Genetic Screening:Oncogene RAS-Based Inhibi*(RMI)

描述（由申请人提供）：胰腺癌是最具侵袭性和破坏性的人类疾病之一。几乎所有被诊断患有这种疾病的患者都死于恶性肿瘤，中等生存期不到6个月。临床上，由于缺乏特异性症状和诊断方法的限制，该病往往在早期阶段逃避检测。更糟糕的是，胰腺癌对化疗、放疗和联合治疗等大多数治疗方法都有抗药性。胰腺癌临床预后如此糟糕的一个最重要的原因是缺乏对人体胰腺生理和病理生理条件下的基本生物学的基本理解。美国国家癌症研究所胰腺癌进展审查小组最近的一项研究得出结论，与其他癌症部位相比，胰腺癌在临床和基础研究中的代表性都不足。尽管许多与胰腺癌发展相关的遗传变化已经被揭示，但我们对这些遗传改变如何导致胰腺癌的发生、发展和维持的理解存在重大空白。这些信息对于开发新的有效的胰腺癌诊断和治疗方法至关重要。胰腺癌研究的一个主要障碍是缺乏基因可处理的人类癌细胞模型系统来研究胰腺癌的起源和进展。为了克服这一障碍，我们最近开发了一种遗传定义的人类胰腺癌细胞模型，使用已知在胰腺癌中经常改变的遗传成分。我们将使用我们的基因定义的人类胰腺癌模型来筛选化学文库，以发现优先杀死癌细胞而不是正常人类胰腺细胞的化合物。这些研究可能会导致胰腺癌潜在的新的和有效的治疗方法的确定。此外，这种基于机制的化学抑制剂的鉴定也将有助于阐明这些明确定义的遗传改变的下游信号通路，这些改变对这种破坏性疾病的发生和发展很重要。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most aggressive and devastating human disease. Almost all patients diagnosed with the disease die from the malignancy with a medium survival of less than six months. Clinically, the disease often evades detection during its early stages due to the lack of specific symptoms and limitation in diagnostic methods. Adding to this problem, pancreatic cancer is resistance to most forms of treatments such as chemotherapy, radiation, and combination therapy. One single most important cause for such a dismal clinic prognosis of pancreatic cancer is the lack of fundamental understanding of basic biology of human pancreas both under physiological and pathophysiological conditions. A recent study by the National Cancer Institute Pancreatic Cancer Progress Review Group concluded that pancreatic cancer is disproportionately underrepresented in both clinical and basic research compared with other cancer sites. Although many of the genetic changes associated with pancreatic cancer development have been revealed, significant gaps exist in our understanding of how these genetic alterations lead to the initiation, development, and maintenance of pancreatic cancer. This information is essential for develop new and effective diagnostics and treatments for pancreatic cancer. One major roadblock for pancreatic cancer research is the lack of genetically tractable human cancer cell model systems to investigate the origins and progression of pancreatic cancer. To overcome this barrier, we have recently developed a genetically defined human pancreatic cancer cell model using genetic components known to be frequently altered in pancreatic cancer. We will use our genetically defined human pancreatic cancer model to screen chemical libraries for the purpose of discovering of chemical compounds that preferentially kill the cancer cells but not normal human pancreatic cells. These studies may lead to the identification of potential novel and effective treatments for pancreatic cancer. In addition, the identification of such mechanism-based chemical inhibitors will also aid the elucidation of down-stream signaling pathways of these well-defined genetic alterations that are important for the initiation and development of this destructive disease.