosphorylation and downstream cellular phenotypes. We will characterize our novel FAK scaffold inhibitors that target both the Y397 autophosphorylation site and FAK-HER-2 binding, using molecular, biochemical, cellular and structural readouts. The second specific aim will define the mechanism of resistance to FAK-Y397 scaffold inhibitors. We will test the mechanism of resistance and sensitivity to FAK-Y397 scaffold and FAK kinase inhibitors in cancer stem cells (CSCs) and patient-derived xenograft (PDX) CSC models. We will test the mechanism of resistance and sensitivity to FAK Y397 inhibitors by using a combination therapy approach with inhibitors of cancer stem cell markers and targeted therapeutics. We will determine new approaches to overcome resistance to FAK Y397 inhibitors by using a combinational therapy approach with inhibitors of cancer stem cell markers and targeted therapeutics. We will test synergy of FAK-Y397 scaffold, FAK kinase, and other FAK-scaffold inhibitors to overcome resistance. The third specific aim will develop FAK-related biomarkers in human tumor samples that predict response to FAK-targeted therapeutics. We will correlate tumor expression of FAK (total and phosphorylated), selected RTKs, CSC-markers, and other proposed FAK biomarkers with patient and tumor-specific data and outcomes using tissue microarrays (TMAs) and our extensive Roswell Park Cancer Institute (RPCI) databases and biorepository. Using data from these aims, we will evaluate tumor response to mono- and combinational FAK-therapy (scaffold and kinase) in FAKlow and FAKhigh stratified breast PDX models to validate our biomarker studies.

描述（由申请人提供）：粘着斑激酶（FAK）是癌症中的关键生存信号，也是一种有前途的治疗靶点，正在使用激酶抑制剂进行的几项临床试验中进行评价。FAK支架为开发针对其相互作用组的高度特异性治疗提供了新的领域，并且可以针对个体肿瘤表型进行个性化。在这段支持期间，我们已经证明，我们可以成功地用小分子抑制剂靶向FAK支架，阻断FAK Y397自磷酸化，抑制FAK依赖性下游信号传导，并开发有效的治疗方法。我们假设有不同的FAK驱动的细胞场景，需要FAK支架和/或激酶抑制剂，以实现最佳的肿瘤反应。我们还假设有不同的肿瘤表型会导致对FAK抑制剂的耐药性，通过鉴定这些分子机制，我们将开发新的治疗方法来克服耐药性。第一个具体目标将定义与FAK激酶抑制剂相比对FAK支架抑制剂敏感性的分子机制。我们将确定FAK支架伴侣HER-2和VEGFR-3在FAK激酶活性不存在的情况下对FAK转磷酸化和下游信号传导的直接影响。我们将分析我们的原型FAK支架抑制剂阻断FAK转磷酸化和下游细胞表型。我们将使用分子、生物化学、细胞和结构读数来表征我们的新型FAK支架抑制剂，其靶向Y397自磷酸化位点和FAK-HER-2结合。第二个具体目标将定义对FAK-Y397支架抑制剂的抗性机制。我们将在癌症干细胞（CSC）和患者来源的异种移植（PDX）CSC模型中测试对FAK-Y397支架和FAK激酶抑制剂的抗性和敏感性的机制。我们将通过使用癌症干细胞标志物抑制剂和靶向治疗剂的联合治疗方法来测试对FAK Y397抑制剂的耐药性和敏感性的机制。我们将确定新的方法来克服耐药性FAK Y397抑制剂通过使用癌症干细胞标记物和靶向治疗剂的抑制剂的组合治疗方法。我们将测试FAK-Y397支架、FAK激酶和其他FAK-支架抑制剂的协同作用以克服耐药性。第三个具体目标是在人类肿瘤样本中开发FAK相关的生物标志物，预测对FAK靶向治疗的反应。我们将使用组织微阵列（TMAs）和我们广泛的Roswell Park癌症研究所（RPCI）数据库和生物储存库，将FAK（总的和磷酸化的）、选定的RTK、CSC标记物和其他拟议的FAK生物标记物的肿瘤表达与患者和肿瘤特异性数据和结果相关联。使用来自这些目标的数据，我们将在FAKlow和FAKhigh分层乳腺PDX模型中评估肿瘤对单一和组合FAK治疗（支架和激酶）的反应，以验证我们的生物标志物研究。

项目成果

期刊论文数量（68）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics.

DOI：
10.1126/scisignal.2004021
发表时间：
2013-03-26
期刊：
Science signaling
影响因子：
7.3
作者：
Cance WG;Kurenova E;Marlowe T;Golubovskaya V
通讯作者：
Golubovskaya V

Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide.

DOI：
10.1158/1535-7163.mct-12-0701
发表时间：
2013-02
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Golubovskaya VM;Huang G;Ho B;Yemma M;Morrison CD;Lee J;Eliceiri BP;Cance WG
通讯作者：
Cance WG

Vascular endothelial growth factor receptor-3 promotes breast cancer cell proliferation, motility and survival in vitro and tumor formation in vivo.

DOI：
10.4161/cc.8.14.9101
发表时间：
2009-07-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Kurenova EV;Hunt DL;He D;Fu AD;Massoll NA;Golubovskaya VM;Garces CA;Cance WG
通讯作者：
Cance WG

The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth.