In Vivo Selection of Aptamers Targeting Pancreatic Cancer

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的主要原因之一，即使可以选择手术，诊断预后也很差。这种肿瘤是出了名的耐药，因为目前针对这种疾病的化疗方案通常是无效的，并且只能延长几周的生存期。目前的标准治疗药物，如吉西他滨，是通过抑制细胞代谢和原发肿瘤非特异性通路来起作用的。新的、更具体的治疗方法需要针对癌细胞而不是宿主组织。创造胰腺癌靶向适配体是实现这一目标的一种方法。适配体是单链DNA或RNA寡核苷酸配体，其独特的三维结构由其序列决定。由于它们对靶蛋白的高亲和力和特异性，它们已成为用于一系列生物学研究应用的有吸引力的工具。利用迭代选择策略从大型组合文库中分离适配体。最近，一种体内适体选择被描述为针对更复杂的靶标（如肿瘤）选择适体。我们建议使用这种新技术来分离在基因工程小鼠胰腺癌模型中发展的肿瘤的适配体，该模型概括了人类胰腺癌的临床、组织学和遗传特征。我们将通过鉴定其特定的蛋白质和细胞靶标来表征选定的适体。选择过程不仅有可能识别新的或意想不到的靶标，而且适体本身也可能被用作成像或治疗剂。

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.