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Establishing MAGE-A4/RAD18 as a novel cancer-specific chemotherapeutic target

将 MAGE-A4/RAD18 确立为新型癌症特异性化疗靶点

基本信息

批准号：
10132267
负责人：
Kenneth Hugh Pearce
金额：
$ 40.26万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-02 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132267
关键词：
Affect Affinity Antigens Antineoplastic Agents Binding Biological Testing Cancer Model Carcinogenesis Mechanism Cause of Death Cell Survival Cells Cellular Assay Chemicals Chemoresistance Complex DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis Engineering Environmental Risk Factor Genes Genomic Instability Germ Cells Goals Knowledge Libraries Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mission Mitotic Mitotic spindle Molecular Mutagens Normal Cell Nude Mice Oncogenes Oncogenic Pathologic Pathway interactions Patients Peptide Phage Display Library Peptides Permeability Phenotype Physiological Platinum Poison Problem Solving Process Prognosis Proteins Public Health Research Resistance Role Signal Pathway Signal Transduction Somatic Cell Stress Structure Testing Therapeutic Therapeutic Agents Tissues Topoisomerase II Toxic effect Transgenic Mice Ubiquitin United States National Institutes of Health Work base cancer cell cancer testis antigen cancer therapy carcinogenesis chemotherapeutic agent chemotherapy defined contribution drug discovery druggable target environmental agent experience experimental study improved in vivo inhibitor/antagonist innovation melanoma mortality neoplastic cell new therapeutic target novel preclinical study preneoplastic cell pressure prevent replication stress response screening side effect small molecule targeted treatment taxane therapeutic target therapy resistant tumor tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

SUMMARY There are fundamental gaps in our understanding of how cancer cells acquire DNA damage-tolerance and evade chemotherapy (termed ‘chemoresistance’). The gaps in our knowledge of DNA damage tolerance (and how it differs between normal and neoplastic cells), limit our ability to kill tumors without causing side effect toxicities to normal healthy tissues. Our long-term goals are to solve the problem of how neoplastic cells tolerate therapy, and identify new molecular vulnerabilities that can be specifically targeted for improved treatment. The objective here is to define a novel tumor-specific mechanism of chemoresistance and to establish its tractability as a therapeutic target. Remarkably, we discovered that Melanoma Antigen-A4 (MAGE-A4, a Cancer/Testes Antigen or 'CTA') is an activating binding partner of the DNA repair protein RAD18 (an E3 ubiquitin ligase). MAGE-A4 is absent from all normal somatic cells but pathologically activates DNA repair in cancer cells. MAGE-A4 also activates the E3 ligase TRIM69 which confers resistance to mitotic spindle poisons. MAGE-A4 expression is associated with poor patient prognosis yet its potential impact on the responsiveness of tumors to chemotherapy in a physiological setting is untested. Based on exciting and compelling preliminary studies, we will test the central hypothesis that MAGE-A4 pathologically reprograms ubiquitin signaling in tumors to confer chemoresistance to genotoxins and spindle poisons. The rationale is that defining the contribution of MAGE-A4 to chemoresistance will allow extraordinarily specific therapeutic strategies that target a unique molecular vulnerability of neoplastic cells. The Specific Aims are: SA1 Define contribution of pathologically-activated DNA repair to chemoresistance in vivo. SA2 Establish chemical tractability of MAGE-A4/RAD18 as a therapeutic target. SA3 Mechanistically define MAGE-A4/TRIM69 functions in mitotic progression and resistance to spindle poisons. In SA1 We will use a new transgenic mouse and orthotopic lung cancer models to determine how MAGE-A4/RAD18 impacts responses to chemotherapy in vivo. In SA2 we will screen peptide phage display libraries to identify sequence motifs that bind MAGE-A4 and disrupt the MAGE-A4/RAD18 interaction. Bioactive MAGE-A4 inhibitor peptides will be tested for anti-neoplastic activity. In SA3 we will define a novel role of MAGE-A4 in regulating TRIM69 and conferring resistance to spindle poisons. We will mechanistically define the MAGE-A4/TRIM69 signaling pathway and establish its role in tolerance of therapeutic taxanes. These experiments will likely establish MAGE-A4 as a druggable target for ameliorating chemoresistance in cancer cells, serving as a crucial gateway in the drug discovery process. The proposed ideas and research are innovative because they are the first studies to test how biological activities of CTAs affect cancer therapy. The proposed work is significant because it will provide new paradigms for chemoresistance due to pathological ubiquitin signaling leading directly to novel targeted therapies for chemoresistant cancer.

总结我们对癌细胞如何获得DNA损伤耐受性的理解存在根本性的差距，避免化疗（称为“化疗耐药”）。我们对DNA损伤耐受性的知识缺口（以及它在正常细胞和肿瘤细胞之间的区别），限制了我们杀死肿瘤而不引起副作用的能力对正常健康组织的毒性。我们的长期目标是解决肿瘤细胞耐受治疗，并确定新的分子脆弱性，可以专门针对改善治疗本研究的目的是确定一种新的肿瘤特异性化疗耐药机制，确立了其作为治疗靶点的易处理性。值得注意的是，我们发现黑色素瘤抗原A4 （MAGE-A4，癌症/睾丸抗原或'CTA'）是DNA修复蛋白的活化结合配偶体 RAD 18（E3泛素连接酶）。MAGE-A4不存在于所有正常体细胞中，但在病理学上激活癌细胞中的DNA修复MAGE-A4还激活E3连接酶TRIM 69，其赋予对有丝分裂的抗性。纺锤体毒素MAGE-A4表达与患者预后不良相关，但其对患者预后的潜在影响在生理环境中肿瘤对化疗的反应性尚未测试。基于令人兴奋和令人信服的初步研究，我们将测试中心假设，MAGE-A4病理重编程肿瘤中的泛素信号传导以赋予对基因毒素和纺锤体毒物的化学抗性。其基本原理是确定MAGE-A4对化疗耐药性的贡献将允许非常特异性的治疗，针对肿瘤细胞独特的分子脆弱性的策略。具体目标是：SA 1定义病理激活的DNA修复对体内化学抗性的贡献。SA 2建立化学品 MAGE-A4/RAD 18作为治疗靶点的易处理性。SA 3机械定义MAGE-A4/TRIM 69 在有丝分裂进程和对纺锤体毒素的抗性中起作用。在SA 1中，我们将使用新的转基因小鼠和原位肺癌模型，以确定MAGE-A4/RAD 18如何影响对体内化疗。在SA 2中，我们将筛选肽噬菌体展示文库以鉴定结合MAGE-A4并破坏MAGE-A4/RAD 18相互作用。生物活性MAGE-A4抑制剂肽将被进行抗肿瘤活性测试。在SA 3中，我们将定义MAGE-A4在调节TRIM 69和TRIM 68中的新作用。赋予对纺锤体毒素的抗性。我们将机械地定义MAGE-A4/TRIM 69信号传导途径，并确定其在治疗性紫杉烷耐受性中的作用。这些实验可能会建立 MAGE-A4作为改善癌细胞化疗耐药性的药物靶点，作为关键的门户在药物发现过程中。提出的想法和研究是创新的，因为它们是第一个研究以测试CTA的生物活性如何影响癌症治疗。拟议的工作意义重大因为它将为由于病理性泛素信号传导导致的化学抗性提供新的范例，直接用于治疗耐药癌症的新型靶向疗法。