Understanding the origin,initiation,and progression of high-grade serous ovarian cancer

了解高级别浆液性卵巢癌的起源、发生和进展

• 批准号: 9182056
• 负责人: Jaeyeon Kim
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9182056
• 关键词: Address; Advanced Malignant Neoplasm; Animal Model; Antiestrogen Therapy; Biological Assay; Biology; Cancer Etiology; Cancer cell line; Carcinoma; Career Choice; Cell Lineage; Cells; Cessation of life; Collaborations; Complex; Contraceptive Usage; Coupled; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drug Targeting; Early Diagnosis; Environment; Epidemiology; Epithelial; Epithelium; Estrogen Receptors; Estrogens; Etiology; Failure; Genetic; Goals; Health; Human; Human Genetics; Knock-out; Knockout Mice; Knowledge; Lead; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Maps; Medical center; Medicine; Mentors; Mesenchyme; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Names; Nature; Neoplasm Metastasis; Oral Contraceptives; Ovarian; Ovarian Serous Adenocarcinoma; Ovarian hormone; Ovary; Phase; Postmenopause; Prognostic Marker; Relapse; Research; Research Personnel; Risk; Role; Screening for Ovarian Cancer; Serous; Signal Transduction; Staging; Stromal Cells; TP53 gene; Testing; Texas; Therapeutic; Tissues; Training; Tumor Biology; Tumor Tissue; Tumor-Associated Process; anticancer research; base; cancer diagnosis; cancer initiation; college; diagnostic screening; early detection biomarkers; effective therapy; epithelial to mesenchymal transition; experience; hormone therapy; improved; insight; mortality; mouse model; mutant; mutant mouse model; novel; post-doctoral training; pre-clinical trial; prevent; receptor expression; reproductive tract; screening; targeted treatment; tumor; tumor progression

DESCRIPTION (provided by applicant): Ovarian cancer is a deadly disease because most cases are diagnosed at advanced stages, when the cancer has already metastasized. Yet no effective diagnostic or screening tests are currently available for the early detection of ovarian cancer. The main reason for this failure is that little has been known about the early tumor process of this cancer. Though named "ovarian cancer," the most deadly type, high-grade serous ovarian carcinoma (HGSC), appears to originate, not in the ovary, but instead in the fallopian tube. Beyond this emerging concept of tissue origin, yet most early tumor mechanisms still remain elusive, which poses a major roadblock to developing an effective diagnostic or screening test for early detection. Thus, the overall goal of this proposal is to improve our understanding on the molecular mechanisms of deadly ovarian cancer, especially the cell of origin, initiation, and progression of HGSC. Remarkably recapitulating deadly human high- grade serous ovarian cancer, the Dicer-Pten double-knockout (DKO) and p53-Dicer-Pten triple-mutant (TKO) mouse models will be instrumental in the proposed research. During the mentored K99 phase, the research will focus on employing and characterizing these DKO and TKO models. In particular, pre-clinical trials using DKO mice as well as cell-based assays using human ovarian cancer cell lines will be performed to evaluate the therapeutic potential of antiestrogen therapy in advanced ovarian cancer. Elucidating the cell of origin and early progression of HGSC will require cell-lineage tracing by mouse genetic fate-mapping analysis, which will begin in the K99 phase but be pursued extensively during the independent R00 phase. In addition, defining the role of p53 mutation in the initiation and early progression of HGSC will be investigated in detail by analyzing TKO mice and generating multiple p53 double-mutant mice during this independent phase. In pursuing these projects, Baylor College of Medicine, also part of the world-largest Texas Medical Center, offers extraordinary research and academic environments for my postdoctoral training and continuing development into an independent investigator. Coupled with my in-depth doctoral training in ovarian biology and also established collaborations with relevant experts, my extensive postdoctoral research experience in developing and analyzing mouse models of ovarian cancer will enable me to pursue and achieve the aims in the proposed research. This will undoubtedly lead to a successful career path as an independent investigator in cancer research with an emphasis on ovarian cancer. More important, the knowledge we will gain from these proposed studies will offer vital translational insights ? not only for the early detection and screening of ovarian cancer, but also for a new treatment for advanced ovarian cancer.

描述（由申请人提供）：卵巢癌是一种致命的疾病，因为大多数病例是在癌症已经转移时在晚期诊断出来的。然而，目前尚无有效的诊断或筛查测试可用于早期检测卵巢癌。造成这种失败的主要原因是，对这种癌症的早期肿瘤过程知之甚少。虽然称为“卵巢癌”，但最致命的高级浆液卵巢癌（HGSC）似乎起源于卵巢，而是在卵巢中，而是在输卵管中。除了这种新兴的组织起源概念之外，大多数早期肿瘤机制仍然难以捉摸，这为开发有效的诊断或筛查试验构成了重大障碍。因此，该提案的总体目标是提高我们对致命卵巢癌的分子机制的理解，尤其是HGSC的起源细胞，起始和进展。明显地概括了致命的人类高级浆液卵巢癌，DICER-PTEN双敲击（DKO）和P53-DICER-PTEN-PTEN三突变剂（TKO）小鼠模型将在拟议的研究中发挥作用。在指导的K99阶段，该研究将着重于采用和表征这些DKO和TKO模型。特别是，将使用DKO小鼠以及使用人卵巢癌细胞系的基于细胞的测定进行临床前试验，以评估晚期卵巢癌中抗雌激素治疗的治疗潜力。阐明原始细胞和HGSC的早期进展将需要小鼠遗传命运分析进行细胞训练，这将在K99期开始，但在独立的R00期间进行广泛追踪。此外，将通过分析TKO小鼠并在此独立阶段生成多个p53双突变小鼠，来详细研究p​​53突变在HGSC的起始和早期进展中的作用。在追求这些项目时，贝勒医学院也是世界上最大的德克萨斯医学中心的一部分，为我的博士后培训提供了非凡的研究和学术环境，并继续发展成为独立研究者。再加上我在卵巢生物学方面的深入博士培训，并与相关专家建立了合作，我在开发和分析卵巢癌老鼠模型方面的广泛博士后研究经验将使我能够追求并实现拟议研究的目标。毫无疑问，这将导致成为癌症研究独立研究者的成功职业道路，重点是卵巢癌。更重要的是，我们将从这些拟议的研究中获得的知识将提供重要的翻译见解？不仅用于早期检测和筛查卵巢癌，还用于治疗晚期卵巢癌的新治疗方法。