D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline/temozolomide.

Background: Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas. Methods: Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry. Results: The MTD of minocycline was 150 mg twice per day (N = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1. Conclusions: Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.

A time to build and a time to burn: glucose metabolism for every season.

Luengo et al. (2020) demonstrate that pyruvate dehydrogenase (PDH) overactivation blunts NAD+ regeneration by overcharging the mitochondrial membrane potential and driving ATP synthesis beyond demand. Under these conditions, some cells prioritize aerobic glycolysis to meet the need for oxidized cofactors in biosynthetic metabolism.

Biomarkers in Precision Cancer Immunotherapy: Promise and Challenges.

The rapid expansion of modern cancer immunotherapeutics has led to a dramatic improvement in patient survival and sustained remission for otherwise refractory malignancies. However, a significant limitation behind these current treatment modalities is an irregularity in clinical response, which is especially pronounced among checkpoint inhibition. This unpredictability leads to significant side effects, financial costs, and health care burden, with unsatisfactory clinical benefit in the majority of treated patients. Additionally, although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit. This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting. Herein, we discuss current advantages of predictive biomarkers, as well as limitations in their clinical use and application. We also review future directions, ideal characteristics, and trial design needed for proper precision immuno-oncology and biomarker development.

Crystal structure of Spot 14, a modulator of fatty acid synthesis.

Spot 14 (S14) is a protein that is abundantly expressed in lipogenic tissues and is regulated in a manner similar to other enzymes involved in fatty acid synthesis. Deletion of S14 in mice decreased lipid synthesis in lactating mammary tissue, but the mechanism of S14's action is unknown. Here we present the crystal structure of S14 to 2.65 Å and biochemical data showing that S14 can form heterodimers with MIG12. MIG12 modulates fatty acid synthesis by inducing the polymerization and activity of acetyl-CoA carboxylase, the first committed enzymatic reaction in the fatty acid synthesis pathway. Coexpression of S14 and MIG12 leads to heterodimers and reduced acetyl-CoA carboxylase polymerization and activity. The structure of S14 suggests a mechanism whereby heterodimer formation with MIG12 attenuates the ability of MIG12 to activate ACC.