H2020Индивидуална стипендия2017–2019

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2017-09-01 → 2019-08-31
Финансиране от ЕС: 170 122 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните промени в пътя Wnt при хипермутантни тумори на дебелото черво се анализират чрез тестове с конкретни инхибитори. Това може да помогне за подобряване на оцеляемостта на пациенти със синдром на Линч и други видове рак.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

Colorectal cancer (CRC) is a leading cause of death related to cancer with 1.6 million new cases per year worldwide and more than 800.000 deaths per year. Hypermutant CRC tumors affect 15-20% of all CRC patients and are characterized by presenting mutations in key components of the DNA mismatch repair (MMR) machinery, resulting in amplifications in repetitive sequences in the genome known as microsatellites (MS). Beyond sporadic hypermutant tumors, hereditary nonpolyposis CRC (HNPCC) or Lynch Syndrome is a hereditary cancer-prone syndrome where patients develop multiple tumors as a consequence of germinal mutations in MMR genes. These mutations lead to a strong hypermutant phenotype characterized by a high rate of mutations, up to a 1000 fold increase, compared to normal cells, and a MS inestability phenotype. Lynch Syndrome accounts for 3-6% of CRC patients and predisposes to develop multiple tumors, particularly cancers of the colon and rectum, stomach, small intestine and endometrium, with bad prognosis and very few therapeutic opportunities. Investigating new therapeutic approached for Lynch Syndrome patients can improve the survival of these patients. In addition, this research can pave the way to develop new therapeutic strategies for patients with sporadic CRC hypermutant tumors. Moreover, the study of new Wnt inhibitors could be used for other types of cancer with upstream or downstream mutations in Wnt signaling pathway. The main objectives of this project are: 1) Characterize the molecular epidemiology of Wnt-related genetic alterations (RNF43 and ZNRF3) in Lynch Syndrome cases, as a paradigm of MMR-deficient hypermutant tumors 2) Study the efficacy of porcupine inhibitor WNT974 or tankyrase inhibitors in MMR-deficient in vivo models that present upstream or downstream mutations in components of the oncogenic Wnt pathway. The conclusions of our project so far are: 1) Lynch syndrome tumors presented a high frequency of mutations in RNF43 and ZNRF3 genes, particularly in CRC lesions but not in benign malignancies (e.g. adenomas) or other tumors developed by the same patient (e.g. endometrial cancer). More importantly, RNF43G659fs mutation was presented in 9 out of 10 CRC samples analyzed. 2) Our in vivo results did not show any statistically significant antitumor effect, survival benefit or immune infiltration after porcupine inhibitor WNT974 or tankyrase inhibitor G007 monotherapy or combination with PD-1 inhibitor. However, more experiments should be performed in order confirm our results.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

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