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Overcoming survival signaling in Multiple Myeloma

Multiple Myeloma (MM) is a clonal plasma cell malignancy and the second commonest haematological malignancy. Although major advances in the treatment of MM have taken place in the past two decades MM remains incurable, with patients multiply relapsing until all treatment options are exhausted. Novel treatment approaches capable of circumventing mechanisms of resistance to existing treatments constitute an urgent unmet clinical need. The PI3K/AKT/mTOR pathway is increasingly recognised to play a key role in development of relapsed and refractory MM. Recent efforts to target this pathway in relapsed and refractory MM have proven successful, with a clinical response rate of 78% in combination with proteasome inhibitor bortezomib. A phase I study of carfilzomib in combination with afuresertib will begin recruiting at our centre in early 2015. Though effective in combination, single agent activity has been modest and short-lived. We hypothesise that targeting survival pathways active in the setting of AKT inhibitor resistance will overcome processes that underlie disease progression and development of resistance. We will investigate mechanisms of resistance to AKT inhibition in vitro and in primary patient samples at commencement of AKT inhibitor trial and again at relapse, when resistance has developed. Multiplatform profiling will be utilised including genome sequencing, RNA sequencing and Reverse Phase Protein Array to determine at DNA, RNA and protein level the changes which have led to resistance and to identify drug targets for combination with AKT inhibitors or as monotherapy in resistance. It is hypothesised that the PIM kinases play a role in AKT inhibitor resistance, given overlapping signaling, key role of PIM2 in MM and the observation of PIM upregulation in response to AKT inhibition in other cancers. Preclinical investigation of rational drug combinations will be performed. It is anticipated that these research findings will provide rationale for clincial studies in refractory MM.