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Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination
Andrew Sulaiman1,2,3,4, Sarah McGarry1, Sara El-Sahli1
1Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Abstract:
Triple-negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer-related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC), as well as appropriate animal models to accurately evaluate treatment efficacy for clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. We developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NP) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and accumulation of NPs. NF-κB, Wnt, and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls, and tumors progression and CSC subpopulations were analyzed. MRI imaging indicated high vascularization of PDX tumors. IVIS imaging showed accumulation of NPs in PDX tumors. In comparison with control-NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-κB, Wnt, and YAP that have been shown to be crucial for cancer growth, CSC development, and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-κB, Wnt, and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of patients with TNBC.
Insights
A novel nanoparticle drug delivery system effectively targets triple-negative breast cancer (TNBC) and its stem cells. This combination therapy significantly inhibits tumor growth and key cancer pathways, offering a promising new treatment for TNBC.
Area of Science:
- Oncology
- Nanotechnology
- Biomedical Engineering
Background:
- Triple-negative breast cancer (TNBC) is a deadly subtype with limited treatment options.
- Targeting both bulk tumor and cancer stem cells (CSCs) is crucial for effective TNBC therapy.
- Lack of suitable models hinders clinical translation of novel TNBC treatments.
Purpose of the Study:
- To develop and evaluate a hybrid nanoparticle co-delivery platform (PV-NP) for targeting TNBC and CSCs.
- To assess the efficacy of PV-NPs in a patient-derived xenograft (PDX) TNBC model.
- To investigate the molecular mechanisms underlying PV-NP treatment, including NF-κB, Wnt, and YAP pathway inhibition.
Main Methods:
- Development of hybrid nanoparticles co-delivering paclitaxel and verteporfin (PV-NP).
- Utilized Magnetic Resonance Imaging (MRI) and In Vivo Imaging System (IVIS) to assess tumor vascularity and NP accumulation.
- Employed reporter assays to measure NF-κB, Wnt, and YAP activity in TNBC PDX models.
- Analyzed tumor progression and CSC subpopulations following PV-NP treatment.
Main Results:
- MRI confirmed high vascularization in TNBC PDX tumors, suitable for nanoparticle delivery.
- IVIS imaging demonstrated significant accumulation of PV-NPs within the tumors.
- PV-NPs significantly inhibited TNBC PDX tumor growth compared to controls.
- PV-NPs effectively repressed NF-κB, Wnt, and YAP signaling pathways.
Conclusions:
- The developed PV-NP platform demonstrates synergistic efficacy against both bulk TNBC and CSCs.
- Concurrent inhibition of NF-κB, Wnt, and YAP pathways by PV-NPs is a key mechanism of action.
- This combination nanotherapy, validated in a PDX model, shows potential for clinical translation in treating TNBC patients.
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