Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs
Babita Madan,David M. Virshup +1 more
TLDR
Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials and may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.Abstract:
Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of β-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/β-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.read more
Citations
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Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer.
TL;DR: Recent evidence implicating altered lipid metabolism in different aspects of the cancer phenotype is summarized and potential strategies by which targeting lipid metabolism could provide a therapeutic window for cancer treatment are discussed.
Journal ArticleDOI
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
TL;DR: 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.
Journal ArticleDOI
Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors
Zachary Steinhart,Zvezdan Pavlovic,Megha Chandrashekhar,Traver Hart,Xiaowei Wang,Xiaoyu Zhang,Mélanie Robitaille,Kevin R. Brown,Sridevi Jaksani,René M Overmeer,Sylvia F. Boj,Jarrett Adams,James Pan,Hans Clevers,Sachdev S. Sidhu,Jason Moffat,Jason Moffat,Stephane Angers +17 more
TL;DR: The results show that CRIPSR-based genetic screens can be leveraged to identify and validate cell surface targets for antibody development and therapy and uncover an underappreciated level of context-dependent specificity at the Wnt receptor level.
Journal ArticleDOI
WNT signalling in prostate cancer
TL;DR: Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression.
Journal ArticleDOI
The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies
Ke Yang,Xin Wang,Hongmei Zhang,Hongmei Zhang,Zhongliang Wang,Zhongliang Wang,Guoxin Nan,Guoxin Nan,Yasha Li,Yasha Li,Fugui Zhang,Fugui Zhang,Maryam K. Mohammed,Rex C. Haydon,Hue H. Luu,Yang Bi,Yang Bi,Tong-Chuan He,Tong-Chuan He +18 more
TL;DR: This review is intended to serve as a refresher of the current understanding about the physiologic and pathogenic roles of WNT/β-catenin signaling pathway, and to outline potential therapeutic opportunities by targeting the canonical WNT pathway.
References
More filters
Journal ArticleDOI
Comprehensive molecular characterization of human colon and rectal cancer
Donna M. Muzny,Matthew N. Bainbridge,Kyle Chang,Huyen Dinh,Jennifer Drummond,Gerald R. Fowler,Christie Kovar,Lora Lewis,Margaret Morgan,Irene Newsham,Jeffrey G. Reid,Jireh Santibanez,Eve Shinbrot,Lisa R. Trevino,Yuan Qing Wu,Min Wang,Preethi H. Gunaratne,Preethi H. Gunaratne,Lawrence A. Donehower,Chad J. Creighton,David A. Wheeler,Richard A. Gibbs,Michael S. Lawrence,Douglas Voet,Rui Jing,Kristian Cibulskis,Andrey Sivachenko,Andrey Sivachenko,Petar Stojanov,Aaron McKenna,Eric S. Lander,Eric S. Lander,Stacey Gabriel,Li Ding,Robert S. Fulton,Daniel C. Koboldt,Todd Wylie,Jason Walker,David J. Dooling,Lucinda Fulton,Kim D. Delehaunty,Catrina Fronick,Ryan Demeter,Elaine R. Mardis,Richard K. Wilson,Andy Chu,Hye Jung E. Chun,Andrew J. Mungall,Erin Pleasance,A. Gordon Robertson,Dominik Stoll,Miruna Balasundaram,Inanc Birol,Yaron S.N. Butterfield,Eric Chuah,Robin J.N. Coope,Noreen Dhalla,Ranabir Guin,Carrie Hirst,Martin Hirst,Robert A. Holt,Darlene Lee,Haiyan I. Li,Michael Mayo,Richard A. Moore,Jacqueline E. Schein,Jared R. Slobodan,Angela Tam,Nina Thiessen,Richard Varhol,Thomas Zeng,Yongjun Zhao,Steven J.M. Jones,Marco A. Marra,Adam J. Bass,Alex H. Ramos,Gordon Saksena,Andrew D. Cherniack,Stephen E. Schumacher,Barbara Tabak,Scott L. Carter,Nam Pho,Huy V. Nguyen,Robert C. Onofrio,Andrew Crenshaw,Kristin G. Ardlie,Rameen Beroukhim,Wendy Winckler,Matthew Meyerson,Alexei Protopopov,Angela Hadjipanayis,Eunjung Lee,Ruibin Xi,Lixing Yang,Xiaojia Ren,Narayanan Sathiamoorthy,Peng Chieh Chen,Psalm Haseley,Yonghong Xiao,Semin Lee,Jonathan G. Seidman,Lynda Chin,Peter J. Park,Raju Kucherlapati,J. Todd Auman,Katherine A. Hoadley,Ying Du,Matthew D. Wilkerson,Yan Shi,Christina Liquori,Shaowu Meng,Ling Li,Yidi J. Turman,Michael D. Topal,Donghui Tan,Scot Waring,Elizabeth Buda,Jesse Walsh,Corbin D. Jones,Piotr A. Mieczkowski,Darshan Singh,Junyuan Wu,Anisha Gulabani,Peter Dolina,Tom Bodenheimer,Alan P. Hoyle,Janae V. Simons,Matthew G. Soloway,Lisle E. Mose,Stuart R. Jefferys,Saianand Balu,Brian O'Connor,Jan F. Prins,Derek Y. Chiang,D. Neil Hayes,Charles M. Perou,Toshinori Hinoue,Daniel J. Weisenberger,Dennis T. Maglinte,Fei Pan,Benjamin P. Berman,David Van Den Berg,Hui Shen,Timothy J. Triche,Stephen B. Baylin,Peter W. Laird,Gad Getz,Michael S. Noble,Doug Voat,Nils Gehlenborg,Daniel DiCara,Juinhua Zhang,Hailei Zhang,Chang-Jiun Wu,Spring Yingchun Liu,Sachet A. Shukla,Lihua Zhou,Pei Lin,Richard W. Park,Marc Danie Nazaire,James A. Robinson,Helga Thorvaldsdottir,Jill P. Mesirov,Vesteinn Thorsson,Sheila Reynolds,Brady Bernard,Richard Kreisberg,Jake Lin,Lisa Iype,Ryan Bressler,Timo Erkkilä,Madhumati Gundapuneni,Yuexin Liu,Adam Norberg,Thomas Robinson,Da Yang,Wei Zhang,Ilya Shmulevich,Jorma J. de Ronde,Jorma J. de Ronde,Nikolaus Schultz,Ethan Cerami,Giovanni Ciriello,Arthur P. Goldberg,Benjamin Gross,Anders Jacobsen,Jianjiong Gao,Bogumil Kaczkowski,Rileen Sinha,B. Arman Aksoy,Yevgeniy Antipin,Boris Reva,Ronglai Shen,Barry S. Taylor,Marc Ladanyi,Chris Sander,Rehan Akbani,Nianxiang Zhang,Bradley M. Broom,Tod D. Casasent,Anna K. Unruh,Chris Wakefield,Stanley R. Hamilton,R. Craig Cason,Keith A. Baggerly,John N. Weinstein,David Haussler,Christopher C. Benz,Joshua M. Stuart,Stephen C. Benz,J. Zachary Sanborn,Charles J. Vaske,Jingchun Zhu,Christopher Szeto,Gary K. Scott,Christina Yau,Sam Ng,Theodore C. Goldstein,Kyle Ellrott,Eric A. Collisson,Aaron E. Cozen,Daniel R. Zerbino,Christopher Wilks,Brian Craft,Paul T. Spellman,Robert Penny,Troy Shelton,Martha Hatfield,Scott Morris,Peggy Yena,Candace Shelton,Mark Sherman,Joseph Paulauskis,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Jay Bowen,Nilsa C. Ramirez,Nilsa C. Ramirez,Aaron D. Black,Robert E. Pyatt,Robert E. Pyatt,Lisa Wise,Peter White,Peter White,Monica M. Bertagnolli,Jen Brown,Timothy A. Chan,Gerald C. Chu,Christine Czerwinski,Fred Denstman,Rajiv Dhir,Arnulf Dörner,Charles S. Fuchs,Jose G. Guillem,Mary Iacocca,Hartmut Juhl,Andrew Kaufman,Bernard Kohl,Xuan Van Le,Maria C. Mariano,Elizabeth N. Medina,Michael Meyers,Garrett M. Nash,P. Paty,Nicholas J. Petrelli,Brenda Rabeno,William G. Richards,David B. Solit,Pat Swanson,Larissa K. Temple,Joel E. Tepper,Richard Thorp,Efsevia Vakiani,Martin R. Weiser,Joseph Willis,Gary Witkin,Zhaoshi Zeng,Michael J. Zinner,Carsten Zornig,Mark A. Jensen,Robert Sfeir,Ari B. Kahn,Anna L. Chu,Prachi Kothiyal,Zhining Wang,Eric E. Snyder,Joan Pontius,Todd Pihl,Brenda Ayala,Mark Backus,Jessica Walton,Jon Whitmore,Julien Baboud,Dominique L. Berton,Matthew C. Nicholls,Deepak Srinivasan,Rohini Raman,Stanley Girshik,Peter A. Kigonya,Shelley Alonso,Rashmi N. Sanbhadti,Sean P. Barletta,John M. Greene,David Pot,Kenna R. Mills Shaw,Laura A.L. Dillon,Kenneth H. Buetow,Tanja Davidsen,John A. Demchok,Greg Eley,Martin L. Ferguson,Peter Fielding,Carl F. Schaefer,Margi Sheth,Liming Yang,Mark S. Guyer,Bradley A. Ozenberger,Jacqueline D. Palchik,Jane Peterson,Heidi J. Sofia,Elizabeth J. Thomson +320 more
TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Journal ArticleDOI
Wnt/beta-catenin signaling in development and disease.
TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
Journal ArticleDOI
Comprehensive molecular characterization of gastric adenocarcinoma
Adam J. Bass,Vesteinn Thorsson,Ilya Shmulevich,Sheila Reynolds,Michael Miller,Brady Bernard,Toshinori Hinoue,Peter W. Laird,Christina Curtis,Hui Shen,Daniel J. Weisenberger,Nikolaus Schultz,Ronglai Shen,Nils Weinhold,David P. Kelsen,Reanne Bowlby,Andy Chu,Katayoon Kasaian,Andrew J. Mungall,A. Gordon Robertson,Payal Sipahimalani,Andrew D. Cherniack,Gad Getz,Yingchun Liu,Michael S. Noble,Chandra Pedamallu,Carrie Sougnez,Amaro Taylor-Weiner,Rehan Akbani,Ju Seog Lee,Wenbin Liu,GB Mills,Da Yang,Wei Zhang,Angeliki Pantazi,Michael Parfenov,Margaret L. Gulley,M. Blanca Piazuelo,Barbara G. Schneider,Jihun Kim,Alex Boussioutas,Margi Sheth,John A. Demchok,Charles S. Rabkin,Joseph Willis,Sam Ng,Katherine S. Garman,David G. Beer,Arjun Pennathur,Benjamin J. Raphael,Hsin-Ta Wu,Robert D. Odze,Hark Kyun Kim,Jay Bowen,Kristen M. Leraas,Tara M. Lichtenberg,Stephanie Weaver,Michael D. McLellan,Maciej Wiznerowicz,Ryo Sakai,Michael S. Lawrence,Kristian Cibulskis,Lee Lichtenstein,Sheila Fisher,Stacey Gabriel,Eric S. Lander,Li Ding,Beifang Niu,Adrian Ally,Miruna Balasundaram,Inanc Birol,Denise Brooks,Yaron S.N. Butterfield,Rebecca Carlsen,Justin Chu,Eric Chuah,Hye Jung E. Chun,Amanda Clarke,Noreen Dhalla,Ranabir Guin,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Haiyan A. Li,Emilia L. Lim,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Karen Mungall,Ka Ming Nip,Jacqueline E. Schein,Angela Tam,Nina Thiessen,Rameen Beroukhim,Scott L. Carter,Andrew D. Cherniack,Juok Cho,Daniel DiCara,Scott Frazer,Nils Gehlenborg,David I. Heiman,Joonil Jung,Jaegil Kim,Pei Lin,Matthew Meyerson,Akinyemi I. Ojesina,Chandra Sekhar Pedamallu,Gordon Saksena,Steven E. Schumacher,Petar Stojanov,Barbara Tabak,Doug Voet,Mara Rosenberg,Travis I. Zack,Hailei Zhang,Lihua Zou,Alexei Protopopov,Netty Santoso,Semin Lee,Jianhua Zhang,Harshad S. Mahadeshwar,Jiabin Tang,Xiaojia Ren,Sahil Seth,Lixing Yang,Andrew Wei Xu,Xingzhi Song,Ruibin Xi,Christopher A. Bristow,Angela Hadjipanayis,Jonathan G. Seidman,Lynda Chin,Peter J. Park,Raju Kucherlapati,Shiyun Ling,Arvind Rao,John N. Weinstein,Sang Bae Kim,Yiling Lu,Gordon B. Mills,Moiz S. Bootwalla,Phillip H. Lai,Timothy J. Triche,David Van Den Berg,Stephen B. Baylin,James G. Herman,Bradley A. Murray,B. Arman Askoy,Giovanni Ciriello,Gideon Dresdner,Jianjiong Gao,Benjamin Gross,Anders Jacobsen,William Lee,Ricardo Ramirez,Chris Sander,Yasin Senbabaoglu,Rileen Sinha,S. Onur Sumer,Yichao Sun,Lisa Iype,Roger Kramer,Richard Kreisberg,Hector Rovira,Natalie Tasman,Santa Cruz Sam Ng,David Haussler,Josh Stuart,Roeland Verhaak,Mark D.M. Leiserson,Barry S. Taylor,Aaron D. Black,Julie Ann Carney,Julie M. Gastier-Foster,Carmen Helsel,Cynthia McAllister,Nilsa C. Ramirez,Teresa R. Tabler,Lisa Wise,Erik Zmuda,Robert Penny,Daniel Crain,Johanna Gardner,Kevin Lau,Erin Curely,David Mallery,Scott Morris,Joseph Paulauskis,Troy Shelton,Candace Shelton,Mark E. Sherman,Christopher C. Benz,Jae Hyuk Lee,Konstantin V. Fedosenko,Georgy Manikhas,Olga Potapova,Olga Voronina,Smitry Belyaev,Oleg Dolzhansky,W. Kimryn Rathmell,Jakub Brzezinski,Matthew Ibbs,Konstanty Korski,Witold Kycler,Radoslaw ŁaŸniak,Ewa Leporowska,Andrzej Mackiewicz,Dawid Murawa,Pawel Murawa,Arkadiusz Spychała,Wiktoria Maria Suchorska,Honorata Tatka,M. Teresiak,Raafat Abdel-Misih,Joseph J. Bennett,Jennifer Brown,Mary Iacocca,Brenda Rabeno,Sun Young Kwon,Ariane Kemkes,Erin Curley,Iakovina Alexopoulou,Jay Engel,John M. S. Bartlett,Monique Albert,Do-Youn Park,Rajiv Dhir,James D. Luketich,Rodney J. Landreneau,Yelena Y. Janjigian,Eunjung Cho,Marc Ladanyi,Laura H. Tang,Shannon J. McCall,Young Soo Park,Jae Ho Cheong,Jaffer A. Ajani,M. Constanza Camargo,Shelley Alonso,Brenda Ayala,Mark A. Jensen,Todd Pihl,Rohini Raman,Jessica Walton,Yunhu Wan,Greg Eley,Kenna R. Mills Shaw,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jean C. Zenklusen,Tanja M. Davidsen,Carolyn M. Hutter,Heidi J. Sofia,Robert Burton,Sudha Chudamani,Jia Liu +257 more
TL;DR: A comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project is described and a molecular classification dividing gastric cancer into four subtypes is proposed.
Journal ArticleDOI
Wnt/β-catenin signaling and disease.
Hans Clevers,Roel Nusse +1 more
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.
Journal ArticleDOI
RNAscope: A Novel in Situ RNA Analysis Platform for Formalin-Fixed, Paraffin-Embedded Tissues
Fai Wang,John G. Flanagan,Nan Su,Li Chong Wang,Son Bui,Allissa Nielson,Xingyong Wu,Hong Thuy Vo,Xiao Jun Ma,Yuling Luo +9 more
TL;DR: RNAscope is described, a novel RNA ISH technology with a unique probe design strategy that allows simultaneous signal amplification and background suppression to achieve single-molecule visualization while preserving tissue morphology and may enable rapid development of RNAISH-based molecular diagnostic assays.
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