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

Projektinformationen

Wnt and CRC

ID Finanzhilfevereinbarung: 704319

DOI 10.3030/704319

Abgeschlossenes Projekt

EK-Unterschriftsdatum 5 April 2016

Startdatum 1 September 2017

Enddatum 31 August 2019

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten € 170 121,60

EU-Beitrag € 170 121,60

Koordiniert durch

FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON (VHIO)
Spain

Ziel

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.

Wissenschaftliches Gebiet

• medical and health sciences › medical biotechnology › genetic engineering › gene therapy
• medical and health sciences › health sciences › public health › epidemiology
• medical and health sciences › basic medicine › immunology
• medical and health sciences › clinical medicine › oncology › colorectal cancer
• natural sciences › biological sciences › genetics › mutation

Programm/Programme

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility

Thema/Themen

• MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)

Aufforderung zur Vorschlagseinreichung

H2020-MSCA-IF-2015

Finanzierungsplan

MSCA-IF-EF-ST - Standard EF

Koordinator

FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON (VHIO)

• Netto-EU-Beitrag: € 170 121,60
• Adresse: CALLE NAZARET 115-117 ; 08035 Barcelona ; Spanien
• Region: Este › Cataluña › Barcelona
• Aktivitätstyp: Research Organisations
• Gesamtkosten: € 170 121,60