Nanoparticles Loaded with Wnt and YAP/Mevalonate Inhibitors in Combination with Paclitaxel Stop the Growth of TNBC Patient‐Derived Xenografts and Diminish Tumorigenesis

Abstract

Triple negative breast cancer (TNBC) accounts for the majority of breast cancer‐related deaths and remains the hardest breast cancer to treat due to the lack of specific therapeutic targets. While chemotherapy is the mainstay of systemic treatment for TNBC, it is associated with chemotherapy‐induced cancer stem cells (CSCs) and tumor regeneration. Here, it is found that Wnt and YAP target genes that have been closely associated with CSCs are highly expressed in TNBC patient tumors and negatively correlated with patient survival. Therefore, a nanotherapeutic strategy is employed, using nanomaterials that are approved by the FDA, and two co‐delivery nanoparticle platforms (NPs) are developed to target TNBC. These NPs contain Wnt inhibitor PRI‐724 (in clinical trials) and YAP/mevalonate inhibitor simvastatin (FDA‐approved). Toward clinical translation, nanotherapeutic efficacy is assessed in clinically relevant patient‐derived xenograft (PDX) models. These NPs in combination with the chemotherapeutic drug paclitaxel effectively halt the growth of both paclitaxel‐resistant and paclitaxel‐sensitive PDX tumors, and diminish the paclitaxel‐induced CSC enrichment around two to fourfold. Importantly, NPs also decrease the paclitaxel‐enhanced PDX tumorigenesis after secondary transplantation. Together, this study demonstrates the efficacy of two NP platforms using clinically translatable TNBC PDX models, suggesting their application potential for the treatment of TNBC.

Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC

“…Similarly, our own research has been demonstrated in TNBC in vivo mouse models using patient-derived xenografts (patient tumors implanted immediately and only as solid tumors into immunocompromised mice) that post-chemotherapy exposure led to increased CD44 + /CD24 -and ALDH high CSC populations [64]. Afterward using a serial dilution assay (the gold standard for functional tumorigenicity) it was found that compared to the control, chemotherapy-treated PDX tumors demonstrated enhanced tumor formative capabilities (forming tumors at a rate of 80% upon injection of 1,000,000 cells versus the control which formed tumors at a rate of 20% with an injection of 1,000,000 cells) [64]. These studies demonstrate that chemotherapy-induced CSC enrichment represents a major factor in relapse and tumor reconstitution.…”

“…This is highlighted by Creighton et al who demonstrated that in post-chemotherapy breast cancer patients there were increased CD44 + /CD24 -CSCs populations compared to the proportion present before treatment [60]. In breast cancer tissue samples post-letrozole treatment, it was found that there was an increase in FN1, SNAI2, VIM, FOXC2, MMP2, and MMP3 (mesenchymal related genes) as well as diminished CDH1 (an epithelial related gene) suggesting an enrichment of mesenchymal properties and EMT (epithelial to mesenchymal transition), a process through which epithelial cells gain mesenchymal properties which correlate into enhanced migration and invasion properties allowing for increased metastasis in cancer models [51,56,[60][61][62][63][64]. This report demonstrated clinical evidence that post-chemotherapy, CSCs can be enriched and gain a mesenchymal phenotype in breast cancer models [60].…”

Clinically Translatable Approaches of Inhibiting TGF-β to Target Cancer Stem Cells in TNBC

“…Similarly, our own research has been demonstrated in TNBC in vivo mouse models using patient-derived xenografts (patient tumors implanted immediately and only as solid tumors into immunocompromised mice) that post-chemotherapy exposure led to increased CD44 + /CD24 -and ALDH high CSC populations [70]. Afterwards, using a serial dilution assay (the gold standard for functional tumorigenicity), it was found that compared to the control, chemotherapy-treated PDX tumors demonstrated enhanced tumor formative capabilities (forming tumors at a rate of 80% upon an injection of 1,000,000 cells versus the control, which formed tumors at a rate of 20% with an injection of 1,000,000 cells) [70]. These studies demonstrate that chemotherapy induced CSC enrichment represents a major factor in relapse and tumor reconstitution.…”

“…This is highlighted by Creighton et al who demonstrated that in post-chemotherapy breast cancer patients there was an increased frequency of CD44 + /CD24 -CSCs populations compared to the proportion present before treatment [66]. In breast cancer tissue samples post-letrozole treatment it was found that there was an increase in FN1, SNAI2, VIM, FOXC2, MMP2, and MMP3 (mesenchymal-related genes) as well as diminished CDH1 (an epithelial-related gene) suggesting an enrichment of mesenchymal properties and EMT (epithelial to mesenchymal transition) [57,62,[66][67][68][69][70]. EMT is a process through which epithelial cells gain mesenchymal properties which correlate into enhanced migration and invasion properties allowing for increased metastasis in cancer models [57,62,[66][67][68][69][70].…”

“…In breast cancer tissue samples post-letrozole treatment it was found that there was an increase in FN1, SNAI2, VIM, FOXC2, MMP2, and MMP3 (mesenchymal-related genes) as well as diminished CDH1 (an epithelial-related gene) suggesting an enrichment of mesenchymal properties and EMT (epithelial to mesenchymal transition) [57,62,[66][67][68][69][70]. EMT is a process through which epithelial cells gain mesenchymal properties which correlate into enhanced migration and invasion properties allowing for increased metastasis in cancer models [57,62,[66][67][68][69][70]. Creighton et al provided clinical evidence that post-chemotherapy, CSCs can be enriched and gain a mesenchymal phenotype in breast cancer models [66].…”