Biom-112. Magmas Silencing Enhances the Efficacy to GBM Standard of Care: A Preclinical Study

Glioblastoma is a highly aggressive CNS cancer that affects 3 in 100,000 people annually in the U.S. Most patients experience recurrence within the first year after initial diagnosis, following standard of care. Treatment options are limited for patients suffering from recurrent GBM as tumors become resistant to chemotherapy. Resistance can be attributed to several factors, including DNA damage response (DDR), glioma stem cells (GSCs), tumor microenvironment (TME), cell cycle arrest, and metabolic reprogramming. Mitochondria-associated granulocyte macrophage colony-stimulating factor molecule (MAGMAS), a mitochondria protein and subunit of the translocase of the inner membrane 23 (TIM23) complex, regulates protein trafficking into the mitochondria by recruiting DNAJC19 to the TIM23 complex. Here, we investigated the role of MAGMAS in GBM tumor biology and mechanisms of temozolomide (TMZ) resistance. Computational analysis of MAGMAS/PAM16 expression levels from the CGGA and TCGA datasets revealed that MAGMAS levels are significantly elevated in recurrent tumors and positively correlate with MGMT expression in primary GBM patient tissues. We generated genetically modified glioma cells expressing shpam16 constructs and found that MAGMAS-deficient glioma cells were sensitized to standard of care treatment, which includes TMZ, radiation, and tumor-treating fields (TTFs). MAGMAS knockdown plus TMZ significantly increased overall survival compared to MAGMAS knockdown or TMZ alone in a mouse orthotopic glioma model. Additionally, we discovered that silencing PAM16/MAGMAS reduced MGMT expression and reduced extracellular excretion of lactic acid. Interestingly, we also discovered that the cytokine IL7 was significantly upregulated in MAGMAS KD cells. Taken together, our results demonstrate that MAGMAS plays a crucial role in chemotherapy resistance, metabolic reprogramming, and modulating the tumor microenvironment (TME). By targeting MAGMAS, we can promote favorable conditions to enhance anti-tumor responses using immunotherapy approaches in the future.