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HDL Nanodiscs Loaded with Liver X Receptor Agonist Decreases Tumor Burden and Mediates Long-term Survival in Mouse
Troy A Halseth1, Anzar A Mujeeb2,3, Lisha Liu4
1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI, 48109, USA.
Abstract:
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a 5-year survival rate of 7%. Previous studies have shown that GBM tumors have a reduced capacity to produce cholesterol and instead depend on the uptake of cholesterol produced by astrocytes. To target cholesterol metabolism to induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists and CpG oligonucleotides for targeting GBM are investigated. LXR agonists synergize with sHDL nanodiscs by increasing the expression of the ABCA1 cholesterol efflux transporter, resulting in further depletion of cholesterol reserves within tumors, and CpG oligonucleotides are established adjuvants used in cancer immunotherapy that work through the toll-like receptor 9 pathway. In the present study, treatment with GW-CpG-sHDL nanodiscs increases the expression of cholesterol efflux transporters on murine GL261 cells leading to enhanced cholesterol removal. Experiments in GL261-tumor-bearing mice reveal combining GW-CpG-sHDL nanodiscs with radiation (IR) therapy significantly increases median survival compared to GW-CpG-sHDL or IR alone. Furthermore, 66% of long-term survivors from the GW-CpG-sHDL +IR treatment group show no tumor tissue when rechallenged.
Insights
This study shows that combining synthetic high-density lipoprotein (sHDL) nanodiscs with radiation therapy significantly improves survival for glioblastoma multiforme (GBM) brain tumors. The treatment also led to long-term survivors showing no tumor regrowth upon rechallenge.
Area of Science:
- Oncology
- Nanotechnology
- Immunotherapy
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- GBM relies on external cholesterol sources due to impaired endogenous cholesterol production.
- Targeting cholesterol metabolism presents a potential therapeutic strategy for GBM.
Purpose of the Study:
- To investigate the efficacy of synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists and CpG oligonucleotides for GBM treatment.
- To evaluate the combined effect of GW-CpG-sHDL nanodiscs and radiation therapy (IR) on GBM survival and tumor recurrence.
Main Methods:
- Utilized GW-CpG-sHDL nanodiscs engineered to target GBM by modulating cholesterol metabolism.
- Assessed the impact of GW-CpG-sHDL on cholesterol efflux transporter expression in murine GL261 cells.
- Evaluated the therapeutic effect of GW-CpG-sHDL combined with IR in GL261-tumor-bearing mice.
Main Results:
- GW-CpG-sHDL treatment enhanced cholesterol removal from GL261 cells by upregulating cholesterol efflux transporters.
- Combination therapy of GW-CpG-sHDL and IR significantly increased median survival in mice compared to monotherapies.
- A substantial proportion (66%) of long-term survivors exhibited no tumor tissue upon rechallenge, indicating durable immune response.
Conclusions:
- The combination of GW-CpG-sHDL nanodiscs and radiation therapy offers a promising therapeutic strategy for glioblastoma.
- Targeting cholesterol metabolism in conjunction with immunotherapy and radiation can induce significant anti-tumor effects and long-term survival.
- This approach may overcome GBM's reliance on external cholesterol and stimulate a robust anti-tumor immune response.
