Grant: Operating Grant - PA: Alberta Cancer Foundation - Research (bridge funding)

Multiple myeloma is the second most common form of blood cancers and remains incurable despite the addition of novel therapeutic agents to the treatment armamentarium for this disease. As such, while the proteasome inhibitor Bortezomib has significantly improved the survival outcomes of myeloma (MM) patients, the malignant cells invariably acquire resistance to its effects. We have identified a novel therapeutic approach that takes advantage of the unstable genome in MM cells by altering their ability to maintain their DNA integrity. Combining a PARP inhibitor with Bortezomib, which impairs the DNA repair machinery, results in a catastrophic and irreversible DNA damages that are lethal to MM cells. Therefore inhibition of PARP in the presence of proteasome inhibitors might have just uncovered the Achilles' heel of MM cells. In the current research proposal we first intend to study in depth the mechanisms through which PARP and proteasome inhibitors induce myeloma cell death and also uncover potential mechanisms of resistance to these drugs. In addition we will conduct a clinical trial to define the safety and efficacy of the combination of PARP and proteasome inhibitors in MM patients.