Assessing the Notch Pathway as a Therapeutic Target in Lung Cancer Adenocarcinoma

评估Notch通路作为肺癌腺癌的治疗靶点

• 批准号: 8529202
• 负责人: Khaled Hassan
• 金额: $ 17.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8529202
• 关键词: Address; Adenocarcinoma; Adjuvant; Apoptosis; Apoptotic; Biologic Characteristic; Cancer Etiology; Cancer cell line; Cell Cycle Arrest; Cell Death; Cell Line; Cell Maintenance; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Clinical Trials; Colorectal Cancer; Complex; Data; Development; Diagnosis; Disease; Enzymes; Foundations; Future; Gene Expression Profiling; Gene Targeting; Genetic; Genetic Transcription; Growth; Homeostasis; Human; In Vitro; Laboratories; Ligands; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mus; NOD/SCID mouse; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Notch Signaling Pathway; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Primary Neoplasm; Process; Property; Public Health; Radiation; Radiation therapy; Receptor Activation; Recurrence; Reporter; Research Personnel; Resistance; Role; Series; Serum-Free Culture Media; Signal Pathway; Signal Transduction; Solid Neoplasm; Specificity; Specimen; Staging; Stem cells; Surgical Replantation; Survival Rate; Therapeutic; Therapeutic Agents; Tissues; Tumor Tissue; Undifferentiated; United States; Work; Xenograft procedure; base; cancer cell; cancer recurrence; cancer stem cell; cancer therapy; chemotherapy; cofactor; gamma secretase; implantation; improved; in vivo; inhibitor/antagonist; killings; leukemia; lung carcinogenesis; malignant breast neoplasm; neoplastic cell; notch protein; novel; novel strategies; prevent; receptor; self-renewal; stem; stem cell population; theories; therapeutic target; tumor; tumor growth; tumor initiation; tumor xenograft; vector

ABSTRACT Lung cancer is the leading cause of cancer-related death in the world with a 5-year survival rate of less than 15% which has not changed for the past three decades. At diagnosis, most patients already have advanced-stage disease and the use of chemotherapy and radiotherapy is rarely curative. This poor overall survival may be due to the fact that both chemotherapy and radiation therapy preferentially kill actively dividing cancer cells, which survive such treatment and eventually cause cancer recurrence and death. Thus, novel approaches to target quiescent tumor cells are needed. The cancer stem cell hypothesis proposes that cancers arise from relatively inactive stem cells that are capable of self-renewal, proliferation, and differentiation into more mature cancer cells. Evidence supports the existence of cancer stem cells in several tumor types and recent studies have identified putative stem cells in lung cancer. We have been evaluating the biologic characteristics of lung cancer stem cells in an effort to develop novel strategies for treatment that would reduce recurrence rates and improve patient survival. Notch is a highly conserved signaling pathway that regulates cell fate decisions during development and in tissue homeostasis. Notch signaling regulates the self-renewal potential of stem/progenitor cell populations in multiple contexts and has been proposed to support the self-renewal capability of some cancer stem cell populations. Gene expression profiling of non-small-cell lung cancer specimens has shown elevated expression of downstream effectors of Notch signaling, suggesting an important role of Notch signaling in lung carcinogenesis. Data from our laboratory and from other investigators have shown that inhibition of Notch signaling by gamma secretase inhibitors (GSI) can decrease cell proliferation and induce apoptosis in some lung cancer cell lines. However, the specific mechanisms underlying this activity of GSI and the effect of Notch inhibition on lung cancer and lung cancer stem cells have not been explored. Our preliminary data show that different lung cancer cell lines have variable expression of Notch receptors and its pathway components. In these cell lines, the GSI MRK003 induces growth inhibition due to cell cycle arrest leading to apoptotic cell death. In addition, treating lung cancer mouse xenografts with MRK003 limits the serial reimplantation potential of these tumors, suggesting a possible inhibitory effect on cancer stem cells. Thus, it is important to distinguish global effects of the drug on cancer cells, and the specific effects on cancer stem cells. In this application, we propose to investigate the specific role of the Notch pathway in lung cancer stem cells utilizing primary human lung tumor tissue and assess the impact of Notch inhibition on tumor formation. This work presents a novel approach in treating lung cancer by targeting cancer stem cells and provides basis for future clinical trials.

摘要 肺癌是世界上与癌症相关的死亡的主要原因，其5年生存率不到15%，这一点在过去30年中没有改变。在确诊时，大多数患者已经是晚期疾病，使用化疗和放射治疗很少能治愈。总体存活率较低可能是因为化疗和放射治疗都优先杀死主动分裂的癌细胞，这些癌细胞在这种治疗中存活下来，最终导致癌症复发和死亡。因此，需要新的方法来靶向静止的肿瘤细胞。 癌症干细胞假说认为，癌症是由相对不活跃的干细胞引起的 能够自我更新、增殖和分化为更成熟的癌细胞。有证据支持在几种肿瘤类型中存在癌症干细胞，最近的研究已经确定在肺癌中可能存在干细胞。我们一直在评估肺癌干细胞的生物学特性，以努力开发新的治疗策略，以降低复发率和提高患者存活率。凹槽 是一条高度保守的信号通路，在发育和组织动态平衡中调节细胞命运的决定。Noch信号在多种环境下调节干细胞/祖细胞群体的自我更新能力，并被认为支持某些癌症干细胞群体的自我更新能力。 非小细胞肺癌标本的基因表达谱显示Notch信号下游效应物的表达升高，提示Notch信号在肺癌发生中起重要作用。我们实验室和其他研究人员的数据表明，用伽马分泌酶抑制剂(GSI)抑制Notch信号可以抑制某些细胞的增殖并诱导某些细胞凋亡 肺癌细胞株。然而，GSI这种活性的具体机制以及Notch抑制对肺癌和肺癌干细胞的影响尚未被探索。我们的初步数据显示，不同的肺癌细胞系有不同的Notch受体及其通路成分的表达。在这些细胞系中，GSI MRK003由于细胞周期停滞导致细胞死亡而诱导生长抑制。此外，用MRK003治疗肺癌小鼠移植瘤限制了这些肿瘤的连续再移植潜力，这表明可能对癌症干细胞有抑制作用。因此，区分药物对癌细胞的整体作用和对癌症干细胞的具体作用是很重要的。 在这一应用中，我们建议利用原代人肺肿瘤组织来研究肺癌干细胞中Notch通路的特定作用，并评估Notch抑制对肿瘤形成的影响。这项工作为靶向肿瘤干细胞治疗肺癌提供了一种新的方法，并为未来的临床试验提供了基础。