The main objective of this project is to provide a rationale for future therapeutic targeting of the c-myc IRES which mediates cap-independent translation in multiple myeloma cells. IRES-dependent myc translation is critical for tumor cell survival during ER stress in this tumor model.
The aims i nclude studying the mechanism by which the MNK kinase, the hnRNP A1 ITAF and the ribosomal protein RPS25 mediate IRES function; the mechanism and importance of myc inducing A1 and RPS25 expression and the potential for an inhibitor of IRES function in myeloma. The viability versus death of myeloma cells as well as their ability to achieve c-myc translation and IRES activity in vitro will be studied. In addition, a murine model of c-myc-driven myeloma will be exploited to determine the in vivo roles of hnRNPA1 and IRES activity in tumor progression as well as the potential efficacy of our IRES inhibitors.
The goal of the project is to provide experimental support for development of inhibitors that prevent the synthesis of the oncoprotein c-myc in multiple myeloma. If successful, this new category of agents would present a significant addition to the current armamentarium of drugs used for this incurable malignancy.