ALK är inblandad i många olika cancerformer
Projektets mål är att utröna receptor tyrosin kinaset ALK inom utvecklingen av mammalieceller, samt varför ALK är en onkgen och dess inverkan på initiering och progression av barncancersjukdomen neuroblastom. Biologin och bakgrunden till sjukdomen är begränsad, men ALK kan vara en möjlig måltavla för medicinering av vissa neuroblastom. Tidigare har ALKs onkogena aktivitet varit uteslutande kopplat till kromosomala translokationer där ALKs kinasdomän har stått för den illavarslande aktiviteten och translokationspartnern har stått för lokalisationen i cellen.
Our project aims are to understand the role of the Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase (RTK). Anaplastic Lymphoma Kinase, an oncogene, is involved in the development of neuroblastoma. Previously, the oncogenic activity of ALK RTK had been restricted to the classical production of an activated fusion protein as a result of chromosomal translocation. ALK was first described in the mid-nineties as a novel tyrosine kinase gene, which was fused to the nucleolar protein gene, nucleophosmin (NPM), in non-Hodgkin's lymphoma. Since then ALK has been shown to be involved in many other translocations in Anaplastic Large Cell Lymphoma (ALCL) as well as in other neoplasms such as Non-Small-Cell lung cancers (NSCLC) and Inflammatory Myofibroblastic Tumors (IMTs). A number of studies, investigating over 1900 NSCLC cases, suggest a frequency of EML4-ALK translocation fusion of up to 7.9% of all NSCLC (reported in 7 independent investigations). This is equivalent to around 80 000 patients worldwide. Thus, oncogenic activation of the ALK protein is now implicated in non-hematopoietic, hematopoietic and also neuroendocrine tumours. Year 2008 five independent groups reported that ALK is an oncogene in a group of both familial and sporadic neuroblastoma, which is a malignant condition of the developing sympathetic nervous system that most commonly affects young children (Caren et al., Biochem. J., 2008, Chen et al., Nature, 2008, George et al., Nature, 2008, Janoueix-Lerosey et al., Nature, 2008, Mosse et al., Nature 2008). Neuroblastomas vary according to age at diagnosis, extent of disease and the biology behind the tumour formation. Certain tumours will regress, while 50 % of all cases are classified as high risk for disease relapse with an overall survival rate of less than 40 %. Until very recently the etiology of neruoblastoma was rather enigmatic. It was reported that in certain familial and high-risk non-familial neuroblastomas the RTK ALK gene has been mutated within the kinase domain, transforming the receptor into a constitutively active oncogenic version (Mosse et al., Nature 2008) Our laboratory is investigating differences in the constitutively active ALK RTK's found in neuroblastoma patients. In our approach we intend to investigate differences in constitutively active ALK RTK mediate signalling at the molecular level as compared with wild type ALK in relevant cell models. This work is also carried out in mouse models which we have developed in with the aim of addressing ALK signalling in vivo