The Anaplastic Lymphoma Kinase (ALK) has been discovered as the result of chromosomal translocations in Anaplastic Large Cell Lymphomas (ALCL) (Chiarle et al Nat Rev Cancer. 2008, 8:11). In ALCL, the role of the ALK oncogenic translocations has been established in vitro and in transgenic mouse models. Recent findings have shown ALK translocations, mutations or amplifications in other types of solid cancers, such as lung carcinoma (Soda et al. Nature. 2007, 448:561) and neuroblastoma (Mossè et al. Nature 2008, 455: 930). However, the role of ALK gene mutations in these solid tumours remains largely undetermined. This lack of knowledge is even worse given the fact that a therapy that targets ALK in these tumours could be feasible. Aim 1. Targeting of ALK in ALCL lymphomas. ALCL ALK positive lymphomas will be tested for small molecule inhibitors of the activity of ALK. In addition, a combination of gene silencing, such as small interfering RNA (siRNA), and vaccination against ALK will be validated as selective ALK therapies. Aim 2. Characterization of the role of ALK in lung cancer through the generation of mouse models. We propose to characterize the pathogenetic role of ALK in lung cancer by in vitro studies and by generating mouse models for ALK positive lung cancers. These mouse models will be fundamental to validate the innovative therapies against ALK positive lung carcinoma. Aim 3. Validation of ALK as an oncogene and a therapeutic target in neuroblastoma. We plan to develop mouse models of neuroblastoma to investigate the pathogenetic role of ALK in the onset and maintenance of neuroblastoma in vivo. These mouse model of neuroblastoma will be used for the validation of ALK specific therapies. Overall, the proposed project will define the role of ALK in lymphoma, neuroblastoma and lungcancer and validate its potential use as a a target for therapy in those tumours. The impact of these novel therapies will be of great value in these deadly tumours.
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