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Wnt and CRC

Therapeutic inhibition of the oncogenic Wnt/beta-catenin pathway in mismatch repair deficient hypermutant tumors

Total Cost €

EC-Contrib. €

Partnership

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Outcomes and
results

Wnt and CRC project word cloud

Explore the words cloud of the Wnt and CRC project. It provides you a very rough idea of what is the project "Wnt and CRC" about.

patients syndrome efficacy lynch presenting mmr amplification porcupine mutations believe beta treatment colorectal companies cancer enzyme deficient preferentially hotspot deficiency worldwide codifiying microsatellites opportunity genetic alterations hosting generation accelerate sporadic 6 clinical pharmaceutical therapeutic prone garraway wnt974 genome ing genes inhibitor apc acquisition group hopefully maturation death components druggable repetitive inhibitors mutated repair crc mismatch disease hereditary porcn link clevers enrichment oncology znrf3 highlighted consequence tumorigenesis dna accounting ligands germinal service axin2 hypermutant sequences codifying team benefit canonical few rnf43 dr ctnnb1 microsatellite wnt patient catenin tumors translation

Project "Wnt and CRC" data sheet

The following table provides information about the project.

Coordinator	FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON Organization address address: CALLE NAZARET 115-117 city: BARCELONA postcode: 8035 website: http://www.vhio.net contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	Spain [ES]
Project website	http://www.vhio.net/es/stem-cells-and-cancer-group/
Total cost	170˙121 €
EC max contribution	170˙121 € (100%)
Programme	1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
Code Call	H2020-MSCA-IF-2015
Funding Scheme	MSCA-IF-EF-ST
Starting year	2017
Duration (year-month-day)	from 2017-09-01 to 2019-08-31

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON Organization address address: CALLE NAZARET 115-117 city: BARCELONA postcode: 8035 website: http://www.vhio.net contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	ES (BARCELONA)	coordinator	170˙121.00

Map

Project objective

Colorectal cancer (CRC) is a leading cause of death worldwide. Mutations in components of the canonical Wnt/beta-catenin pathway such as APC, CTNNB1/beta-catenin, AXIN2 and more recently RNF43 or ZNRF3 can contribute to CRC tumorigenesis. The hosting team and Dr. Clevers’ group have recently described that inhibitors of the porcupine enzyme, that is essential for the maturation of Wnt-ligands, have therapeutic efficacy in tumors with RNF43 and ZNRF3 mutations. Hypermutant tumors are characterized by mutations in key components of the DNA mismatch repair (MMR) genes, resulting in the amplification in non-codifiying repetitive sequences in the genome known as microsatellites. Recent studies from the hosting team and Dr. Garraway’s group highlighted that mutations in RNF43 and ZNRF3 preferentially occur in a codifying microsatellite (hotspot) in MMR-deficient tumors. Lynch Syndrome is a hereditary cancer-prone disease where patients also develop MMR-deficient tumors as a consequence of germinal mutations in MMR genes accounting for 3-6% of CRC patients with very few therapeutic opportunities. In this proposal we aim to: 1) characterize Wnt-related genetic alterations in Lynch Syndrome patients and determine enrichment of RNF43 and ZNRF3 mutations compared to CRC sporadic tumors; 2) link MMR-deficiency and acquisition of the druggable Wnt-related mutations in RNF43 and ZNRF3; 3) evaluate the efficacy of PORCN/Wnt inhibitor WNT974 on tumors mutated in RNF43 and ZNRF3. We believe that not only Lynch Syndrome but any cancer patient with tumors presenting RNF43 and ZNRF3 mutations could benefit from the treatment with such new generation of Wnt/beta-catenin inhibitors. Our collaboration with the Oncology Service and pharmaceutical companies will accelerate the translation of our findings into the clinical practice and hopefully provide a new therapeutic opportunity for CRC patients. This would therefore have a general impact on cancer treatment in Europe.

Publications

List of publications.
year	authors and title	journal	last update
2018	Puig I, Tenbaum SP, Chicote I, ArquÃ©s O, MartÃnez-Quintanilla J, Cuesta-BorrÃ¡s E, RamÃrez L, Gonzalo P, Soto A, Aguilar S, Eguizabal C, CaratÃ¹ G, Prat A, ArgilÃ©s G, Landolfi S, Casanovas O, Serra V, Villanueva A, Arroyo AG, Terracciano L, Nuciforo P, Seoane J, Recio JA, Vivancos A, Dienstmann R, Tabernero J, Palmer HG. TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence. published pages: , ISSN: 0021-9738, DOI: 10.1172/jci96393	J Clin Invest.	2020-02-25

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