Hooking myeloma by the GILZ: separating the efficacy of steroids from side effects in the treatment of multiple myeloma

Contemporary treatment of multiple myeloma and acute lymphoblastic leukaemia (ALL) still relies heavily on steroids (glucocorticoids - like prednisolone and dexamethasone) as a therapeutic backbone. Although initially effective at controlling disease and reducing symptoms, myeloma and leukaemia become resistant to steroids with continued exposure. Primary resistance to steroids is a poor prognostic factor, particularly in ALL. Thus, understanding and overcoming resistance to steroids is a key research goal. Even when steroids are effective as treatment, side effects are significant with ongoing exposure, mimicking Cushing's Syndrome. Toxicities include diabetes, hypertension, osteoporosis and mood disorders. In experiments designed to both overcome steroid resistance and reduce steroid side effects, we have identified GILZ (or TSC22D3) as a steroid effector protein that can kill myeloma and ALL cells but does not carry the toxic metabolic side effects. The current project seeks to evaluate methods to turn GILZ into a treatment for blood cancers using technologies like CRISPR/Cas9 screening and lipid-nanoparticle based delivery systems. In evaluating GILZ as a potential therapeutic, we will also learn more about overcoming steroid resistant in myeloma and ALL.