Identification of therapeutic sensitivities and pathways driving adrenocortical carcinoma

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Tumours of the adrenal cortex are relatively common with a prevalence of 1-10%. Most of these are benign, however, in rare case adrenocortical carcinoma (ACC) can develop which is aggressive and has a poor 5 year prognosis. Understanding pathways that drive ACC progression is essential to the development of more effective treatments and for the prediction of individual outcomes. Next generation sequencing studies have revealed recurrent alterations present in human disease. These studies have identified mutations in the WNT signalling pathway, including activating mutations in CTNNB1, to be one of the most frequent alterations. Studies in mice have shown that activating mutations in Ctnnb1 can give rise to tumour formation in the adrenal cortex, highlighting the value of this model to study adrenal tumourigenesis. We have identified HOXB9 as a gene expressed in the early stages of adrenal cortex development and upregulated in adrenal tumours driven by activating Ctnnb1 mutations in mice. Human ACC tumours also show upregulation of HOXB9 expression that correlates with WNT signalling dysregulation and decreased survival frequency suggesting a role for this gene in carcinogenesis. In preliminary studies, we have generated transgenic mice with elevated Hoxb9 expression in developing and adult adrenal cortical cells. Mice that contain this transgene and an activating Ctnnb1 mutation showed acceleration of tumourigenesis characterised by increased cell proliferation and tumour weight and in the appearance of cells with a neoplastic undifferentiated spindle shaped phenotype. These studies indicate that HOXB9 can cooperate with the WNT signalling pathway to drive adrenal tumour progression. The aim of this project is to investigate the cellular and molecular mechanisms and pathways by which HOXB9 drives tumour progression. Using in vitro and in vivo approaches we will determine the role of this gene in adrenocortical tumour cell proliferation and survival, cell fate and differentiation. We will identify the molecular pathways associated with HOXB9, including its interaction with the WNT signalling pathway.An additional aim of this project is to characterise the drug sensitivities associated with the WNT signalling pathway in adrenocortical carcinoma. Using various ACC models with dysregulated WNT signalling we will investigate the effect of drugs targeting this pathway on cell survival in vivo and in vitro. Using high throughput drug library screens we will identify combinations therapies that will increase the effectiveness of these targeted compounds. In a complementary approach, we will use RNA interference screens to identify the key nodal points in the WNT signalling pathway that when inhibited achieve a therapeutic response in ACC. The ultimate goal of the studies proposed is to identify novel pathways and drug sensitivities in adrenocortical carcinogenesis that will provide important information that will aid in the development of clinical therapies to treat this rare and aggressive disease.