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Delivery of the Porcupine Inhibitor WNT974 in Mice

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Wnt Signaling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1481))

Abstract

We describe here a technique for delivering the porcupine inhibitor WNT974 (formerly LGK974) in mice. The protocol entails once-a-day oral delivery of WNT974 for up to 3 months at a concentration sufficient to achieve systemic Wnt pathway inhibition with limited toxicity as measured by weight change. This route of delivery enables extended durations of Wnt signaling inhibition in a mammalian model organism.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-4939-6393-5_18

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References

  1. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, Harris JL (2013) Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc Natl Acad Sci U S A 110:20224–20229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Boulter L, Guest RV, Kendall TJ, Wilson DH, Wojtacha D, Robson AJ, Ridgway RA, Samuel K, Van Rooijen N, Barry ST, Wigmore SJ, Sansom OJ, Forbes SJ (2015) WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest 125:1269–1285

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F (2013) Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A 110:12649–12654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Koo BK, van Es JH, van den Born M, Clevers H (2015) Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proc Natl Acad Sci U S A 112:7548–7550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, Jeyaraj DA, Pendharkar V, Ghosh K, Virshup IH, Manoharan V, Ong EH, Sangthongpitag K, Hill J, Petretto E, Keller TH, Lee MA, Matter A, Virshup DM (2015) Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene 35:2197–2207

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lum L, Chen C (2015) Chemical disruption of Wnt-dependent cell fate decision-making mechanisms in cancer and regenerative medicine. Curr Med Chem 22:4091–4103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205

    Article  CAS  PubMed  Google Scholar 

  8. Proffitt KD, Madan B, Ke Z, Pendharkar V, Ding L, Lee MA, Hannoush RN, Virshup DM (2012) Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res 73:502–507

    Article  PubMed  Google Scholar 

  9. Zhong Y, Katavolos P, Nguyen T, Lau T, Boggs J, Sambrone A, Kan D, Merchant M, Harstad E, Diaz D, Costa M, Schutten M (2015) Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1. Toxicol Pathol 44:267–278

    Article  PubMed  Google Scholar 

  10. Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dodge ME, Moon J, Tuladhar R, Lu J, Jacob LS, Zhang LS, Shi H, Wang X, Moro E, Mongera A, Argenton F, Karner CM, Carroll TJ, Chen C, Amatruda JF, Lum L (2012) Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine. J Biol Chem 287:23246–23254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

This work was supported by the NIH (R01 CA168761, R01CA196851), CPRIT (RP130212), and the Welch Foundation (I-1665).

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Zhang, Ls., Lum, L. (2016). Delivery of the Porcupine Inhibitor WNT974 in Mice. In: Barrett, Q., Lum, L. (eds) Wnt Signaling. Methods in Molecular Biology, vol 1481. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6393-5_12

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  • DOI: https://doi.org/10.1007/978-1-4939-6393-5_12

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6391-1

  • Online ISBN: 978-1-4939-6393-5

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