Wnt addiction of genetically defined cancers reversed by PORCN inhibition
Babita Madan,Zhiyuan Ke,Nathan Harmston,Soo Yei Ho,A O Frois,Jenefer Alam,Duraiswamy Athisayamani Jeyaraj,Vishal Pendharkar,Kakaly Ghosh,I H Virshup,Vithya Manoharan,Esther Hq Ong,Kanda Sangthongpitag,Jeffrey Hill,Enrico Petretto,Thomas H. Keller,May Ann Lee,Alex Matter,David M. Virshup,David M. Virshup +19 more
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TLDR
A novel potent, orally available PORCN inhibitor, ETC-1922159, that blocks the secretion and activity of all Wnts is developed that is remarkably effective in treating RSPO-translocation bearing colorectal cancer patient-derived xenografts.Abstract:
Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.read more
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NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition
Babita Madan,Zhiyuan Ke,Zhengdeng Lei,Frois Ashley Oliver,Masanobu Oshima,May Ann Lee,Steve Rozen,David M. Virshup +7 more
TL;DR: Notum is identified as a potential biomarker for Wnt driven cancers and it is shown that coordinate regulation of NOTUM and AXIN2 expression may be a useful predictor of response to PORCN inhibitors.
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Advances in Molecular Profiling and Categorisation of Pancreatic Adenocarcinoma and the Implications for Therapy
TL;DR: There is optimism that by developing a better understanding of the translational aspects of this cancer, future informed therapeutic strategies may prove more successful.
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WNT Signaling as a Therapeutic Target for Glioblastoma
TL;DR: In this article, the authors deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance, and provide an analysis of the pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation.
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Angiogenesis-Related Functions of Wnt Signaling in Colorectal Carcinogenesis.
TL;DR: A review of the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis aims to improve the understanding of the mechanisms of metastasis as well as improve the management of this cancer.
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Wnt Signaling: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma
Zeeshan Javed,Hafiz Muhammad Farooq,Mukhtar Ullah,Muhammad Zaheer Iqbal,Qamar Raza,Haleema Sadia,Raffaele Pezzani,Bahare Salehi,Javad Sharifi-Rad,William C. Cho +9 more
TL;DR: The vital functions of Wnt signaling in the stem cell growth and differentiation are depicted by focusing on current druggable targets that have been ascribed by recent studies and show how it can regulate normal physiological processes and curtail the development of cancer.
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