Despite advances in molecularly characterizing glioblastoma (GBM), metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analysis coupling global metabolomic and gene expression profiling on patient-derived glioma identified fatty acid β-oxidation (FAO) as a metabolic node in GBM. We determined that the biologic consequence of enhanced FAO is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A dependent autocrine manner in nutrient favorable conditions, while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Rational combinatorial strategies designed to target these dynamic roles FAO plays in gliomagenesis resulted in necroptosis-mediated metabolic synthetic lethality in GBM. In summary, we identified FAO as a dominant metabolic node in GBM that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in GBM.

Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT). LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood-brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. .

Background: Ubiquitination-dependent proteasome degrades CRY1. However, the deubiquitination enzyme for CRY1 is unknown. Results: USP2a deubiquitinates and stabilizes CRY1 in vitro and in vivo. TNF-␣ stabilizes CRY1 via USP2a. Conclusion: USP2a functions to stabilize CRY1 during a circadian cycle and in response to TNF-␣ treatment. Significance: USP2a-dependent stabilization of CRY1 may mediate disruption of the clock function during inflammation.

Background:The epigenetic mechanism underlying E4BP4-dependent repression of hepatic Fgf21 during refeeding is unknown. Results: E4BP4 interacts with G9a, and knockdown of G9a by shRNA abolishes suppression of Fgf21 by refeeding in vivo. Conclusion: G9a is a co-repressor required for E4BP4-dependent repression of Fgf21 expression. Significance: G9a is a critical histone methyltransferase in E4BP4-dependent repression of Fgf21 during refeeding.

We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-␤ (A␤) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. A␤ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in A␤ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation may be beneficial in Alzheimer's disease.