JCJC SVSE 1 - JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique

Autophagy : new therapeutic target in ALK-dependant tumors? – ALK-PHAGIE

Submission summary

The anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase involved in a still growing spectrum of cancers. First identified as the driver translocation in 80% of Anaplastic Large Cell Lymphoma (ALCL), its role in the pathogenesis of some B cell lymphomas, inflammatory myofibroblastic tumors, colon cancers, neuroblastomas, and more recently, in a fraction (5%) of Non Small Cell Lung Carcinoma (NSCLC) has been demonstrated. Thus, the number of patients suffering from an ALK-dependent cancer is increasing each year. Since the ongoing ALK-dependent tumors therapies, mainly based on chemotherapy, are not optimal (general loss of quality of life, relapses of the disease), it is fundamentally essential to design animal models for ALK-dependent cancers, ideally allowing studies on the mechanisms of ALK tumor development, regression and eventual relapse. Such animal models not only offer researchers a tool to decipher ALK oncogenesis mechanisms but also provide an integrated system to test the efficiency of ALK tyrosine kinase and/or downstream effectors inhibitors. In this field, both the academic and industrial researches have undergone a considerable development over the last ten years. One compound so far, the crizotinib/PF-02341066, is in clinical trials for ALK-dependent lung cancers and the first mutations in the ALK tyrosine kinase domain, conferring resistance to Crizotinib, have just been reported. Thus, despite the therapeutic success of tyrosine kinase inhibitors in cancer treatments, acquired drug resistances universally develop. In ALK-dependent cancers, as previously reported in other oncogenic tyrosine kinase-induced tumors, we anticipate that the identification and inhibition of secondary critical oncogenic pathways may represent a valuable therapeutic strategy to combat drug resistant cancer cells. Recently, autophagy, a catabolic lysosomal degradation process, which could act either as a survival or cell death mechanism, has been proposed as a new target for cancer therapy. Indeed, it is proposed that according to the cancer type, either autophagy inducers or inversely, autophagy inhibitors could lead to a therapeutic benefit. We have already generated conditional animal models for ALK lymphoma. Because of the high prevalence of lung cancer in the world, our first objective in this proposal is to create a conditional animal model for ALK-dependent lung cancer. Second, we want to accurately measure autophagy in the development and maintenance of these two different ALK-dependent cancers. Third, we want to determine whether autophagy inducers or inhibitors could eradicate ALK tumor cells and thus be used either to treat ALCL and NSCLC or to optimize their current treatments.

Project coordination

Sylvie GIURIATO (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE MIDI-PYRENEES LIMOUSIN) – sylvie.giuriato@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM-UMR1037 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE MIDI-PYRENEES LIMOUSIN

Help of the ANR 317,000 euros
Beginning and duration of the scientific project: December 2011 - 36 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter