Targeting EGFR Therapeutic Resistance Using EMT-Seeking Aptamers in Lung Cancer
Abstract
This proposal focuses on two of the Fiscal Year 2016 Lung Cancer Research Program areas of emphasis: (1) Understanding susceptibility or resistance to treatment and (2) identifying innovative strategies for prevention and treatment of early and/or localized lung cancer. Lung cancer is the most lethal cancer type in the United States, affecting both military and civilian populations, with an estimated 162,460 deaths in 2015. The majority (85%) of all lung cancer cases are non-small cell lung cancer (NSCLC). The overall 5-year survival rate currently stands at a dismal 15% due to poor detection of early-stage disease and paltry responses to first-line therapeutics. To complement first-line cytotoxic chemotherapies, a class of tyrosine kinase inhibitors (TKIs) specifically targeting the epidermal growth factor receptor (EGFR) was approved for clinical treatment of NSCLC. While this strategy met with great initial success for those patients with activating EGFR mutations, invariably patients that demonstrated an initial response developed drug resistance. Furthermore, 25%-30% of the patients with EGFR activating mutations were intrinsically resistant and completely refractory to treatment. Thus, there is an unmet clinical need to better target drug-resistant NSCLC. Development of a drug-resistant phenotype has been attributed to attainment of cellular plasticity in different cancer types including lung cancer largely due to cells undergoing the epithelial-to-mesenchymal transition (EMT). Strategies to detect and target these EMT-positive cells have thus far met with limited success. Therefore, it is critical to develop novel strategies that could detect the EGFR-resistant lung cancer cells and simultaneously target them without affecting the normal cells of the body. We will first develop a novel RNA aptamer to directly bind only cancer cells that are in the EMT state. Aptamers are small molecules that can bind to targets (proteins, other small molecules, or a complete microorganism) with similar affinity and specificity as antibodies. Development of an EMT cell-specific aptamer holds many unique advantages over the use of antibodies in that they are more affordable to produce, are less variable from batch to batch, they are more stable, less toxic, and can be modified to function as a delivery vehicle for targeted delivery of cytotoxic reagents. EMT-specific aptamers will be identified through SELEX (Systematic Evolution of Ligands by Exponential enrichment), which allows for unbiased enrichment of those aptamers that specifically bind to EMT positive cells and not cells in the epithelial state. Our innovative approach for developing an EMT-specific aptamer is unbiased and does not rely on previous knowledge of a specific target. This is advantageous as the most robust biomarker for targeting EMT cells may not currently be known. Taking this unbiased approach will also allow us to identify what the target of the aptamer is, potentially expanding our understanding of this critical program while also identifying new targets for therapeutic intervention. Ultimately our goal is to eradicate EGFR therapeutic-resistant EMT-positive NSCLC cells. To achieve this, we will harness our specific targeted aptamer to deliver chemotherapeutics directly to the EMT cells. Using the RNA aptamer to deliver drugs only to the target cells will limit off-target side effects and toxicities associated with current treatment strategies. Successful completion of this study will develop a robust and versatile tool that can be harnessed for both diagnostics and targeted therapeutic delivery. Development of the unbiased RNA aptamer will impact both the scientific and patient communities, allow discovery of the most efficient and effective way to EGFR-resistant NSCLC cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710296
Entities
People
- Jason Herschkowitz
Organizations
- State University of New York at Albany
- United States Army