Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin

Abstract

Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential 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 high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer.

Low serum cholesterol levels predict inferior prognosis and improve NCCN‐IPI scoring in diffuse large B cell lymphoma

“…combined HDL‐like nanoparticles with B‐cell receptor (BCR) signaling inhibitor ibrutinib, which respectively targeted cellular cholesterol uptake and BCR‐associated de novo cholesterol synthesis. They achieved cellular cholesterol reduction and induced apoptosis in resistant activated B‐cell (ABC) DLBCL cell lines . Pinheiro et al .…”

“…They achieved cellular cholesterol reduction and induced apoptosis in resistant activated B-cell (ABC) DLBCL cell lines. 46 Pinheiro et al used LDL or cholesterol-rich microemulsions (LDE) that bind to LDL receptors as carriers of antineoplastic agents to concentrate those drugs into cancer tissues. 47 Moreover, targeting cholesterol uptake disruption, Guillaumond et al revealed that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduced uptake of cholesterol and altered its distribution, decreased tumor cell proliferation, and limited activation of extracellular regulated protein kinases 1/2 survival pathway.…”

Targeting Scavenger Receptor Type B1 In Cholesterol-Addicted Lymphomas Abolishes Glutathione Peroxidase 4 and Results in Ferroptosis

“…Ramos cell line) and DLBCL (e.g. SUDHL4 cell line), is accompanied by compensatory increases in the expression of genes required for de novo cholesterol synthesis (21). In fact, our data showed lymphoma cells not initially sensitive to HDL NP-mediated cholesterol depletion, including activated B cell (ABC) lymphoma (e.g.…”

“…Scavenger receptor type B-1 (SCARB1) is a high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), which has been implicated as a target in human cancers based upon its role in cancer cell cholesterol uptake (17)(18)(19)(20)(21)(22)(23)(24)(25) and in membrane-anchored second messenger signaling pathways (21,(26)(27)(28)(29), among other factors (30)(31)(32)(33). Our group developed cholesterol-poor high-density lipoprotein (HDL)-like nanoparticles (HDL NPs) to target and tightly bind SCARB1 to prevent the cellular uptake of cholesterol ester from HDLs (21,24,34).…”

“…We have demonstrated that certain B cell lymphomas highly express SCARB1, and targeted treatment with the HDL NPs potently induces in vitro and in vivo cell death by inhibiting cholesterol ester uptake and reducing cell cholesterol (21,24,25). We have shown that HDL NPmediated inhibition of cholesterol ester uptake in highly sensitive B cell lymphoma cells, including Burkitt's lymphoma (e.g.…”