Localized Hydrogel-Mediated Docetaxel-Carboplatin Combination Chemotherapy Targets Ganglioside Metabolism to Mitigate Tumor Progression.

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.