Katie Antilla PhD Thesis Defense
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Katie Antilla
PhD Candidate
Chemical Engineering
Academic advisor: Professor Shan X. Wang
Abstract: A Magnetoresistive Biosensor Assay for Detecting KRAS-Mutated Circulating Tumor DNA in Non-Small Cell Lung Cancer
Lung cancer is currently the leading cause of cancer death worldwide, and about 80% of those cases are non-small cell lung cancer (NSCLC). One way people are working to improve NSCLC outcomes is by replacing or supplementing existing treatment methods (like chemotherapy and radiation therapy) with targeted drugs, which can have significantly fewer adverse side effects. The effectiveness of these targeted drugs generally depends on the presence of specific genetic mutations in the tumor, which can change over time. Currently, the standard way to detect these mutations in the clinic is by taking tissue biopsies, which are expensive and very invasive. However, one promising new alternative for mutation detection is the use of liquid biopsies based on circulating tumor DNA (ctDNA), which is released by tumor cells into the bloodstream.
First, we show the development of an assay using giant magnetoresistive (GMR) sensors and magnetic nanoparticles to detect six key mutations in the gene Kirsten rat sarcoma proto-oncogene (KRAS), which are relevant for a number of targeted drugs which are now approved (sotorasib, adagrasib) or in clinical trials. Assay testing with synthetic DNA showed limits of detection of 0.1-3% mutant allelic fraction (MAF).
Next, we show validation of the assay for clinical translation using blood draws from a pilot cohort of 27 NSCLC patients. Results from this patient sample testing showed that the area under the curve (AUC) values for baseline mutation classification were 0.91-0.93 for the two mutations with 8-10 samples and 0.62-0.86 for the three mutations with 2-3 samples, with potential improvements through the use of logistic regression models. For the 16 patients with follow-up blood draws, we found an 80% concordance between our assay’s treatment response classifications and gold-standard computed tomography (CT) imaging results, with the potential to predict response and detect the emergence of secondary resistance mutations weeks or even months earlier than with the current standard of care.
Overall, such assays could ultimately be used to replace or complement lung tissue biopsies with blood-based liquid biopsies, allowing for less invasive and less expensive NSCLC treatment selection and monitoring.