Thiosemicarbazones reprogram pancreatic cancer bidirectional oncogenic signaling between cancer cells and stellate cells to suppress desmoplasia.

Future Med Chem

Centre for Cancer Cell Biology & Drug Discovery, Griffith Institute of Drug Discovery, Griffith University & School of Environment & Science (N34), Nathan, Brisbane, Queensland, 4111, Australia.

Published: July 2022

Standard treatments have shown dismal activity against pancreatic cancer (PC), due in part to the development of a dense stroma (desmoplasia). This perspective discusses the development of the di-2-pyridylketone thiosemicarbazones that overcomes bidirectional oncogenic signaling between PC cells and pancreatic stellate cells (PSCs), which is critical for desmoplasia development. This activity is induced by the up-regulation of the metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which inhibits oncogenic signaling via HGF, IGF-1 and Sonic Hedgehog pathway. More recent studies have deciphered additional pathways including those mediated by Wnt and tenascin C that are secreted by PSCs to activate β-catenin and YAP/TAZ signaling in PC cells. Suppression of bidirectional signaling between cell types presents a unique therapeutic opportunity.

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http://dx.doi.org/10.4155/fmc-2022-0050DOI Listing

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