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      Discovery of BAR502, as potent steroidal antagonist of leukemia inhibitory factor receptor for the treatment of pancreatic adenocarcinoma

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          Abstract

          Introduction

          The leukemia inhibitory factor (LIF), is a cytokine belonging to IL-6 family, whose overexpression correlate with poor prognosis in cancer patients, including pancreatic ductal adenocarcinoma (PDAC). LIF signaling is mediate by its binding to the heterodimeric LIF receptor (LIFR) complex formed by the LIFR receptor and Gp130, leading to JAK1/STAT3 activation. Bile acids are steroid that modulates the expression/activity of membrane and nuclear receptors, including the Farnesoid-X-Receptor (FXR) and G Protein Bile Acid Activated Receptor (GPBAR1).

          Methods

          Herein we have investigated whether ligands to FXR and GPBAR1 modulate LIF/LIFR pathway in PDAC cells and whether these receptors are expressed in human neoplastic tissues.

          Results

          The transcriptome analysis of a cohort of PDCA patients revealed that expression of LIF and LIFR is increased in the neoplastic tissue in comparison to paired non-neoplastic tissues. By in vitro assay we found that both primary and secondary bile acids exert a weak antagonistic effect on LIF/LIFR signaling. In contrast, BAR502 a non-bile acid steroidal dual FXR and GPBAR1 ligand, potently inhibits binding of LIF to LIFR with an IC 50 of 3.8 µM.

          Discussion

          BAR502 reverses the pattern LIF-induced in a FXR and GPBAR1 independent manner, suggesting a potential role for BAR502 in the treatment of LIFR overexpressing-PDAC.

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          Most cited references89

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          Cancer statistics, 2020

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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            VMD: Visual molecular dynamics

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              Comparison of simple potential functions for simulating liquid water

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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                14 March 2023
                2023
                : 13
                : 1140730
                Affiliations
                [1] 1 Department of Medicine and Surgery, University of Perugia , Perugia, Italy
                [2] 2 Department of Pharmacy, University of Naples Federico II , Naples, Italy
                [3] 3 Net4Science srl, University “Magna Græcia” , Catanzaro, Italy
                [4] 4 Department of Pharmacy, University of Salerno , Salerno, Italy
                [5] 5 Department of Gastroenterology, Azienda Ospedaliera di Perugia , Perugia, Italy
                Author notes

                Edited by: Stephen Safe, Texas A&M University, United States

                Reviewed by: Li Zhang, University of Minnesota Twin Cities, United States; Jianjun Liu, Dalian Medical University, China

                *Correspondence: Stefano Fiorucci, stefano.fiorucci@ 123456unipg.it

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2023.1140730
                10043345
                36998446
                2e4c05a8-8ab2-4dac-a947-086a7b9f918c
                Copyright © 2023 Di Giorgio, Bellini, Lupia, Massa, Bordoni, Marchianò, Rosselli, Sepe, Rapacciuolo, Moraca, Morretta, Ricci, Urbani, Monti, Biagioli, Distrutti, Catalanotti, Zampella and Fiorucci

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 January 2023
                : 20 February 2023
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 90, Pages: 17, Words: 9995
                Funding
                Funded by: Ministero dell'Istruzione, dell'Università e della Ricerca , doi 10.13039/501100003407;
                Award ID: 2017FJZZRC
                Funded by: European Regional Development Fund , doi 10.13039/501100008530;
                Funded by: Università degli Studi di Napoli Federico II , doi 10.13039/100007195;
                This work was partially supported by a grant from the Italian MIUR/PRIN 2017 (2017FJZZRC). BC acknowledges the support from the European Regional Development Fund-POR Campania FESR 2014/2020 (Satin). VS and FM acknowledge the support from University of Napoli “Federico II” (Grant FRA—Line B—2020- MoDiGa).
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                pdac,lif,lifr,bile acids,steroid,proliferation,emt
                Oncology & Radiotherapy
                pdac, lif, lifr, bile acids, steroid, proliferation, emt

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