Targeting the evolving proteome in healthy and malignant stem cell development.

Cancer is swiftly becoming the leading cause of death in western populations, and it is estimated that 1 in 2 people born in the U.K. after 1960 will be diagnosed with cancer during their lifetime. Approximately 375,000 new cases of cancer are diagnosed in the U.K. every year (>1,000 per day) and only 50% of those are expected to survive. That equates to more than 450 cancer related deaths per day. Demonstrating a critical need for a better understanding of the underlying biology of cancer and development of new effective therapies. Acute myeloid leukaemia (AML) is a blood cancer with very poor prognosis. Treatment options have remained largely unchanged in the last 30 years, with good initial response to therapy, but high rates of relapse and very poor overall survival. One of the key problems with current therapy is the inability to deplete the cells at the apex of the disease, so called leukaemic stem cells (LSCs). These cells are highly resistant to therapy and are the origins of relapse and ultimately the root cause of poor prognosis in AML. In this fellowship, I will study how the repertoire of proteins (the functional effectors within cells) changes during the transition of healthy blood cells to leukaemia. Using novel models of leukaemic transformation and state-of-the-art proteomic (monitoring all proteins in a cell) techniques I will chart functional changes in the protein biology of primitive blood cells, from the earliest stages of leukaemia development, to the critical mass of frank leukaemia. By comparing healthy and malignant cells side by side, I will uncover key differences that could represent vulnerabilities that are leukaemia specific. Using this approach, it is possible to test new targeting protocols that specifically kill leukaemic cells and preserve healthy cells, in contrast to current chemotherapeutic protocols which kill all growing cells, be they healthy or leukaemic. During this fellowship I will use newly generated data on LSCs alongside previously published data on niche-derived factors to model where LSCs grow and what they require from their niche to evade chemotherapy. This will bring in an extra layer of complexity to the project, which will help account for niche-derived mechanisms which can be the underlying cause of chemotherapeutic evasion. This part of the fellowship will also provide a deep understanding of the bone marrow niche as leukaemia develops and help to find new ways to preserve cells supportive of healthy blood production and selectively deplete cells supportive of leukaemia development. Finally, the information gained from these approaches will be validated in a cohort of primary patient AML samples, which I will curate in collaboration with the haematological research network (hmrn.org) based at York. It is vitally important to test the new biological mechanisms for their relevance in primary human AML, especially as targeting these mechanisms could have clinical impact. Alongside primary patient AML samples, I will work with the Anthony Nolan Research Institute (the largest bone marrow transplantation service in the U.K.) to test how new therapeutic approaches affect healthy blood production and how to avoid killing healthy cells or impeding bone marrow transplantation approaches. This represents a key ethos within my fellowship: to target malignant cells, whilst preserving healthy tissue. Ultimately this provides the opportunity to treat AML in a more targeted and strategic manner, but also offers the opportunity to bring those patients once classified as clinically unfit for intensive chemotherapy (e.g. the elderly), and with a dismal prognosis, back into suitability for more intensive protocols with far superior outcomes.