The University of Texas at Austin
Project Term: July 1, 2023 - June 30, 2026
We have investigated the consequences of p53 loss on stem cell properties, namely clonogenic growth, self-renewal, and drug resistance in multiple myeloma. We have found that both the level of Notch signaling and BCMA impact these properties, and we will explore novel strategies to improve outcomes in p53 mutant multiple myeloma.
The outcome of patient with multiple myeloma varies according to chromosomal abnormalities. Of the various chromosomal mutations the loss of the short arm of chromosome 17 (del17p) is associated with the worst outcomes due to short remissions and the development of drug resistance. The major gene impacted in del17p is thought to be p53, and we have generated multiple myeloma cells in which the p53 gene is selectively deleted. We have found that the loss of p53 leads to increased ability to form new tumor cells as well as drug resistance of these proliferative cells. Recently, novel immunotherapies that target a protein called BCMA on myeloma cells can generate a high rate of responses in patients with advanced myeloma. We also found that multiple myeloma cells that have lost p53 are also resistant to killing by immune cells. We subsequently found that the loss of p53 leads to activation of the Notch pathway that is active during embryonic formation, and a drug called a gamma secretase inhibitor that blocks the Notch pathway could decrease tumor forming potential and restore sensitivity to chemotherapy and immunotherapy. Gamma secretase inhibitors can also modulate the expression of BCMA, therefore, we will examine the impact of BCMA levels on the tumor initiating potential of myeloma in hopes to develop new drugs for this especially lethal form of multiple myeloma.