Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer

开发 PEA 15 作为卵巢癌靶向治疗基因

• 批准号: 7500877
• 负责人: Naoto T Ueno
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500877
• 关键词: Address; Adenovirus Vector; Adenoviruses; Affect; Agar; Animal Model; Apoptosis; Basic Science; Binding; Biological; Biological Assay; Breast; Bromodeoxyuridine; Cancer Biology; Cancer Etiology; Cancer cell line; Carboplatin/Cisplatin; Cell Cycle; Cell Death; Cell Nucleus; Cell Proliferation; Cells; Cessation of life; Cisplatin; Clinic; Clinical Trials; Combined Modality Therapy; Complex; Condition; Cytoplasm; Development; Diagnostic; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Fluorescence-Activated Cell Sorting; Foundations; Genes; Genetic Transcription; Goals; Grant; Hand; In Vitro; Induction of Apoptosis; Injection of therapeutic agent; Lead; Liposomes; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Molecular; Molecular Target; Mus; Outcome; Ovarian; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Phosphoproteins; Phosphorylation; Phosphorylation Site; Phosphotransferases; Platinum Compounds; Protein Overexpression; Purpose; Regulation; Research; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Small Interfering RNA; Taxane Compound; Therapeutic; Thinking; Transfection; Translating; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumorigenicity; United States; Variant; Woman; Work; Xenograft Model; base; cancer cell; cancer therapy; cell growth; chemotherapy; clinical Diagnosis; design; docetaxel; gene delivery system; gene therapy; human TNF protein; improved; in vivo; innovation; knock-down; malignant breast neoplasm; mutant; novel; novel therapeutics; pre-clinical; prevent; response; size; taxane; therapeutic gene; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Our long-term goal is to develop novel targeted therapy strategies to treat advanced ovarian cancer. In our previous studies of E1A gene therapy for ovarian and breast cancer, we identified PEA15 as being responsible for the antiproliferative effects of E1A on cancer cells. Our subsequent explorations of the molecular mechanism of this phenomenon led us to the central hypothesis of this proposal: that PEA15 has a critical role in ovarian cancer tumorigenicity and treatment response. Supporting evidence for this hypothesis is as follows. First, PEA15 is known to sequester ERK in the cytoplasm, and ERK is known to be involved in cell cycling and enhanced survival of cancer cells. Second, cells in which PEA15 is not phosphorylated at serine 116 undergo apoptosis via tumor-necrosis factor (TNF) signaling, a major apoptosis pathway. Third, overexpression of PEA15 suppresses viability of ovarian cancer cells. Fourth, patients with ovarian cancers that overexpress PEA15 survive longer than those with low-PEA15-expressing tumors. Collectively, these findings implicate PEA15 as a key molecule in ovarian cancer via its ability to block ERK and enhance TNF signaling, and thus could be exploited as a dual-pathway therapeutic gene for patients with ovarian cancer. Our first major goal in this proposal is to delineate the mechanistic and functional significance of PEA15 in ovarian cancer cells. The second major goal is to develop PEA15 as a targeted molecule. To address these two goals, we have developed a comprehensive plan comprising three specific aims: (1) Determine the role of PEA15 in ovarian cancer tumorigenicity; (2) Determine the effects of PEA15 on the sensitivity of ovarian cancer cell to chemotherapy; and (3) Establish how PEA15 modulates erlotinib sensitivity in ovarian cancer cells. This proposal is innovative because PEA15 is thought to target both ERK and TNF signaling pathways, which have been implicated in cancer aggressiveness, induction of apoptosis, and regulation of sensitivity to chemotherapy and EGFR-tyrosine kinase inhibitors. The proposed research is highly relevant to improving outcomes for patients with ovarian cancer because understanding the biology of cancer will lead to the discovery of novel targets to be used in clinical diagnosis and treatment. The ultimate purpose of this project is to build a foundation upon which to design a clinical trial, based on basic research, of PEA15 as a novel target. The proposed research is highly relevant to improving outcomes for patients with ovarian cancer because understanding the biology of cancer will lead to the discovery of novel targets (PEA15 or molecules related to PEA-15) to be used in clinical diagnosis and treatment.

描述（由申请人提供）：我们的长期目标是制定新颖的靶向治疗策略来治疗晚期卵巢癌。在我们先前对E1A基因治疗卵巢癌和乳腺癌的研究中，我们确定PEA15是负责E1A对癌细胞的抗增殖作用。我们随后对这种现象的分子机制的探索使我们提出了这一建议的中心假设：PEA15在卵巢癌肿瘤性和治疗反应中具有关键作用。该假设的支持证据如下。首先，已知PEA15在细胞质中隔离ERK，并且已知ERK参与细胞循环和增强癌细胞的存活。其次，在丝氨酸116上未磷酸化的PEA15的细胞通过肿瘤 - 肿瘤因子（TNF）信号传导（一种主要的凋亡途径）进行凋亡。第三，PEA15的过表达抑制了卵巢癌细胞的生存能力。第四，过表达PEA15的卵巢癌的患者的生存时间比表达低PEA15的肿瘤的患者的生存更长。总的来说，这些发现表明PEA15是卵巢癌中的关键分子，其能够阻止ERK和增强TNF信号传导，因此可以将其作为卵巢癌患者的双通道治疗基因。该提案中我们的第一个主要目标是描述PEA15在卵巢癌细胞中的机械和功能意义。第二个主要目标是将PEA15作为靶向分子开发。为了解决这两个目标，我们制定了一个全面的计划，其中包括三个具体目标：（1）确定PEA15在卵巢癌肿瘤性中的作用； （2）确定PEA15对卵巢癌细胞对化疗的敏感性的影响； （3）确定PEA15如何调节卵巢癌细胞中的厄洛替尼敏感性。该提议具有创新性，因为PEA15被认为针对ERK和TNF信号传导途径，这与癌症的侵袭性，凋亡的诱导以及对化学疗法和EGFR-酪氨酸激酶抑制剂的敏感性有关。拟议的研究与改善卵巢癌患者的预后高度相关，因为了解癌症的生物学将导致发现用于临床诊断和治疗的新型靶标。该项目的最终目的是建立一个基础，该基础是根据PEA15的基础研究设计临床试验作为一个新的目标。拟议的研究与改善卵巢癌患者的预后高度相关，因为了解癌症的生物学将导致在临床诊断和治疗中发现新的靶标（PEA15或与PEA-15相关的分子）。