Therapeutic efficacy of galectin-1 inhibitor in treating malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited treatment options. Galectin-1 (Gal-1) is crucial in Ras activation, which is crucial in MPNST pathology. We aimed to disrupt the Gal-1/Ras interaction as a therapeutic strategy. Targeting the Ras binding pocket on Gal-1, we designed LLS30, a Gal-1 inhibitor to bind where H-Ras(G12V) interacts with Gal-1. Here, we show that LLS30 disrupts Gal-1–Ras interactions, causing Ras delocalization and subsequent suppression of the Ras/ERK pathway in MPNST cells. In vivo, LLS30 significantly inhibited tumor growth and metastasis in human MPNST xenograft models. RNA-seq analysis revealed LLS30’s impact on key cellular pathways, including p53, interferon gamma, EMT, and proliferation. These findings highlight LLS30 as a potent, rationally designed Gal-1 inhibitor with promising therapeutic implications for MPNST and potentially other malignancies driven by Gal-1 and Ras.