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New mechanisms of thyroid cancer progression

English title New mechanisms of thyroid cancer progression
Applicant Kiss Bernhard
Number 176175
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik für Urologie Inselspital Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cellular Biology, Cytology
Start/End 01.11.2017 - 30.04.2022
Approved amount 597'101.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Experimental Cancer Research

Keywords (6)

Papillary; Thyroid; BRAF; Cancer; Notch; Anaplastic

Lay Summary (French)

Lead
Le cancer anaplastique de la thyroïde est un des plus agressif chez l’homme. Pourtant, la connaissance des gènes impliqué dans la maladie est encore très limitée. L’étude de modèles murins peux apporter de nouvelles solutions thérapeutiques.
Lay summary
Contenu et objectif du travail de recherche

 

Alors que 90% des patients atteint de cancer de la thyroïde peuvent être traité voir guéri, la totalité des patients atteint du sous-type anaplastique sont condamnés avec une survie moyenne de moins d’un an.

Le projet porte sur l’étude d’un modèle murin qui récapitule la progression de la maladie du sous-type papillaire qui peux être traité en clinique (chirurgie et iode radioactif) au sous-type anaplastique afin de comprendre les voies de signalisations cellulaires qui sont recrutées lors de cette progression.

Dans un premier temps, le modèle sera utilisé pour obtenir une évaluation des gènes recrutés lors de la progression de la maladie chez les animaux. Puis lors de la deuxième phase ces données seront confrontées aux données des patients pour en analyser la pertinence. Finalement les gènes les plus intéressant seront tester pour déterminer leur implication passive ou active dans le processus de progression.

 

Contexte scientifique et social du projet de recherche.

Ce projet de recherche dite « translationelle » ou préclinique se positionne entre les laboratoires de recherche fondamentale et les cliniciens utilisant les modèles de laboratoires pour proposer de nouvelles solutions pour traiter les patients.

 

Direct link to Lay Summary Last update: 29.09.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
BRAFV600E overrides NOTCH signaling in thyroid cancer.
Traversi Florian, Stooss Amandine, Dettmer Matthias S, Charles Roch-Philippe (2020), BRAFV600E overrides NOTCH signaling in thyroid cancer., in Thyroid, thy.2019.0-thy.2019.0.
MEK Inhibition Induces Therapeutic Iodine Uptake in a Murine Model of Anaplastic Thyroid Cancer
ElMokh Oussama, Taelman Vincent, Radojewski Piotr, Roelli Matthias A., Stoss Amandine, Dumont Rebecca A., Dettmer Matthias S., Phillips Wayne A., Walter Martin A., Charles Roch-Philippe (2019), MEK Inhibition Induces Therapeutic Iodine Uptake in a Murine Model of Anaplastic Thyroid Cancer, in Journal of Nuclear Medicine, 60(7), 917-923.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ATA 89th Annual Meeting Talk given at a conference BRAFV600Eoverrides NOTCH signaling in thyroid cancer. 30.10.2019 Chicago, United States of America Charles Roch-Philippe;


Associated projects

Number Title Start Funding scheme
149824 Progression from papillary to anaplastic thyroid carcinoma in mice, genetic dissection of Notch pathway’s role and potential treatments 01.02.2014 Project funding (Div. I-III)

Abstract

BRAF is a serine/threonine kinase that is found mutated in 7% of all human cancers. It is even more frequently mutated in melanoma and thyroid cancer. BRAFT1799A is the most common mutation found in patients. Based on this mutation we have developed in the lab several models of thyroid cancer in mice that we use as pre-clinical platform for testing of novel therapeutic approaches. Papillary thyroid carcinoma, the most frequent form of thyroid cancer, is cured in more than 93% of the cases while anaplastic thyroid carcinomas have a survival average below 6 months. During the last decades, the incidence of thyroid cancer has been increasing steadily and it is now the most prevalent form of endocrine cancer. Interestingly, many papillary thyroid cancer patients present a stable disease for years before presenting a sudden decline and progression to anaplastic thyroid cancer.Despite tremendous advances in molecular thyroid pathology over the last years, the mechanisms and genes that underlie tumor progression from papillary thyroid carcinoma to anaplastic thyroid carcinoma, which can also arise de novo, are not well understood. There is a clear lack of knowledge around the intimate mechanisms that are promoting a manageable disease to become a highly lethal threat. In contrast to overall medical advances, the treatment and prognosis of ATC has not significantly changed during the last 40 years. It is obvious that deeper insights of genes involved in tumor formation, progression and maintenance to provide novel strategies to target this cancer are urgently needed. In this grant, we want to use our pre-clinical mouse model to understand better the intimate mechanisms driving tumor changes to a more aggressive form of the disease using two axes: 1- Reverse genetics by using Notch-related modified genes to enhance or block the pathway in order to evaluate the importance of this signaling pathway in thyroid cancers and 2- Forward genetics by using a gene expression screening from mouse and human tumors to uncover new genes involved in cancer progression. To that end, we will use our mouse model, in silico analysis from publicly available databases and patient derived samples. In both cases, we aim at unveiling new markers for prognosis or eventually new potential targets for drug therapies.This project will bring a better understanding of anaplastic thyroid cancer and the driving forces behind the disease progression. The data from this work done in our pre-clinical models will generate substantial information for clinicians in order to improve patients’ care, either by improving prognosis with the discovery of early warning signs of tumor progression or by validating drug targets and treatment that could be readily translated into clinical practice.
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