Investigating the role of the Notch atypical ligand delta-like homologue 1 (DLK1) in adrenocortical carcinoma

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Adrenocortical carcinoma (ACC) is a rare, aggressive tumour occurring in the adrenal cortex, the steroid-producing outer layer of the adrenal gland. Early diagnosis and surgical resection is crucial to long-term survival. In many cases, the cancer has spread by the time of diagnosis and the prognosis is bleak, with five-year survival rate in advanced disease under 15%. The only approved medical treatment is the drug mitotane but it is poorly tolerated and often fails to prevent disease progression. It is important to correctly identify ACC to ensure its prompt management. Current practice revolves around prediction of malignancy based upon clinical, biochemical and radiological features. Once a mass has been removed, histological diagnosis is based upon properties of the tumour and a further prediction of malignant potential. This is often complex especially in borderline cases. Therefore it is important to identify new biological markers that can aid in the diagnosis, prognosis and monitoring of disease. It is not known which cells are involved in the development of ACC, nor is it known which cells within an established tumour confer resistance to chemotherapeutic drugs and may be responsible for tumour relapse. We have recently identified a novel population of cells in the adrenal gland, which we believe might be the precursor of adrenal cancer. These cells express a protein called delta-like homologue 1 (DLK1). DLK1 is not normally found in most healthy human tissues. However, expression has been reported in other malignancies and in some of these increased DLK1 expression is associated with a worse prognosis. This makes it an attractive option for further investigation not only as a novel biomarker in ACC but also as a player in the development of this malignancy and as such a potential target for novel therapeutic intervention.In this project I will be investigating the role of DLK1 in adrenocortical carcinoma on two fronts. First, I will be studying its role as a potential novel biomarker in this condition. I will be doing this by looking at expression of DLK1 in collected tumour samples and in blood and seeing if there is a relationship with survival rates as well as clinical and biochemical presentation of disease. In addition, I will also be looking at DLK1+ adrenocortical carcinoma cells and characterising how they differ from other cells in the cancer.To carry out this project, I have developed collaborations with one of the largest groups investigating this condition from Germany (Prof. Fassnacht, University of Würzburg) and also my local pathology department to gain access to over 100 tissue sections of ACC along with the clinical records to assess details of presentation and long-term outcomes.I am collecting ACC tumour samples from four surgical centres across London. From our local hospital I am also collecting normal adrenal tissue from patients having surgery for other non-cancerous pathologies. In addition, I will be performing experiments using two new patient derived adrenocortical carcinoma cells lines through a collaboration developed with University of Colorado Denver in addition the commercially available, H295R cell line.This project combines cellular biological investigation with a clinical focus. It has the promise to identify and characterise a new molecular biomarker for diagnosis and prognosis of ACC, to deliver new biology defining a cell population in this malignancy and to identify targets which may be amenable to novel therapeutic intervention.