SLMS Academic Careers Office

20. Identification of mitochondrial biomarkers and therapeutic targets in pancreatic cancer  

Supervised by Dr Jan-Willem Taanman and Professor Brian R Davidson
Based in Department of Clinical Neurosciences, UCL Institute of Neurology

Pancreatic cancer is a devastating disease for which there has been minimal improvement in survival over the last 20 years; however, despite the extremely poor prognosis, our understanding of the molecular basis of the sequential steps from normal through dysplasia and in situ cancer to invasive pancreatic cancer has advanced significantly in recent years. It is now known that some common abnormalities of the pancreas increase the risk of cancer, including mucinous cysts, ductal hyperplasia and chronic pancreatitis. These tissues will be the focus of this project.

There are two biochemical pathways in the cell that generate energy: the glycolytic pathway in the cytosol and the oxidative phosphorylation pathway in mitochondria. The latter produces much more energy than the former and is used for the generation of energy in normal cells. Cancer cells, however, rely on glycolysis to produce energy. Why cancers switch their energy production from oxidative phosphorylation to glycolysis is unknown but the change is fundamental to malignant progression and response to therapy. Our hypothesis is that during the progression from normal pancreas to pre-malignancy, pancreatic intra-epithelial neoplasia and invasive cancer there is a progressive change in mitochondrial morphology and function, and a shift towards reliance on glycolysis. Understanding the control mechanism for the energy supply of cancer tissues and how it differs from normal or pre-cancerous tissue could lead to new targets for cancer therapy and markers that help monitor patients with pre-malignant conditions.

This project will determine when the glycolytic switch takes place by comparing the energy generating pathways in normal pancreas, pre-cancerous tissue and pancreatic cancer, using a wide range of biochemical techniques. Thus, this project will indicate which pathway and molecules could be used for monitoring malignant transformation or act as therapeutic targets for mitochondrial therapies.

The project brings together the expertise in pancreatic cancer treatment and research of the Division of Surgery & Interventional Science (Prof B.R. Davidson) and that in mitochondrial biology of the Department of Clinical Neurosciences (Dr J.-W. Taanman). The project is distinctly inter-disciplinary and highly collaborative in nature, with 50% of time in the Division of Surgery & Interventional Science where pancreas tissues are routinely collected under current ethical licensing. Training will be received in the handling and processing of human tissues, and the governance requirements for research involving patients. The second 50% will be in the Department of Clinical Neurosciences where research on molecular biological aspects of mitochondrial pathology is routinely performed, using state-of-the-art techniques in mitochondrial research.

Both departments provide extensive PhD mentoring and use the UCL on line system for monitoring and ensuring research progress. There are regular small-group tutorials, and presentations at department-wide postgraduate research meetings and journal clubs. The student will attend the multi-disciplinary treatment clinical meetings where disease pathology, patient treatment options and outcomes are presented. The student will be encouraged to attend appropriate national and international meetings. This project would suit a Life Sciences/Medical Sciences graduate with interest in cancer biology and molecular biology. The work is particularly attractive for those interested in translational research as the findings of this project will lay the groundwork for a diagnostic test and a new treatment strategy of pancreatic cancer. Importantly, new therapeutic approaches identified in this project may also be applicable to other types of cancer.