Poster #011, CHLA LA-HIP
Targeted Micelles Delivery of PI3K, AKT, and mTOR inhibitors in Wilms Tumor Cancer Stem Cells as a Novel Therapeutic Strategy
Mentors: Osanna Kosoyan, MS and Laura Perin, PhD
Wilms tumor (WT) is the most common pediatric kidney cancer. Although current treatments have improved survival, children with relapsed or high-risk disease often experience poor outcomes and significant treatment-related toxicity. Previous work in our laboratory established Wilms tumor cancer stem cells (WT-CSCs) as key drivers of tumor initiation, self-renewal, and chemoresistance. It was further demonstrated that the PI3K/AKT/mTOR signaling pathway is critical for WT-CSC survival and that these cells express high levels of the chemokine receptor CCR2, making it a promising target for selective drug delivery. We hypothesized that CCR2-targeted peptide amphiphile micelles (WT-PAMs) could selectively deliver PI3K/AKT/mTOR inhibitors to WT-CSCs and suppress signaling pathways involved in cancer stem cell maintenance. Microscopy was used to evaluate the uptake of fluorescently labeled targeted and non-targeted micelles in the WT total population. Subsequently, WT-CSCs were exposed to CCR2-targeted micelles loaded with PI3K inhibitor, AKT inhibitor, and mTOR inhibitor drugs, and western blot analysis was performed to evaluate inhibition of the PI3K/AKT/mTOR pathway and downstream self-renewal markers SIX2 and CITED1. CCR2-targeted micelles demonstrated enhanced uptake in WT cells compared with non-targeted micelles. Drug-loaded WT-PAMs effectively inhibited PI3K/AKT/mTOR signaling and reduced the expression of downstream markers SIX2 and CITED1, indicating successful intracellular drug delivery and modulation of pathways associated with WT-CSC self-renewal. These findings support CCR2-targeted micelles as a promising strategy for selectively delivering therapies to WT-CSCs. This nanotherapeutic approach may improve treatment specificity while reducing systemic toxicity, providing a potential new therapeutic strategy for pediatric Wilms tumor.