Genetics and Biology of Pancreatic Duct Adenocarcinoma

描述(申请人提供)：胰腺导管腺癌(PDAC)是癌症死亡的主要原因之一，几乎所有的病例都伴随着顽固性疼痛、恶病质、绝望和死亡的快速和无情的病程。反复的临床试验失败突显了对PDAC发病机制更好理解的必要性，促使这个由基础、转化和临床科学家组成的多学科团队的形成，他们拥有癌细胞信号、发育和干细胞生物学、肿瘤生物学和血管生成、癌症小鼠模型、基因组学和信息学、分子成像、实验病理学以及小分子化学和生物治疗学方面的知识。 P01的目标是进一步阐明疾病的遗传学和生物学，以指导单独和联合使用有效的靶向药物的合理开发。具体地说，我们试图(I)提炼人PDAC的小鼠模型，以了解PDAC特征突变的肿瘤生物学作用，(Ii)识别、验证和表征新的人类PDAC癌基因，以便为药物发现奠定基础，(Iii)利用小鼠和人类系统阐明和验证PI3K通路在PDAC中的作用，目的是识别关键的治疗靶点并指导针对该途径的临床试验，(Iv)利用基因工程小鼠和人类肿瘤来定义支配PDAC微环境的进化和维持的信号事件，并利用这些信息在改进的人类PDAC小鼠模型中设计和进行创新的临床前试验，(V)确定PDAC细胞的起源及其在小鼠中的遗传事件，以阐明一条可能的化学预防途径，以及(Vi)鉴定和鉴定小鼠和人类肿瘤中的PDAC癌症干细胞。最先进的成像和抗体技术，以及强大的实验病理学和生物显微镜信息库，将使对PDAC肿瘤生物学和信号的深入和动态分析变得前所未有的详细。这些基础和临床前工作的长期目标是利用和整合小鼠和人类系统，识别和指导靶向药物发现以及诊断试剂和生物标记物的开发机会。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is among the leading causes of cancer death, with nearly all cases following a rapid and merciless course of intractable pain, cachexia, hopelessness and death. Repeated cycles of clinical trial failures have underscored the need for an improved understanding of PDAC pathogenesis, motivating the formation of this multi-disciplinary team of basic, translational and clinical scientists, with knowledge in cancer cell signaling, developmental and stem cell biology, tumor biology and angiogenesis, mouse models of cancer, genomics and informatics, molecular imaging, experimental pathology, and small molecule chemistry and biotherapeutics. The goal of this P01 is to further elucidate the genetics and biology of the disease to a level that will guide the rational development of effective targeted agents, alone and in combination. Specifically, we seek to (i) refine mouse models of human PDAC in order to understand the tumor biological role of PDAC signature mutations, (ii) identify, validate and characterize new human PDAC oncogenes in order to set the stage for drug discovery, (iii) illuminate and validate the role of the PI3K pathway in PDAC using mouse and human systems with the goal of identifying key therapeutic targets and guiding clinical trials targeting this pathway, (iv) utilize genetically engineered mice and human tumors to define signaling events governing the evolution and maintenance of the PDAC microenvironment, and to use this information to design and conduct innovative preclinical trials in refined mouse models of human PDAC, (v) determine the PDAC cell of origin and its genetic events in the mouse so as to illuminate a possible path to chemoprevention, and (vi) identify and characterize PDAC cancer stem cells in murine and human tumors. State-of-the-art imaging and antibody technologies, as well as strong experimental pathology and biospecimens repositories, will enable in-depth and dynamic analyses of PDAC tumor biology and signaling in unprecedented detail. The long-term goal of these basic and preclinical efforts, employing and integrating both mouse and human systems, is to identify and guide opportunities for targeted drug discovery and for the development of diagnostic agents and biomarkers.