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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The Regulation of Bone Metabolism and Disorders by Wnt Signaling
Kazuhiro Maeda,Yasuhiro Kobayashi,Masanori Koide,Shunsuke Uehara,Masanori Okamoto,Akihiro Ishihara,Tomohiro Kayama,Mitsuru Saito,Keishi Marumo +8 more
TL;DR: The clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed, and its role in bone metabolism and its involvement in skeletal disorders are covered.
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Biomarker-guided therapy for colorectal cancer: strength in complexity
TL;DR: An overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC is provided, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.
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Treatment sequencing in metastatic colorectal cancer
TL;DR: Current treatment approaches and optimal treatment sequencing across the first-, second- and third-line settings in mCRC are reviewed, including biological aspects affecting sequencing and rechallenge.
Xenome--a tool for classifying reads from xenograft samples
Thomas C. Conway,Jeremy Wazny,Andrew J. Bromage,Martin Tymms,Dhanya Sooraj,Elizabeth D. Williams,Bryan Beresford-Smith +6 more
TL;DR: A technique, with an associated tool Xenome, which performs fast, accurate and specific classification of xenograft-derived sequence read data, which has evaluated it on RNA-Seq data from human, mouse and human-in-mouse xenografted datasets.
Journal ArticleDOI
Wnt Signaling in Cancer Stem Cell Biology
TL;DR: This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.
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