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Progression from papillary to anaplastic thyroid carcinoma in mice, genetic dissection of Notch pathway’s role and potential treatments

English title Progression from papillary to anaplastic thyroid carcinoma in mice, genetic dissection of Notch pathway’s role and potential treatments
Applicant Charles Roch-Philippe
Number 149824
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cellular Biology, Cytology
Start/End 01.02.2014 - 31.03.2017
Approved amount 382'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Experimental Cancer Research

Keywords (7)

Cancer; BRAF; Thyroid; Papillary; Anaplastic; Notch; RadioIodine

Lay Summary (French)

Lead
Le cancer de la thyroïde est un des cancer les plus agressif chez l'homme. Bien que souvent traitable il peut progresser en une forme très invasive et pour laquelle il n'y a aucun traitement actuellement. Ce projet se concentre sur la compréhension de la génétique de la progression de la maladie, et sur la possibilité d'apporter des solutions innovantes en terme de thérapie.
Lay summary

Le cancer de la thyroïde est le cancer le plus répandu du système endocrinien. Au cours des 30 dernières années l’incidence de ce cancer a presque doublé, en particulier chez les femmes. La vaste majorité des cancers de la thyroïde sont de type « papillaires ». Ce type de cancer peut être traité a plus de 90% par chirurgie et radio-thérapie. La plupart des décès reliés au cancer de la thyroïde sont dus à la progression de la maladie en cancer « anaplasique ». Souvent diffus et placés près des vaisseaux carotide ces cancers sont inopérables et rapidement mortels.

De même que chacun de nous présentons des grains de beautés qui ne dégénèrent que rarement en mélanomes, plus de 50% de la population présente des nodules thyroïdiens parfaitement bénins. Il est important de mieux comprendre les facteurs génétique entrainant le développement de la pathologie afin de la prévenir et optimiser la prise en charge des patients.

 

Ce projet se base sur l’utilisation d’un model murin de cancer de la thyroïde développé précédemment. Ce modèle récapitule fidèlement la phase initiale de la maladie (papillaire) ainsi que la progression vers la phase invasive létale (anaplasique).

 

Deux grands objectifs seront poursuivis :

A- Développement de nouvelles combinaisons thérapeutiques.

Ici nous voulons tester la co-opération de différents cocktails d’inhibiteurs, en compléments des approches cliniques classiques de traitement du cancer de la thyroïde (iode radioactif).

B- Notch est un gène souvent muté dans les cancers mais son action est différente selon le tissue testé. Dans le cancer de la thyroïde il n’est pas clair si Notch a un effet bénéfique ou néfaste sur la maladie. Nous proposons ici une approche génétique en utilisant le modèle murin développé précédemment pour tester son effet.

 

Direct link to Lay Summary Last update: 21.11.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Combined MEK and Pi3’-Kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo
ElMokh Oussama, Ruffieux-Daidié Dorothée, Roelli Matthias A, Stooss Amandine, Phillips Wayne A., Gertsch Jürg, Dettmer Matthias S., Charles Roch-Philippe (2017), Combined MEK and Pi3’-Kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo, in Oncotarget, 24604.

Collaboration

Group / person Country
Types of collaboration
Pr Wayne Philipps / PeterMac Institute Australia (Oceania)
- Publication

Associated projects

Number Title Start Funding scheme
176175 New mechanisms of thyroid cancer progression 01.11.2017 Project funding (Div. I-III)
134205 Thyroid specific expression of oncogenic BRAF(V600E) initiates the genesis of papillary thyroid cancer 01.01.2011 Fellowships for advanced researchers
139744 Thyroid specific expression of oncogenic BRAF(V600E) initiates the genesis of papillary thyroid cancer 01.01.2012 Fellowships for advanced researchers

Abstract

Thyroid malignancies are the most common form of thyroid endocrine cancer. A rough estimation of thyroid cancer incidence would be a tenth of lung cancers’. In the last 30-years, thyroid cancer incidence has more than doubled and is the fastest increasing in women. Most of thyroid cancer related deaths are due to progression to anaplastic thyroid carcinoma that is the most aggressive kind of cancer reported in human. Due to its localization and diffuse characteristic it is often inoperable. Finally, there is no treatment for anaplastic thyroid carcinoma, with a mortality rate higher than 50% after 1 year. Thyroid nodules are, like nevi, fairly common. Again like benign nevi, very few nodules actually progress to malignancies and remain dormant. The genetics of those tumors require then careful investigation in order to better understand the factors involved in tumor formation and progression to, in fine, propose better prognosis avoiding unnecessary surgery at the same time as identifying nodules that would present a life-treat.During my post-doctorate, I managed to develop two models of thyroid cancer. First a model of clinically manageable papillary thyroid carcinoma based on the mutation BRAFV600E that is observed in almost 40% of the human cases. Second, a model of lethal anaplastic thyroid carcinoma that combines BRAFV600E and PIK3CAH1047R that is altered in almost 50% of anaplastic thyroid carcinoma. Using this experience, I propose to investigate the implication of Notch pathway in the context of thyroid cancer.Notch pathway in the cancer field is considered a “double-edged” sword. In some circumstances, it can work as a tumor suppressor or as an oncogene. The current data concerning Notch in thyroid cancer are insufficient and inconclusive. Therefore, I propose to use the mouse model of papillary thyroid cancer that I developed previously to investigate the consequences of Notch pathway manipulations in vivo on tumor progression. I propose here, in combination with BRAFV600E, to either mutationally activate or delete NOTCH1 to determine its actual role in thyroid cancer. I also propose to use a thyroid-specific KRAS mutant model (not able to induce malignant transformation alone) to investigate the potential of Notch pathway alteration in the context of tumor initiation.Anaplastic thyroid cancer lacks therapeutic options. The rise of novel pathway targeted inhibitors brought a lot of hopes, but also concerns and complications. I here propose to use the anaplastic thyroid carcinoma model that I developed to test a combination of drug in order to revert the phenotype. Drug-induced reversion of the phenotype requires continuous drug treatment. I therefore propose to further treat mice with radio-active iodine after drug-induced thyroid function restoration to permanently damage cancer cells and offer a long-term treatment.Overall, this project aims at translating back and forth clinical datas into mice experimentation to finally validate improved management strategies of thyroid cancer. The model of papillary and anaplastic thyroid carcinoma discussed here are highly relevant from the histological, mutational and clinical point of view. In addition, due to the similar mutations involved, the datas could be also relevant for melanoma, pancreas, and lung cancer.
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