In Vivo Selection of Aptamers Targeting Pancreatic Cancer

Duke University, Durham NC

Investigators

Abstract

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.