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Localized Hydrogel-Mediated Docetaxel-Carboplatin Combination Chemotherapy Targets Ganglioside Metabolism to Mitigate
Mohammad Nafees Ansari1,2, Jasleen Kaur2, Ali Khan1
1Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon, Haryana 122413, India.
Abstract:
Gangliosides are sialic acid-enriched glycosphingolipids that play a vital role in regulating multiple signaling pathways during cancer progression. The diversity in their cell- and tissue-specific expression and dysregulations in cancer cells contributes to the unique pathophysiology of triple-negative breast cancer (TNBC). In this study, we follow up on our previously established hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (DTX-CPT-Gel therapy) that ensured effective tumor regression in multiple murine syngeneic and xenograft tumor models. Here, we demonstrate that DTX-CPT-Gel therapy downregulates GM3/GD3/GM1 gangliosides by targeting different ganglioside metabolic genes at the transcriptional and translational levels. DTX-CPT-Gel therapy-mediated alterations in ganglioside metabolism affect the activity of key growth factor receptor-mediated signaling pathways, including the epidermal growth factor receptor (EGFR) and cMET/hepatic growth factor receptor (HGFR), which positively impact tumor mitigation. Our work on DTX-CPT-Gel therapy, in continuum, highlights the potential of this therapy for TNBC treatment by intercepting multiple lipid-mediated signaling pathways and reinforces GD3 synthase/ST8SIA1 as a promising target for TNBC therapy.
Insights
Triple-negative breast cancer (TNBC) therapy using docetaxel, carboplatin, and hydrogel (DTX-CPT-Gel) downregulates key gangliosides. This lipid-targeting approach impacts growth factor signaling, offering a new strategy for TNBC treatment.
Area of Science:
- Oncology
- Cancer Biology
- Biochemistry
Background:
- Gangliosides are crucial regulators of signaling pathways in cancer progression.
- Triple-negative breast cancer (TNBC) exhibits unique pathophysiology due to ganglioside dysregulation.
- Previous research established hydrogel-mediated localized delivery of docetaxel and carboplatin (DTX-CPT-Gel therapy) for tumor regression.
Purpose of the Study:
- To investigate the effects of DTX-CPT-Gel therapy on ganglioside metabolism in TNBC.
- To elucidate the impact of altered ganglioside metabolism on growth factor receptor signaling pathways.
- To identify potential therapeutic targets within ganglioside metabolic pathways for TNBC.
Main Methods:
- Utilized DTX-CPT-Gel therapy in preclinical TNBC models.
- Analyzed ganglioside levels (GM3, GD3, GM1) and their metabolic gene expression.
- Assessed the activity of signaling pathways, including EGFR and cMET/HGFR.
Main Results:
- DTX-CPT-Gel therapy significantly downregulated GM3, GD3, and GM1 gangliosides.
- The therapy targeted ganglioside metabolic genes at transcriptional and translational levels.
- Altered ganglioside metabolism modulated EGFR and cMET/HGFR signaling pathways, contributing to tumor mitigation.
Conclusions:
- DTX-CPT-Gel therapy effectively intercepts multiple lipid-mediated signaling pathways in TNBC.
- This therapeutic approach shows promise for TNBC treatment by targeting ganglioside metabolism.
- GD3 synthase/ST8SIA1 emerges as a potential therapeutic target for TNBC.
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