PO-428 Therapeutic potential of nanoparticle encapsulated Wnt and YAP inhibitors using patient derived xenograft models for the treatment of triple negative breast cancer

Abstract

Introduction Triple negative breast cancer (TNBC) accounts for 15%–20% of all breast cancers but disproportionately accounts for the majority of breast cancer related deaths. Within TNBC, cancer stem cells (CSCs) exist in interconvertible mesenchymal or epithelial sup-populations that cannot be simultaneously targeted by non-specific chemotherapy highlighting the necessity of a therapeutic approach which targets both subpopulations. However, these CSC populations differ dramatically, making therapeutic approaches illusive. Material and methods Initially, we identified that Wnt and YAP signalling suppressed both mesenchymal and epithelial CSCs in vitro and in vivo using TNBC cell lines, patients’ tumour samples, and a database of 2509 patients with invasive breast cancer. Subsequently, we encapsulated Wnt and YAP inhibitors (PRI-724 and simvastatin respectively) in polyethylene glycol–polylactic acid nanoparticles (NPs) to increase intra-tumoral specificity and accumulation. Mice were implanted with patient derived xenografts (PDX) and were treated with NP-encapsulated PRI-724 and simvastatin. Additionally, NP accumulation within the tumour verses other organs was tracked using NP-conjugated fluorophores followed by flow cytometry and in vivo imaging system analysis (IVIS). To determine CSC and tumorigenesis, secondary transplantation was performed after NP treatment. Results and discussions NP-encapsulated PRI-724 and simvastatin effectively suppressed Wnt and YAP gene expression in vitro. NP-encapsulated inhibitors were tolerable in vivo and accumulated in the TNBC PDX tumours. In contrast to paclitaxel (a commonly employed chemotherapeutic agent), NP-encapsulated PRI-724 and simvastatin markedly reduced the epithelial (ALDH+) and mesenchymal (CD44+/CD24-) CSC subpopulations. Additionally, co-administration of NP-encapsulated inhibitors with paclitaxel potently retarded the growth of TNBC PDX tumours but significantly maintained diminished epithelial (ALDH+) and mesenchymal (CD44+/CD24-) CSC populations. Conclusion We developed a novel, tangible approach for the treatment of TNBC using NP-encapsulated Wnt and YAP inhibitors which accumulated in TNBC PDX tumours and potently retarded tumour growth, and inhibited CSC enrichment and tumorigenicity.