Galectin-1 Inhibition as a Strategy for Malignant Peripheral Nerve Sheath Tumor Treatment
Neurofibromatosis type 1, commonly known as NF1, is a genetic disorder that increases an individual’s susceptibility to developing malignant peripheral nerve sheath tumors, or MPNSTs.1 These tumors are highly aggressive sarcomas characterized by limited treatment options and a poor patient prognosis.2 This research investigates the potential of disrupting the interaction between Galectin-1 and Ras proteins as a novel therapeutic approach for MPNSTs.3
Using molecular docking techniques, we identified key amino acid residues that are crucial for the binding of Galectin-1 and H-Ras. Based on this information, we developed a compound named LLS30, specifically designed to target the Ras-binding pocket on Galectin-1, and evaluated its effectiveness. Our experiments showed that LLS30 effectively disrupted the Galectin-1/Ras interaction, leading to the displacement of Ras from the plasma membrane, where it is normally active, and consequently inhibiting Ras signaling pathways.
In vitro studies demonstrated that LLS30 significantly reduced the proliferation of MPNST cells and induced apoptosis, or programmed cell death, in these cancer cells. Furthermore, in vivo experiments using animal models of MPNSTs revealed that LLS30 exhibited potent anti-tumor effects, resulting in a reduction of tumor size, inhibition of metastasis (the spread of cancer to other parts of the body), and an extension of survival in the treated animals.
Transcriptome analysis, which examines the complete set of RNA transcripts in cells, further revealed that LLS30 treatment led to the downregulation of KRAS signaling, another member of the Ras family, and the inhibition of pathways associated with epithelial-mesenchymal transition, a process involved in cancer metastasis.
Taken together, these findings suggest that targeting Galectin-1 with the compound LLS30 offers significant therapeutic potential for MPNSTs TD-139 and could also be beneficial for other types of cancer that are driven by the signaling pathways involving Galectin-1 and Ras proteins.4