Novel Experimental Therapeutics for Pancreatic Cancer

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，两个高度相关的过程，依赖于从Aurora A（AurkA）到HP 1？G9 a途径。突变或异常表达的AurkA或HP 1？- G9 a复合物与不同来源的肿瘤（包括PDAC）的发展有关。我们将测试一个新的AurkA-HP 1？G9 a途径以适合于使用组合疗法的药理学抑制的方式调节有丝分裂进展和PDAC细胞生长。相应地，我们的具体目标是：1。为了表征HP 1？的功能- G9 a复合物作为AurkA对PDAC细胞有丝分裂进程影响的下游介质; 2.表征有助于AurkA-HP 1？抑制作用的细胞和分子机制。G9 a途径对PDAC生长的影响;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？G9 a通路具有重要的生物医学意义。

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 HP1?-G9a pathway. Mutations or aberrant expression of either AurkA or the HP1? -G9a complex are implicated in the development of neoplasms of different origins, including PDAC. We will test the CENTRAL HYPOTHESIS that a novel AurkA-HP1?-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 HP1?-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-HP1?-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-HP1?-G9a pathway bears significant biomedical relevance.