17-AAG

Due to a lack of early diagnosis methods and effective drugs, pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. DNA methylation, transcriptome expression and gene copy number variation (CNV) have critical relationships with development and progression of various diseases. The purpose of the study was to screen reliable early diagnostic biomarkers and potential drugs based on integrative multiomics analysis.

We used methylation, transcriptome and CNV profiles to build a diagnostic model for PDAC. The protein expression of three model-related genes were externally validated using PDAC samples. Then, potential therapeutic drugs for PDAC were identified by interaction information related to existing drugs and genes.

Four significant differentially methylated regions (DMRs) were selected from 589 common DMRs to build a high-performance diagnostic model for PDAC. Then, four hub genes, PHF12, FXYD3, PRKCB and ZNF582, were obtained. The external validation results showed that PHF12, FXYD3 and PRKCB protein expression levels were all upregulated in tumor tissues compared with adjacent normal tissues (P<0.05). Promising candidate drugs with activity against PDAC were screened and repurposed through gene expression analysis of online datasets. The five drugs, including topotecan, PD-0325901, panobinostat, paclitaxel and 17-AAG, with the highest activity among 27 PDAC cell lines were filtered.

Overall, the diagnostic model built based on four significant DMRs could accurately distinguish tumor and normal tissues. The five drug candidates might be repurposed as promising therapeutics for particular PDAC patients.

Introduction: Heat shock protein (Hsp) 90 is one of the most abundant proteins in unstressed cells and regulates stability and functional maintenance of client proteins. In ocular tissue, Hsp90 is widely expressed in the cornea and retina and has multiple roles in these tissues. The expression of HSPs was induced in the retinas of glaucomatous patients and laser-induced glaucoma in monkey while their mechanisms remain to be elucidated. For this reason, we tried to elucidate the role of Hsp90 in intraocular pressure (IOP) regulation in rabbits. Methods: IOP was measured by a pneumatonometer before and after intracameral injection of Hsp90 inhibitors. The aqueous flow rate was measured by fluorophotometry. Trans-epithelial electrical resistance was measured in primary human trabecular meshwork cells. Results: 17-AAG, a specific Hsp90 inhibitor, significantly lowered IOP at concentrations of more than 30 μm in normotensive rabbits. Other Hsp90 inhibitors also significantly lowered IOP in normotensive rabbits at a dose of 100 μm. No reduction of aqueous humor production was observed by injection of 17-AAG in rabbits. Topical administration of pilocarpine tended to attenuate the IOP-lowering effects induced by the Hsp90 inhibitor. No reduction of trans-epithelial electrical resistance was observed by inhibition of Hsp90 in culture cells. Conclusions: These results indicated that intraocular Hsp90 regulates IOP, and the inhibition of Hsp90 by Hsp90 inhibitor decreases IOP without affecting aqueous humor production in rabbits. Further research in elucidating the mechanism of Hsp90 inhibitors will result in a better understanding of the role of Hsp90 in the regulation of IOP.