Connectivity Mapping-based Identification and Pre-clinical Evaluation of ISOX: A Novel Therapeutic for Pancreatic Cancer
Pancreatic Cancer (PC) remains highly lethal due to limited therapeutic options. Here we utilize a genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting. ISOX emerged as a top potential drug from the CMAP pipeline across human PC tissues, cell lines, tumoroids, and patient-derived xenografts datasets. Here, we use PC cells, human and mouse tumoroids, and in vivo mouse models to test the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Transcriptomic and pathway analysis of the ISOX-LINCS signature identified the various pathways as targets for ISOX, suggesting a multiple-target action. Specifically, we discovered that genetic and pharmacological targeting of HDAC6 affected non-histone protein cMYC acetylation leading to cMYC instability, thereby disrupting PC stem cells. Finally, KrasG12D harboring organoids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a novel drug to treat advanced PC patients without toxicity to normal cells Overall design: To understand the mechanism of action of ISOX in PC, CD18/HPAF cells were sequenced with (1uM: 48 hours) and without ISOX treatment. A diffrential expression was then carried out to assess the effect of treatment.