An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

Hunter, Sean; McIntosh, Brianna J.; Shi, Yu; Sperberg, R Andres Parra; Funatogawa, Chie; Labanieh, Louai; Soon, Erin; Wastyk, Hannah C.; Mehta, Nishant; Carter, Catherine; Hunter, Tony; Cochran, Jennifer R.

doi:10.1038/s42003-021-01928-2

Cited by 20 publications

(12 citation statements)

References 55 publications

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“…Several solid tumours exhibit an aberrant upregulation of JAK/STAT3 signalling via LIF autocrine or paracrine production [ 45 , 52 ] and, as shown in the present study, the LIF/LIFR pathway is represented in PDAC ( Figure 1 ). These findings are consistent with the observation that, in comparison to non-neoplastic subjects, circulating levels of LIF are significantly increased in PDAC patients and correlate with poor prognosis and cancer aggressiveness [ 53 , 54 ].…”

Section: Discussionsupporting

confidence: 92%

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

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Section: Discussionsupporting

confidence: 92%

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Giorgio

Lupia

Marchianò

et al. 2022

Cells

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“…Since there are robust evidence that the LIF/LIFR pathway exerts a pro-oncogenic role in PDAC cell lines ( 13 , 20 , 55 ), and because FXR expression is increased in human PDAC tissues, we have focused our attention on the role that natural and synthetic steroids exert in modulating pancreatic cancer cell lines. For these purposes, we have first carried out a series of docking calculations on hLIFR using a small library of natural steroids ( Figure 2 ), including LCA and CDCA ( 56 ), and the semisynthetic bile alcohol steroidal agonist BAR502 ( 57 ).…”

Section: Resultsmentioning

confidence: 99%

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

Giorgio

Bellini²,

Lupia³

et al. 2023

Front. Oncol.

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IntroductionThe 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).MethodsHerein 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. ResultsThe 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 IC50 of 3.8 µM.DiscussionBAR502 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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“…Several recent studies demonstrated that LIF blockade slow tumor progression, augment the efficacy of chemotherapy 12 , and improves therapeutic outcome 13 . Another study using a soluble version of the LIFR as a ligand trap demonstrated that blocking of LIF signaling slows tumor progression in a mouse model of pancreatic cancer 28 . Since TNBC cells express multiple LIFR ligands (LIF, OSM, and CNTF) and co-receptor gp130, aberrant induction of LIFR by HDACi has the potential to contribute to LIFR autocrine signaling loop.…”

Section: Discussionmentioning

confidence: 99%

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

Viswanadhapalli

Santhamma

et al. 2021

Commun Biol

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Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.

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An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

Cited by 20 publications

References 55 publications

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

Repositioning Mifepristone as a Leukaemia Inhibitory Factor Receptor Antagonist for the Treatment of Pancreatic Adenocarcinoma

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

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

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