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.