FASN Inhibition Overcomes Radiation Resistance and Potentiates Anti-PD-1 Therapy in Glioblastoma

Background & Unmet Need

• GBM incidence has risen over the past 15 years, yet median patient survival remains stagnant at 15 months
• Radiation therapy (RT) is the standard-of-care for the management of GBM and is the most widely used treatment for inoperable brain tumors
• GBM recurrence often arises within the irradiated margins, suggesting that RT can generate and/or exacerbate resistance mechanisms to support GBM progression
• Oxidative stressors, like reactive oxygen species (ROS) generated by RT, have been shown to reprogram the metabolism of an irradiated tumor which can promote the aggressivity of GBM
• Unmet Need: Development of novel therapeutic strategies targeting the metabolic escape pathways that drive GBM resistance to RT

Technology Overview

• The Technology: A combination therapy approach using radiation therapy, fatty acid synthase (FASN) inhibitors, and anti-PD-1 antibodies for treating GBM
• The Discovery: RT-induced fatty acid synthesis promotes GBM survival through both ER stress protection and immunosuppression via prostaglandin E2-mediated PD-1/PD-L1 upregulation.
• PoC Data: Triple combination therapy (RT+FASNi+anti-PD1) resulted in >100 days median survival compared to 24-45 days with single agents
• Triple combination therapy resulted in 85% long-term survival, significantly outperforming dual combination treatments which achieved only 30-40% survival rates.
• Triple combination therapy generated protective immune memory leading to long-term survival in surviving mice rechallenged with GBM

Technology Applications

• Primary treatment for newly diagnosed GBM
• Treatment for recurrent GBM
• Potential application in other cancers affected by lipid metabolism (melanoma, breast cancer, prostate cancer)

Technology Advantages

• Overcomes RT-induced resistance mechanisms
• Triggers long-lasting anti-tumor immunity
• Combines with existing standard-of-care treatments

Figure: FASNi in combination with focal radiation therapy and anti-PD-1
prolongs survival of GBM bearing mice.