Novel Experimental Therapeutics for Pancreatic Cancer

描述(申请人提供)：胰腺导管腺癌(PDAC)是一种痛苦、致命和无法治愈的疾病，有效的治疗方法仍有待发现和测试。这项研究的总体目标是确定潜在的PDAC细胞生长调节机制，重点是进一步表征一种新的途径，其中个别成分可以作为药理靶点。以前的研究和我们的初步数据表明，有丝分裂异常和PDAC细胞生长这两个高度相关的过程依赖于从Aurora A(AurkA)到HP1？-G9a途径的信号。AurkA或HP1？-G9a复合体的突变或异常表达与包括PDAC在内的不同来源的肿瘤的发生有关。我们将测试中心假设，即一个新的AurkA-HP1-G9a途径调节有丝分裂进程和PDAC细胞生长的方式服从于药物抑制使用联合治疗。我们的具体目标是：1.研究AurkA-HP1-G9a复合体作为AurkA对PDAC细胞有丝分裂进程影响的下游介体的功能；2.研究AurkA-HP1-G9a通路抑制PDAC生长的细胞和分子机制；3.研究联合靶向AurkA-HP1-G9a通路对PDAC进展的影响。因此，我们的研究将从分子水平到细胞群体，再到整个生物体。这些研究对我们的实验室是可行的，我们的实验室已经制定了适当的概念框架、试剂、训练有素的人员并建立了合作来执行拟议的研究。这项建议的设计是创新的，因为它寻求最大限度地产生影响PDAC肿瘤生长的新的机制知识和药物干预措施。由于PDAC是一种令人沮丧的疾病，这一新的AurkA-HP1-G9a通路的发现和拟议的研究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.