The Development of Different Strategies Using Clinically Translatable Models for the Treatment of Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer, that lacks targeting therapy, making chemotherapy the primary treatment option. However, chemotherapy leads to the enrichment of a subpopulation of cells with tumor initiating capacities called cancer stem cells (CSCs), that are implicated in treatment resistance, metastasis, and recurrence. To address this, I developed a triple-drug combination therapy targeting multiple aspects of tumorigenesis. Due to the limitation of conventional drug treatment, the use of nanoparticles (NPs) as a delivery system was introduced to increase therapeutic index. This triple-drug NPs suppressed bulk TNBC cells, CSC enrichment, and angiogenesis, both in vitro and in the clinically relevant patient-derived xenograft (PDX) model, paving the way for potential clinical application. RNA based therapeutics have emerged as a promising alternative in cancer treatment due to higher specificity in targeting key drivers of tumorigenesis. Using NPs as a delivery system, I showed the successful delivery of mRNA agents in PDX models, highlighting the promise of RNA-based NP therapies for overcoming limitations of conventional treatments in TNBC. As tumors are heterogenous with multiple drivers in play, I developed a NP-based co-delivery platform to deliver siRNA and mRNA for multitargeted gene regulation in cancer. These RNA-loaded NPs simultaneously knocked down and expressed target genes in TNBC in vitro and in vivo, highlighting their potential for multi-targeted therapy. Overall, throughout this thesis, using PDX models, I showed the effective delivery of both Drugs-NP and RNA- agents, laying the groundwork for future therapeutic strategies in TNBC treatment.