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:
  • 金额:
    $ 40.26万
  • 依托单位:
  • 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

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.
概括 我们对癌细胞如何获得 DNA 损伤耐受性和如何获得 DNA 损伤耐受性的理解存在根本性差距。 逃避化疗(称为“化疗耐药”)。我们对 DNA 损伤耐受性的了解存在差距(以及 正常细胞和肿瘤细胞有何不同),限制了我们在不引起副作用的情况下杀死肿瘤的能力 对正常健康组织的毒性。我们的长期目标是解决肿瘤细胞如何 耐受治疗,并识别新的分子漏洞,可以专门针对改善 治疗。这里的目标是定义一种新的肿瘤特异性化疗耐药机制并 确定其易处理性作为治疗靶点。值得注意的是,我们发现黑色素瘤抗原-A4 (MAGE-A4,一种癌症/睾丸抗原或“CTA”)是 DNA 修复蛋白的激活结合伴侣 RAD18(一种 E3 泛素连接酶)。所有正常体细胞中均不存在 MAGE-A4,但会病理性激活 癌细胞中的 DNA 修复。 MAGE-A4 还激活 E3 连接酶 TRIM69,从而赋予有丝分裂抵抗力 纺锤体毒物。 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 肿瘤在生理环境下对化疗的反应尚未经过测试。基于令人兴奋和 令人信服的初步研究,我们将测试 MAGE-A4 病理性重编程的中心假设 肿瘤中的泛素信号传导赋予对基因毒素和纺锤体毒物的化学抗性。理由是 确定 MAGE-A4 对化疗耐药性的贡献将允许非常具体的治疗 针对肿瘤细胞独特的分子脆弱性的策略。具体目标是: SA1 定义 病理激活的 DNA 修复对体内化学耐药性的贡献。 SA2 建立化学品 MAGE-A4/RAD18 作为治疗靶点的易处理性。 SA3 机械定义MAGE-A4/TRIM69 在有丝分裂进展和对纺锤体毒物的抵抗中发挥作用。在SA1中我们将使用一种新的转基因 小鼠和原位肺癌模型以确定 MAGE-A4/RAD18 如何影响对 体内化疗。在 SA2 中,我们将筛选肽噬菌体展示文库以识别序列基序 结合 MAGE-A4 并破坏 MAGE-A4/RAD18 相互作用。生物活性 MAGE-A4 抑制剂肽将 测试了抗肿瘤活性。在 SA3 中,我们将定义 MAGE-A4 在调节 TRIM69 和 赋予对纺锤体毒物的抵抗力。我们将机械地定义 MAGE-A4/TRIM69 信号 途径并确定其在治疗性紫杉烷耐受中的作用。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标,是一个重要的途径 在药物发现过程中。所提出的想法和研究具有创新性,因为它们是第一个 研究测试 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耐药性提供新的范例 直接针对化疗耐药癌症的新型靶向疗法。

项目成果

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Kenneth Hugh Pearce其他文献

Kenneth Hugh Pearce的其他文献

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{{ truncateString('Kenneth Hugh Pearce', 18)}}的其他基金

Discovery of allosteric activators of phospholipase C-gamma2 to treat Alzheimer's disease
发现用于治疗阿尔茨海默病的磷脂酶 C-gamma2 变构激活剂
  • 批准号:
    10901007
  • 财政年份:
    2023
  • 资助金额:
    $ 40.26万
  • 项目类别:
Core B: Discovery Core
核心B:发现核心
  • 批准号:
    10513681
  • 财政年份:
    2022
  • 资助金额:
    $ 40.26万
  • 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
  • 批准号:
    10185322
  • 财政年份:
    2021
  • 资助金额:
    $ 40.26万
  • 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
  • 批准号:
    10399533
  • 财政年份:
    2021
  • 资助金额:
    $ 40.26万
  • 项目类别:
A high-throughput platform to identify selective allosteric inhibitors of the PLC-y isozymes
用于鉴定 PLC-y 同工酶选择性变构抑制剂的高通量平台
  • 批准号:
    10598548
  • 财政年份:
    2021
  • 资助金额:
    $ 40.26万
  • 项目类别:
Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells
肿瘤细胞中 DNA 损伤信号的病理重编程
  • 批准号:
    10530649
  • 财政年份:
    2019
  • 资助金额:
    $ 40.26万
  • 项目类别:
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
  • 批准号:
    10596489
  • 财政年份:
    2019
  • 资助金额:
    $ 40.26万
  • 项目类别:
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
  • 批准号:
    10363652
  • 财政年份:
    2019
  • 资助金额:
    $ 40.26万
  • 项目类别:
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
  • 批准号:
    9905492
  • 财政年份:
    2019
  • 资助金额:
    $ 40.26万
  • 项目类别:
Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells
肿瘤细胞中 DNA 损伤信号的病理重编程
  • 批准号:
    10301006
  • 财政年份:
    2019
  • 资助金额:
    $ 40.26万
  • 项目类别:

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设计针对癌症抗原的高亲和力 T 细胞受体
  • 批准号:
    8704723
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设计针对癌症抗原的高亲和力 T 细胞受体
  • 批准号:
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