Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer

Pentraxin-3 在三阴性乳腺癌的发病机制和治疗中的作用

基本信息

项目摘要

SUMMARY Background. Triple-negative breast cancers (TNBCs) present with advanced histological grade and aggressive clinical behavior. They are overwhelmingly unresponsive to conventional systemic treatments, and patients with refractory disease have increased recurrence and dismal 5-year survival rates. Reliable biomarkers and targeted therapies for TNBC are therefore critically needed, but remain to be defined. Preliminary findings. We found that PTX3 was particularly abundant in TNBC specimens and in patient- derived xenografts (PDX), and that its levels positively and specifically correlated with adverse TNBC patient survival. We show that PTX3 propagated cancer-stem-cell (CSC) -like traits, that it promoted cancer cell growth in suspension, and that it promoted multifold increase in TNBC metastasis. In addition, we demonstrate that PTX3 activated anti-apoptotic pathways and de-sensitized TNBC cells to chemotherapy. Genetic suppression of PTX3 inhibited oncogene-induced cell growth, and quelled malignant features of TNBC cells, such as migration and anchorage-independent growth. Importantly, we show that circulating levels of PTX3, which is secreted by TNBC cells, associated with tumor burden in preclinical models and were particularly elevated in TNBC patients. Finally, we show that antibody neutralization of PTX3 caused TNBC cell death. Hypotheses. We hypothesize that PTX3 is a critical biomarker for risk stratification of TNBC patients, and that it is a decisive functional driver of malignancy and a tractable therapeutic target of translational utility in TNBC management. Specific aims and study design. We will establish PTX3 as a prognostic biomarker in clinical TNBC (aim 1), determine how PTX3 regulates malignant progression (aim 2), and establish PTX3 as a TNBC therapeutic target (aim 3). To this end, we will correlate tumoral and circulating levels of PTX3 to patient survival in retrospective analyses of a large TNBC patient cohort using PCR-, -in situ, and ELISA-based approaches (aims 1.1 and 1.2). We will then determine the role of PTX3 in regulating self-renewal and tumor-initiating functions of CSCs (aim 2.1), identify the metastatic steps facilitated by PTX3 (aim 2.2) and assess its contributions to chemoresistance in vitro and in vivo (aim 2.3). Finally, we will determine the essentiality of PTX3 to the initiation (aim 3.1), survival, and growth of established metastases (aim 3.2) using xenograft models, as well as investigate the ability of anti-PTX3 neutralizing antibodies to suppress tumorigenic growth using patient-derived xenograft and syngeneic murine cancer models (aim 3.3). Impact. Our sought results will introduce novel theranostics of potential groundbreaking utility in managing aggressive and difficult-to-treat breast cancers for which targeted therapies are sorely needed.
概括 背景。三阴性乳腺癌 (TNBC) 具有晚期组织学分级和 攻击性的临床行为。他们对传统的全身治疗绝大多数没有反应,并且 难治性疾病患者的复发率更高,5 年生存率也很低。可靠的 因此,迫切需要 TNBC 的生物标志物和靶向治疗,但仍有待确定。 初步调查结果。我们发现 PTX3 在 TNBC 标本和患者体内特别丰富。 衍生异种移植物 (PDX),其水平与不良 TNBC 患者呈正相关且特异相关 生存。我们证明 PTX3 传播癌症干细胞 (CSC) 样特征,即它促进癌细胞 悬浮生长,并且它促进了 TNBC 转移的成倍增加。此外,我们还展示了 PTX3 激活抗凋亡途径并使 TNBC 细胞对化疗脱敏。遗传 抑制 PTX3 可抑制癌基因诱导的细胞生长,并平息 TNBC 细胞的恶性特征, 例如迁移和不依赖锚地的生长。重要的是,我们表明 PTX3 的循环水平, 它由 TNBC 细胞分泌,与临床前模型中的肿瘤负荷相关,特别是 TNBC 患者中升高。最后,我们证明 PTX3 的抗体中和导致 TNBC 细胞死亡。 假设。我们假设 PTX3 是 TNBC 患者风险分层的关键生物标志物,并且 它是恶性肿瘤的决定性功能驱动因素,也是可转化的治疗靶点 TNBC 管理。 具体目标和研究设计。我们将建立 PTX3 作为临床 TNBC 的预后生物标志物(目标 1)、确定 PTX3 如何调节恶性进展(目标 2),并将 PTX3 确立为 TNBC 治疗药物 目标(目标 3)。为此,我们将 PTX3 的肿瘤和循环水平与患者生存相关联 使用基于 PCR、原位和 ELISA 的方法对大型 TNBC 患者队列进行回顾性分析 (目标 1.1 和 1.2)。然后我们将确定 PTX3 在调节自我更新和肿瘤启动中的作用 CSC 的功能(目标 2.1),确定 PTX3 促进的转移步骤(目标 2.2)并评估其 对体外和体内化学耐药性的贡献(目标 2.3)。最后,我们将确定以下内容的必要性: PTX3 对使用异种移植物的已建立转移的启动(目标 3.1)、存活和生长(目标 3.2) 模型,并研究抗 PTX3 中和抗体抑制致瘤生长的能力 使用患者来源的异种移植和同基因小鼠癌症模型(目标 3.3)。 影响。我们寻求的结果将引入新颖的治疗诊断学,在管理方面具有潜在的突破性效用。 急需靶向治疗的侵袭性且难以治疗的乳腺癌。

项目成果

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Antoine Elias Karnoub其他文献

Antoine Elias Karnoub的其他文献

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{{ truncateString('Antoine Elias Karnoub', 18)}}的其他基金

Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer
Pentraxin-3 在三阴性乳腺癌的发病机制和治疗中的作用
  • 批准号:
    10663281
  • 财政年份:
    2021
  • 资助金额:
    $ 40.98万
  • 项目类别:
Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer
Pentraxin-3 在三阴性乳腺癌的发病机制和治疗中的作用
  • 批准号:
    10437012
  • 财政年份:
    2021
  • 资助金额:
    $ 40.98万
  • 项目类别:
MiR-199~214 cluster at the crossroads of plasticity and malignancy in breastcancer
MiR-199~214簇处于乳腺癌可塑性和恶性的十字路口
  • 批准号:
    10055955
  • 财政年份:
    2016
  • 资助金额:
    $ 40.98万
  • 项目类别:
MiR-199~214 cluster at the crossroads of plasticity and malignancy in breastcancer
MiR-199~214簇处于乳腺癌可塑性和恶性的十字路口
  • 批准号:
    9391658
  • 财政年份:
    2016
  • 资助金额:
    $ 40.98万
  • 项目类别:

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Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer
Pentraxin-3 在三阴性乳腺癌的发病机制和治疗中的作用
  • 批准号:
    10663281
  • 财政年份:
    2021
  • 资助金额:
    $ 40.98万
  • 项目类别:
Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer
Pentraxin-3 在三阴性乳腺癌的发病机制和治疗中的作用
  • 批准号:
    10437012
  • 财政年份:
    2021
  • 资助金额:
    $ 40.98万
  • 项目类别:
FAK in Stress-activated Signaling and Tumor Invasion
应激激活信号传导和肿瘤侵袭中的 FAK
  • 批准号:
    7933387
  • 财政年份:
    2009
  • 资助金额:
    $ 40.98万
  • 项目类别:
FAK in Stress-activated Signaling and Tumor Invasion
应激激活信号传导和肿瘤侵袭中的 FAK
  • 批准号:
    7454380
  • 财政年份:
    2004
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    $ 40.98万
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FAK in Stress-activated Signaling and Tumor Invasion
应激激活信号传导和肿瘤侵袭中的 FAK
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