Publications by authors named "Stephen V Carney"
Article Synopsis
- Mutant isocitrate dehydrogenase 1 (mIDH1) creates excess 2-hydroxyglutarate (2HG), leading to changes in gene expression and making mIDH1 gliomas more resilient to DNA damage and radiation.* -
- Research found mIDH1 glioma cells showed reduced mitochondrial metabolism and increased autophagy, which became their main energy source, indicating they rely heavily on autophagy for survival.* -
- Blocking autophagy weakened the growth of mIDH1 glioma cells and, when combined with radiation, enhanced treatment effectiveness, suggesting targeting autophagy could improve therapies for mIDH1 glioma patients.*
Purpose: Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR).
Experimental Design: We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198.
Article Synopsis
- Gliomas, particularly glioblastomas (GBM), are highly aggressive brain cancers, making up about 80% of central nervous system malignancies, with a median survival of less than 15 months for patients.
- Recent studies have identified crucial genetic factors such as mutations and methylation patterns that affect glioma classification and correlate with patient prognosis.
- The tumor microenvironment in gliomas fosters inflammation, immune suppression, and changes to the blood-brain barrier, which can worsen tumor progression and present new challenges for treatment.
Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies.
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- IDH1-R132H mutation is common in adult gliomas and is associated with specific genetic characteristics, such as mutations in TP53 and ATRX.
- Inhibiting the metabolite D-2HG from this mutation improves survival in glioma-bearing mice and enhances the immune response against tumors.
- Combining D-2HG inhibition with radiation, chemotherapy (temozolomide), and anti-PDL1 therapy showed promising results, leading to complete tumor regression in a significant percentage of mice, suggesting a potential new treatment strategy for certain glioma patients.