Modular oligonucleotide technologies to target, sensitize, and treat mutant EGFR positive lung adenocarcinoma
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Despite various public health initiatives, lung cancer remains a leading cause of death worldwide and is expected to account for ~20% of all cancer related deaths in the United States in 2025. Contributing significantly to these statistics is lung adenocarcinoma (LUAD), one of the most prevalent forms of Non-Small Cell Lung Cancer (NSCLC). Unlike other forms of lung cancer, LUAD is not typically associated with exposure to carcinogens, but is instead often caused by acquired somatic mutations or amplifications in oncogenes and/or tumor suppressors. One such oncogene is the receptor tyrosine kinase, Epidermal Growth Factor Receptor (EGFR), for which gene amplifications or mutations in the tyrosine kinase domain induce survival mechanisms and/or sustained proliferative signaling. Fortunately, EGFR targeted therapies such as tyrosine kinase inhibitors (TKIs) have revolutionized outcomes for patients with mutant EGFR positive LUAD; however, therapeutic resistance and progressive disease are inevitable and typically occur 12-18 months after beginning these treatments. Because second- and third-line therapeutics are often ineffective or toxic, there is an unmet need for alternative or adjuvant methods to treat such cancers. The work described in this dissertation focuses on the application of oligonucleotide technologies to address this unmet need, with a major emphasis on aptamer technology. We take advantage of the modular properties of oligonucleotides to develop multivalent, aptamer-based, cell surface targeting reagents and explore how reagent structure impacts its biodistribution and its ability to target the tumor. Using fluorescent based imaging techniques and a newly developed multiplex screening method, termed Barcoded Aptamer Technology (BApT), we show that bispecific reagents do not always outperform monospecific reagents, and we highlight the poor predictability of in vitro binding assays. In addition, we show how both aptamer and siRNA technologies can be utilized to sensitize or treat a subset of mutant EGFR positive LUADs, either directly or indirectly by modulating immune effector cells. This includes targeting DUSP11, a newly identified innate immune checkpoint (iIC) in LUAD. As aptamers have had limited success translating into the clinic, the discussions prioritize addressing pharmacokinetic (PK) and delivery method barriers for the development of clinically useful reagents.
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Ph. D.