In Vivo Selection of Aptamers Targeting Pancreatic Cancer

描述(申请人提供)：胰腺癌是美国癌症相关死亡的主要原因之一。即使手术是一种选择，这种诊断的预后也很差。这种肿瘤的耐药性是出了名的，因为目前针对这种疾病的化疗方案往往无效，只延长了几个星期的生存时间。像吉西他滨这样的药物，目前的标准护理，是通过抑制细胞新陈代谢和对原发肿瘤非特异性的途径发挥作用的。需要针对癌细胞而不是宿主组织的更具体的新疗法。创建针对胰腺癌的适体是实现这一目标的一种方法。适配子是单链DNA或RNA寡核苷酸配体，其独特的三维结构由其序列决定。由于它们对目标蛋白的高度亲和力和特异性，它们已成为一系列生物研究应用中有吸引力的工具。使用迭代选择策略从大型组合文库中分离出适配子。最近描述了一种体内适配子选择，该适配子选择针对更复杂的靶点，如肿瘤。我们建议使用这项新技术来分离结合在胰腺癌基因工程小鼠模型中发展的肿瘤的适体，这概括了人类胰腺癌的临床、组织学和遗传学特征。我们将通过确定其特定的蛋白质和细胞靶标来鉴定选定的适配子。选择过程不仅有可能识别新的或意想不到的靶点，而且适配子本身也可能被用作成像或治疗试剂。 与公共卫生相关：在美国，每年有超过4.3万人被诊断出患有胰腺癌，其中3.6万人将死于胰腺癌。目前的化疗只能将存活期延长几周。仅针对癌细胞的分子治疗可以提高应答率和长期存活率，并减少对患者的全身毒性。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the leading causes of cancer-related death in the U.S. The diagnosis carries a poor prognosis, even when surgery is an option. This tumor is notoriously chemoresistant, as current chemotherapeutic regimens against the disease are often ineffective and extend survival by only a few weeks. Drugs such as gemcitabine, the current standard-of- care, work by inhibiting cellular metabolism and pathways that are nonspecific to the primary tumor. New, more specific therapies are needed that will target cancer cells and not the host tissues. The creation of pancreatic cancer-targeted aptamers is one way to achieve this. Aptamers are single-stranded DNA or RNA oligonucleotide ligands whose unique 3-dimensional structures are dictated by their sequences. They have become attractive tools for use in an array of biological research applications because of their high affinity and specificity for their target proteins. Aptamers are isolated from large combinatorial libraries using iterative selection strategies. An in vivo aptamer selection has recently been described that selects aptamers against more complex targets such as tumors. We propose using this new technique to isolate aptamers that bind tumors that develop in a genetically engineered mouse model of pancreatic cancer, which recapitulates clinical, histological, and genetic features of human pancreatic cancers. We will characterize selected aptamers by identifying their specific protein and cellular targets. Not only does the selection process have the potential to identify novel or unexpected targets but also the aptamers themselves may be exploited as imaging or therapeutic agents. PUBLIC HEALTH RELEVANCE: More than 43,000 people are diagnosed with pancreatic cancer every year in the United States, and 36,000 will die from it. Current chemotherapies extend survival by only a few weeks. Molecular therapies which target the cancer cells alone can increase the response rate and long-term survival, and decrease systemic toxicities to patients.