Rational Targeting Of Cellular Cholesterol In Diffuse Large B-Cell Lymphoma (Dlbcl) Enabled By Functional Lipoprotein Nanoparticles And The B Cell Receptor Inhibitor Ibrutinib: A Therapeutic Strategy Dependent On Cell Of Origin (Coo)

Introduction: Malignant cells, including lymphoma cells, have altered metabolism and, in some cases, an increased demand for cholesterol and cholesteryl esters. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative, exciting approach. Toward this end, we focused on DLBCL as a model because of differences in cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed bio-inspired high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol and cholesteryl ester uptake through binding to the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). We hypothesized that by inhibiting BCR signaling, and consequently cholesterol biosynthesis with the BTK inhibitor ibrutinib, we could overcome inherent resistance in cholesterol replete ABC DLBCL cell lines in vitro and in a xenograft model.