Genetics and Biology of Pancreatic Duct Adenocarcinoma

描述（由申请人提供）：胰腺导管腺癌（PDAC）是癌症死亡的主要原因之一，几乎所有病例都伴随着快速而无情的顽固性疼痛、恶病质、绝望和死亡。 临床试验失败的反复循环强调了对PDAC发病机制的更好理解的需要，激励了基础，转化和临床科学家的多学科团队的形成，具有癌细胞信号传导，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。 本P01的目的是进一步阐明疾病的遗传学和生物学，以指导有效靶向药物（单独和联合）的合理开发。 具体而言，我们寻求（i）改进人PDAC的小鼠模型，以了解PDAC特征突变的肿瘤生物学作用，（ii）鉴定、验证和表征新的人PDAC癌基因，以为药物发现奠定基础，（三）使用小鼠和人类系统阐明和验证PI3K通路在PDAC中的作用，目的是确定关键治疗靶点并指导临床试验靶向该途径，（iv）利用基因工程小鼠和人肿瘤来定义控制PDAC微环境的进化和维持的信号传导事件，并使用该信息在人PDAC的精制小鼠模型中设计和进行创新的临床前试验，（v）确定小鼠中的PDAC起源细胞及其遗传事件，以阐明化学预防的可能途径，和（vi）鉴定和表征鼠和人肿瘤中的PDAC癌干细胞。 最先进的成像和抗体技术，以及强大的实验病理学和生物标本库，将使PDAC肿瘤生物学和信号传导的深入和动态分析前所未有的细节。 这些基础和临床前工作的长期目标，采用和整合小鼠和人类系统，是识别和指导靶向药物发现和诊断剂和生物标志物的开发的机会。

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.