Mechanistic and Biomarker Studies on Cancer Progression and Taxane Resistance

癌症进展和紫杉烷耐药性的机制和生物标志物研究

基本信息

批准号：
8652824
负责人：
Lauren Michelle Moore
金额：
$ 2.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-15 至 2016-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652824
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 AKT Signaling Pathway Adhesions Adverse effects Apoptosis Apoptotic BCL2 gene Binding Biological Assay Biological Markers Biopsy Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Calcium Calpain Cancer Patient Cancer cell line Cause of Death Cell Death Cell Line Cell Proliferation Cells Clinical Clinical Research Clinical assessments Data Disease Dose ERBB2 gene Epidermal Growth Factor Estrogen Receptors FDA approved Functional disorder Future Homeostasis Human Image Immunoblotting Immunohistochemistry In Vitro Incidence Individual Intervention Lithium Malignant Neoplasms Medical Medical History Modeling Molecular Molecular Target Monitor Neoplasm Metastasis Neurons Neurosecretory Systems Outcome Paclitaxel Pathway interactions Patient Care Patients Pharmaceutical Preparations Phenotype Phosphatidylinositols Phosphotransferases Play Post-Translational Protein Processing Process Prognostic Marker Proteins Proto-Oncogene Proteins c-akt Relapse Resistance Risk Role Signal Pathway Signal Transduction Taxane Compound Technology Therapeutic Therapeutic Intervention Time Tissue Microarray Validation Woman base calpain inhibitor chemotherapeutic agent clinical application cohort in vitro Assay inhibitor/antagonist lymph nodes malignant breast neoplasm migration mortality new therapeutic target novel outcome forecast prevent prognostic public health relevance receptor research study response sensor stable cell line taxane treatment strategy tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The incidence of breast cancer is high, with 1 in 8 women in the U.S. developing this disease over the course of their lifetime. Taxanes are potent chemotherapeutic agents that are a standard component of early and metastatic breast cancer treatment strategies. Despite major therapeutic advances, progression of tumors and taxane resistance continue to be major clinical problems that promote breast cancer mortality. The clinical application of biomarkers have greatly reduced the mortality rates associated with breast cancer; however, there is an urgent need for novel biomarkers that can more effectively identify patients who are 1) at risk for advanced breast cancer progression or 2) resistant to taxane therapy. Using a candidate approach, we sought to investigate the role of neuronal calcium sensor-1 (NCS-1) in breast cancer. NCS-1 (a novel binding partner of the taxane, paclitaxel) has been shown to act as a survival factor in neurons by activating the Phosphoinositide 3- kinase (PI3K)/ Protein Kinase B (AKT) signaling pathway. Our central hypothesis is that NCS-1 promotes breast cancer progression and taxane resistance by altering cancer signaling networks. This hypothesis is based on the functional characterization of NCS-1, in neuronal and neuroendocrine models, as well as our preliminary data. Using immunohistochemistry (IHC) and our novel Automated Quantitative Analysis (AQUA) technology, we quantified the expression of NCS-1 in 619 cases of primary breast carcinomas. We found that NCS-1 was expressed in a cohort of breast cancer patients and significantly correlates with poor clinical outcome independent of Estrogen Receptor (ER), Human Epidermal Growth Factor 2 Receptor (HER-2), and lymph node status. The objectives of our study are to 1) investigate the role of NCS-1 in the molecular mechanisms governing breast cancer progression and taxane resistance and to 2) assess the clinical utility of NCS-1 as a novel predictive/ prognostic breast cancer biomarker. Elucidating the role of NCS-1 in breast cancer progression and taxane resistance may broaden our understanding of these processes and establish NCS-1 as a novel molecular target for future therapeutic intervention. Furthermore, findings from our study may validate NCS-1 as a novel predictive/ prognostic breast cancer biomarker, which may ultimately increase breast cancer survival through individualization of patient care.

描述（由申请人提供）：乳腺癌的发病率很高，美国每 8 名女性中就有 1 人在一生中患上这种疾病。紫杉烷类药物是有效的化疗药物，是早期和转移性乳腺癌治疗策略的标准组成部分。尽管治疗取得了重大进展，但肿瘤进展和紫杉烷耐药性仍然是导致乳腺癌死亡率的主要临床问题。生物标志物的临床应用大大降低了乳腺癌的死亡率；然而，迫切需要新的生物标志物，可以更有效地识别以下患者：1）有晚期乳腺癌进展风险或2）对紫杉烷治疗耐药。使用候选方法，我们试图研究神经元钙传感器-1 (NCS-1) 在乳腺癌中的作用。 NCS-1（紫杉烷紫杉醇的新型结合伴侣）已被证明可通过激活磷酸肌醇 3 激酶 (PI3K)/蛋白激酶 B (AKT) 信号通路作为神经元的生存因子。我们的中心假设是 NCS-1 通过改变癌症信号网络来促进乳腺癌进展和紫杉烷耐药性。该假设基于 NCS-1 在神经元和神经内分泌模型中的功能表征以及我们的初步数据。使用免疫组织化学 (IHC) 和我们新颖的自动定量分析 (AQUA) 技术，我们定量了 619 例原发性乳腺癌病例中 NCS-1 的表达。我们发现 NCS-1 在一组乳腺癌患者中表达，并且与不良临床结果显着相关，与雌激素受体 (ER)、人表皮生长因子 2 受体 (HER-2) 和淋巴结状态无关。我们研究的目的是 1) 研究 NCS-1 在控制乳腺癌进展和紫杉烷耐药的分子机制中的作用，以及 2) 评估 NCS-1 作为新型预测/预后乳腺癌生物标志物的临床效用。阐明 NCS-1 在乳腺癌进展和紫杉烷耐药中的作用可能会拓宽我们对这些过程的理解，并将 NCS-1 确立为未来治疗干预的新分子靶点。此外，我们的研究结果可能会验证 NCS-1 作为一种新型预测/预后乳腺癌生物标志物，它可能最终通过患者护理的个体化来提高乳腺癌的生存率。