Identification and characterisation of kinase inhibitors as therapeutics for the treatment of cancer metastasis

Metastasis, the spreading of cancer cells to different tissues, is clinically the most important process in the progression of most types of cancer. Once tumours undergo metastasis, patient prognosis is often poor because migratory cancer cells, which are widely dispersed and, therefore, not surgically resectable, do not respond to conventional cytotoxic drugs. Therefore, there is an urgent need to identify druggable targets for the development of compounds that have the potential to prevent the spread of cancer cells. This is especially important for the long-term management of inoperable primary tumours that have evolved resistance to initial therapy and to the treatment of cancers that are not diagnosed until the disease has begun to spread, such as cancers of the ovary and pancreas where survival rates are very low. Protein kinases are highly conserved, play critical roles in all the biological processes underlying invasive cell migration and represent important classes of potential therapeutic targets for the treatment of cancer. Building on the results of our genetic screens, we will identify and test new and clinically-approved drugs for their ability to inhibit key pro-migratory kinases and halt invasion in cancer. High-throughput kinase assays screened in the presence of cellular ATP concentrations will facilitate selection of compounds for functional analysis in vivo in a Drosophila model and in a panel of ovarian cancer lines that are resistant or sensitive to conventional chemotherapies. Biomarkers of downstream signalling and drug-resistant kinase alleles will prove target engagement. This project would suit any student with a background in molecular and cellular biology and with an interest in a career in cancer research. Many of the techniques are state-of-the art, which means that there will be good opportunity for career development.

Training:
The student will be associated with active research groups conducting lab-based biochemistry, molecular genetics and cell imaging research highly relevant to the student’s project. Within the groups, several lab members are working on related projects, and adjacent collaborating labs have additional expertise, giving the student access to a large set of other experimentalists to gain advice and intellectual input. The student will be expected to regularly interact with the supervisors to enable rapid progress and to ensure a broad training in the relevant inter-disciplinary approaches. The approaches proposed are state-of-the art (including fluorescence enzyme assays and cell imaging), and the infrastructure and support is exceptionally strong; this means that there will be good career development opportunities for the student. Regular PGR meetings will enable continuous progress checks, so that and technical or other problems can be identified and remedied quickly. Generic skills training will be provided through weekly lab meetings. These will give the student experience of oral presentation of their work, will expose them to other research methods and systems and broaden their scientific outlook. The student will also be expected to attend other seminar series within Liverpool and present their work at a minimum of one international meeting.