Some components of this project are suitable for Honours students, flexible for Medical/clinical students and entire project is suitable for PhD students. Members of the Translational Cancer Discovery Group were involved in the original development of denosumab, a monoclonal antibody against RANKL, which is now approved worldwide for the treatment of bone metastasis and multiple myeloma. Recent research by the lab using preclinial models has demonstrated that antibodies against RANKL improve the anti-tumour efficacy of conventional immunotherapies, such as anti-PD-1/PDL1 or anti-CTLA4 antibodies. This increased efficacy is associated with increased anti-tumour immunity, however, the precise mechanism and cellular target regulated by the RANK(L) pathway are unknown.
These data have rationalised a novel clinical trial of Pre-operative evaluation of anti-PD-1 checkpoint inhibition (nivolumab) combined with RANKL blockade (denosumab) in stage IB-IIIA non-small cell lung cancer (NSCLC) patients (POPCORN trial). We now wish to use mouse tumour models and clinical trial samples to determine the precise mechanism by which RANKL
inhibition enhances immunotherapy. In addition, utilisation of transcriptomics and multiplex IHC applied to clinically annotated cohorts of CRC, NSCLC and melanoma samples will allow an interrogation of the functional status of specific immune cells in relationship to RANKL and potential relationship to immunotherapy response. This is a prime example of the “reverse translation” paradigm, in which clinical trial samples and results will inform mechanistic, pre-clinical studies. The trainee will learn and use recently-developed translational approaches to the clinical trial samples (eg flow cytometry, transcriptomic analysis and mutliplexed immunohistochemistry) and/or experimental mouse models of cancer.