Multiple myeloma is a malignancy of plasma cells, specialized B cells that secrete antibodies. The abnormal clonal accumulation of plasma cells interferes with the normal blood cell production thereby causing cytopenias (e.g. anemia, neutropenia, thrombocytopenia) and aberrant, excessive antibody production. Patients can also experience bone pain, neurological symptoms and renal failure. Currently, with the exception of bone marrow transplantation that is associated with significant morbidity and mortality, there is no cure for patients with multiple myeloma. However, therapies, especially targeted therapies, can control the disease for many years.
The most commonly used drugs for targeted therapies include dexamethasone, vinca alkaloids, melphalan, bortezomib, thalidomide, and lenalidomide. We want to evaluate whether stress or cell death signaling pathways mediate the response of myeloma cells to these standard-of-care agents. For example, mutation of the p53 tumor suppressor or abnormality in the p53 signaling pathway are frequent genetic lesions in tumor cells and would be expected to undermine therapeutic responses to DNA damaging agents such as melphalan.
To systemically address this question, we plan to exploit CRSIPR/Cas9 technology for the genome editing of human multiple myeloma cells that are engineered to be defective for p53 signaling, incompetent to undergo apoptosis by deleting the essential cell death mediators Bax and Bak or unable necroptosis by deleting RIPK3 or MLKL. We will then compare their responses (in survival or proliferation assays), compared to the parental cells, in order to determine what impact these genetic lesions have on their responses to a large panel of standard-of-care agents.
These studies will inform us as to how these agents might act to kill myeloma cells and pre-empt mechanisms by which myeloma cells can become refractory to these drugs.