Rationally Targeting Cellular Cholesterol as a Therapeutic Strategy for Lymphoma

Targeting cholesterol metabolism as cancer therapy is intriguing; however, a rational approach is lacking. Armed with an agent capable of targeted cellular cholesterol reduction, high-density lipoprotein nanoparticles (HDL NP), we used diffuse large B cell lymphoma (DLBCL) to explore rational therapeutic approaches focused on cholesterol because of correlated cholesterol and B cell receptor (BCR) signaling requirements in germinal center (GC) versus activated B cell (ABC) DLBCL. Data from human tissue showed that both GC and ABC DLBCL express scavenger receptor type B-1 (SCARB1), which is a high-affinity ligand for cholesterol-rich high-density lipoproteins (HDL) and cholesterol-deplete HDL NP. The HDL NPs bind to SCARB1, reduce cellular cholesterol, and disrupt BCR signaling in DLBCL cells. The cells respond by enhancing de novo cholesterol synthesis to maintain cell membrane integrity as measured by gene array, RT-PCR, and Western blot data. In GC DLBCL, HDL NP-mediated cholesterol depletion and reduced BCR signaling results in apoptosis. ABC DLBCL is more resilient to HDL NP-mediated cholesterol depletion due to chronically activated BCR signaling, attendant cholesterol biosynthesis, and a higher baseline amount of cellular cholesterol. However, synergistic treatment with an inhibitor of downstream BCR signaling, such as with the BTK inhibitor, Ibrutinib, effectively reduces cellular cholesterol and induces apoptosis. In both GC and ABC DLBCL, therapeutic efficacy is observed both in vitro and in vivo, with no systemic side effects. As HDL NPs enable targeted cellular cholesterol modulation, data provide a rational approach to therapeutic reduction of cellular cholesterol as cancer therapy in lymphoma and, perhaps, other cancers that are sensitive to cholesterol depletion.