Targeting intracellular protein handling as a strategy for cancer therapy; using Multiple Myeloma as a model

Background to the proposal: The requirement of plasma cells to synthesise immunoglobulin and their dependence on protein turnover is central to myeloma cell differentiation, growth and survival, and therefore, provides a unique differential target that can be exploited therapeutically. Our previous work demonstrates myeloma cell apoptosis can be induced either by forcing the premature degradation of survival molecules by inhibiting heat shock protein 90, or by interfering with the unfolded protein response (UPR), a key regulatory pathway of protein folding. Relevance to cancer: Although this work uses myeloma as a model, it is clear that a number of secretory solid tumours also rely heavily on protein turnover for cell survival and metastatic potential, and therefore results will be applicable to other tumours. Aims of the research: In this work we seek to characterise two important intracellular protein turnover pathways in myeloma, and to identify novel therapeutic compounds targeted against them. The project will address two main areas: 1.The development of effective therapeutic strategies to target the heat shock protein response. 2.The development of effective therapeutic strategies to target the UPR via IRE1alpha and XBP1. Outline plan of research: Using ShRNA we will demonstrate the downstream effects of targeting the heat shock protein response concentrating on the HSP70 family members HSP72, HSC70 and HSF1. In order to identify a clinically relevant approach, we will then demonstrate the in vitro and in vivo anti-myeloma effects of small molecule inhibitors of the heat shock response. In order to develop effective therapeutic strategies to target IRE1alpha, XBP1 and the UPR, we will identify IRE1alpha interacting proteins and determine their dependence on IRE1alpha kinase and endoribonuclease activity. In addition we will determine the presence and role of Regulated IRE1alpha Dependent mRNA Decay in myeloma. This data will be used to inform high throughput inhibitor screens, and structure-based drug design aimed at identifying small molecule inhibitors of IRE1alpha kinase and endoribonuclease activity.