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Novel Experimental Therapeutics for Pancreatic Cancer

胰腺癌的新实验疗法

基本信息

批准号：
9121509
负责人：
Gwen Lomberk
金额：
$ 32.99万
依托单位：
MAYO CLINIC ROCHESTER
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：
2014-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121509
关键词：
Adenocarcinoma Adenocarcinoma Cell Cancer Cell Growth Cancer Etiology Cell Death Cell Line Cell division Cells Cessation of life Chromosome abnormality Clinical Collaborations Combined Modality Therapy Complex Cytostatics Data Development Diagnosis Disease Enzymes Figs - dietary G2/M Arrest Genetic Genetically Engineered Mouse Goals Grant Growth Health Human Human Resources Individual Intervention Investigation Investigational Therapies Knowledge Laboratories Link Malignant Neoplasms Malignant neoplasm of pancreas Mediator of activation protein Mitosis Mitotic Modeling Molecular Mutation Nature Neoplasm Metastasis Neoplasms Oncogenic Pain Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmaceutical Preparations Phosphotransferases Population Process Proteins Reagent Regulation Research Resistance STK6 gene Serine Signal Transduction Testing Tissues Training Transferase Ursidae Family Whole Organism Xenograft procedure cell growth chemoradiation combinatorial cytotoxic design effective therapy heterochromatin-specific nonhistone chromosomal protein HP-1 inhibitor/antagonist innovation insight member mouse model novel novel therapeutic intervention novel therapeutics pancreatic cancer cells prevent response senescence targeted treatment transmission process tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a painful, deadly, and incurable disease for which effective treatments remain to be discovered and tested. The OVERALL OBJECTIVES of this study are to define mechanisms underlying the regulation of PDAC cell growth, by focusing on further characterizing a novel pathway for which individual components can be targeted pharmacologically. Previous studies along with our preliminary data indicate that mitotic aberrations and PDAC cell growth, two highly interrelated processes, rely on signaling from Aurora A (AurkA) to the HP1γ-G9a pathway. Mutations or aberrant expression of either AurkA or the HP1γ-G9a complex are implicated in the development of neoplasms of different origins, including PDAC. We will test the CENTRAL HYPOTHESIS that a novel AurkA-HP1γ-G9a pathway regulates mitotic progression and PDAC cell growth in a manner amenable to pharmacological inhibition using combination therapy. Congruently, our SPECIFIC AIMS are: 1. To characterize the function of the HP1γ-G9a complex as a downstream mediator of the effects of AurkA on mitotic progression in PDAC cells; 2. To characterize cellular and molecular mechanisms that contribute to the inhibitory effects of the AurkA-HP1γ-G9a pathway on PDAC growth; and 3. To characterize the effects of combined targeting of the AurkA-HP1?-G9a pathway on PDAC progression in orthotopic xenografts and genetically engineered mice models. Thus, our research will span from the level of molecules to cell populations to the whole organism. These studies are feasible for our laboratory, which has developed the appropriate conceptual framework, reagents, trained personnel and established collaborations to execute the proposed research. The design of this proposal is innovative as it seeks to maximize the yield of new mechanistic knowledge and pharmacological interventions, which impact on PDAC tumor growth. Since PDAC is a dismal disease, the discovery and proposed study of this novel AurkA-HP1γ-G9a pathway bears significant biomedical relevance.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种痛苦、致命且无法治愈的疾病，其有效治疗方法仍有待发现和测试。本研究的总体目的是通过进一步表征单个组分可以靶向的新途径，确定PDAC细胞生长调节的潜在机制。先前的研究沿着我们的初步数据表明，有丝分裂畸变和PDAC细胞生长这两个高度相关的过程依赖于从Aurora A（AurkA）到HP 1 γ-G9 a通路的信号传导。AurkA或HP 1 γ-G9 a复合物的突变或异常表达与不同来源的肿瘤（包括PDAC）的发生有关。我们将测试中心假设，即一种新的AurkA-HP 1 γ-G9 a通路以一种适合于使用联合治疗进行药理学抑制的方式调节有丝分裂进程和PDAC细胞生长。相应地，我们的具体目标是：1。目的：1.探讨HP 1 γ-G9 a复合物作为AurkA调控PDAC细胞有丝分裂的下游介质的功能。表征有助于AurkA-HP 1 γ-G9 a途径对PDAC生长的抑制作用的细胞和分子机制;以及3.为了表征AurkA-HP 1？-原位异种移植物和基因工程小鼠模型中G9 a通路对PDAC进展的影响因此，我们的研究将从分子水平跨越到细胞群体到整个生物体。这些研究对我们的实验室来说是可行的，我们的实验室已经开发了适当的概念框架、试剂、经过培训的人员，并建立了合作关系来执行拟议的研究。该提案的设计是创新的，因为它寻求最大限度地提高新的机制知识和药理学干预的产量，这对PDAC肿瘤生长产生影响。由于PDAC是一种令人沮丧的疾病，这种新的AurkA-HP 1 γ-G9 a通路的发现和拟议的研究具有重要的生物医学意义。