Our project aims 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.
In 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. In this project we will also harness our expertise regarding the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase to ALK positive NSCLC, with the aim of optimizing the therapeutic use of ALK inhibitors in this patient population. We will examine FDA approved drugs, ALK inhibitors alone or in combination with novel specific small inhibitor against downstream target components of ALK signaling. This study will be performed in appropriate cell lines and mouse model systems. Our investigation will build on 15 years of ALK signalling research that has focused on the basic mechanisms of ALK activation, identification of key downstream targets primarily in neuroblastoma models.