Understanding the role of the tumour suppressor Adenomatous Polyposis Coli in Paediatric Craniopharyngioma (360G-Wellcome-344751_Z_26_Z)

Adamantinomatous craniopharyngiomas are a type of brain tumour, arising from the progenitor stem cells of the pituitary gland, with an incidence of 1.7-2.1 cases per million per year. These lesions erode into the surround pituitary tissue resulting in debilitating and life threatening endocrinopathies as well as a profound impact on a child's well being through hypothalamic dysfunction (obesity, adipsia, sleep-wake cycle alteration) and progressive blindness. These lesions are driven by mutations in multiple components in the Wnt-B- catenin pathway, with my PI Dr Gaston-Massuet having carried out earlier instrumental work in understanding how these tumours progress overtime and the molecular biology using murine models. Next generation sequencing of human tumour samples has demonstrated several mutations beyond the original CTNNB1 finding, in particular APC mutations- adenomatous polyposis coli. The benefit of studying this cohort of mutations is that the B-Catenin produced would be degradable and may be responsive to medications which target B-catenin degradation- we would be keen to test two novel therapeutics in this regard. In summary the key steps are 1. Modelling tumour initiation and progression in murine models of APC mutations using LOX-CRE systems, 2. Genotype-phenotype correlation studies (300 samples) to guide clinicians on care and 3. Testing therapeutics.