Rewiring of cortical glucose metabolism fuels human brain cancer growth.

The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose use to drive aggressive growth remains unclear.

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism.

Preclinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-Wild-type Glioblastoma.

Purpose: Navtemadlin is a potent small-molecule inhibitor of MDM2, which has completed a phase 0 window-of-opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient-derived xenografts (PDX).

Experimental Design: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification.

Investigative needle core biopsies support multimodal deep-data generation in glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively.

A pathogenic subpopulation of human glioma associated macrophages linked to glioma progression.

Malignant gliomas follow two distinct natural histories: high grade tumors such as glioblastoma, or lower grade tumors with a propensity to transform into high grade disease. Despite differences in tumor genotype, both entities converge on a common histologically aggressive phenotype, and the basis for this progression is unknown. Glioma associated macrophages (GAM) have been implicated in this process, however GAMs are ontologically and transcriptionally diverse, rendering isolation of pathogenic subpopulations challenging.

Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.

Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e.

A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma.

Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of wild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients with wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg ( = 10) or 240 mg ( = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity.

GUK1 activation is a metabolic liability in lung cancer.

Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis.

Phase I Study of Adavosertib with Radiotherapy and Temozolomide in Newly Diagnosed Glioblastoma and Intratumoral Drug Levels in Recurrent Glioblastoma.

Purpose: Adavosertib is an oral small-molecule inhibitor of Wee1. The Adult Brain Tumor Consortium conducted a phase I study evaluating adavosertib in combination with radiation (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM), as well as a surgical window-of-opportunity study in recurrent GBM.

Patients And Methods: The MTD of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in two separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ.

Pooled Nanoparticle Screening Using a Chemical Barcoding Approach.

We report the development of a small molecule-based barcoding platform for pooled screening of nanoparticle delivery. Using aryl halide-based tags (halocodes), we achieve high-sensitivity detection via gas chromatography coupled with mass spectrometry or electron capture. This enables barcoding and tracking of nanoparticles with minimal halocode concentrations and without altering their physicochemical properties.

DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits.

Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi is critical to avoid unnecessary increased risk of normal tissue toxicity.

Pooled nanoparticle screening using a chemical barcoding approach.

We report the development of a small molecule-based barcoding platform for pooled screening of nanoparticle delivery. Using aryl halide-based tags (halocodes), we achieve high-sensitivity detection via gas chromatography coupled with mass spectrometry or electron capture. This enables barcoding and tracking of nanoparticles with minimal halocode concentrations and without altering their physicochemical properties.

Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma.

Unlabelled: We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact.

Dysregulation of ceramide metabolism causes phytoceramide-dependent induction of the unfolded protein response.

The unfolded protein response (UPR) detects and mitigates the harmful effects of dysregulated endoplasmic reticulum (ER) function. The UPR has been best characterized as a protein quality control response, and the sole UPR sensor in yeast, Ire1, is known to detect misfolded ER proteins. However, recent work suggests the UPR can also sense diverse defects within the ER membrane, including increased fatty acid saturation and altered phospholipid abundance.

DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.

DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma.

Unlabelled: Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins.

The Blood-Brain Barrier: Implications for Experimental Cancer Therapeutics.

The blood-brain barrier is critically important for the treatment of both primary and metastatic cancers of the central nervous system (CNS). Clinical outcomes for patients with primary CNS tumors are poor and have not significantly improved in decades. As treatments for patients with extracranial solid tumors improve, the incidence of CNS metastases is on the rise due to suboptimal CNS exposure of otherwise systemically active agents.

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS.

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment.

The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.

The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated.

Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.

Neuronal activity creates an intense energy demand that must be met by rapid metabolic responses. To investigate metabolic adaptations in the neuron-enriched dentate granule cell (DGC) layer within its native tissue environment, we employed murine acute hippocampal brain slices, coupled with fast metabolite preservation and followed by mass spectrometry (MS) imaging, to generate spatially resolved metabolomics and isotope-tracing data. Here we show that membrane depolarization induces broad metabolic changes, including increased glycolytic activity in DGCs.