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Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies. Glioblastoma patients are treated with Aurora kinase A (AURKA) inhibitors but resistance can occur. Here, the authors show that AURKA inhibition induces metabolic reprogramming, which leads to increased mitochondrial activity and inhibition of oxidative metabolism sensitizes glioblastoma cells to AURKA inhibition.

The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-X L and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-X L or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-X L and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-X L or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.

Cancer is a leading cause of death in both adults and children, but in terms of absolute numbers, pediatric cancer is a relatively rare disease. The rarity of pediatric cancer is consistent with our current understanding of how adult malignancies form, emphasizing the view of cancer as a genetic disease caused by the accumulation and selection of unrepaired mutations over time. However, considering those children who develop cancer merely as stochastically “unlucky” does not fully explain the underlying aetiology, which is distinct from that observed in adults. Here, we discuss the differences in cancer genetics, distribution, and microenvironment between adult and pediatric cancers and argue that pediatric tumours need to be seen as a distinct subset with their own distinct therapeutic challenges. While in adults, the benefit of any treatment should outweigh mostly short-term complications, potential long-term effects have a much stronger impact in children. In addition, clinical trials must cope with low participant numbers when evaluating novel treatment strategies, which need to address the specific requirements of children.

Background Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma. Methods Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM). Results ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM. Conclusion Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood–brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.

In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell‐to‐cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium‐enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell‐to‐cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM‐mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network. We draw an analogy between the proposed therapeutic outlook and the Alcatraz Federal Penitentiary, where inmates faced an impassable sea barrier and experienced both spatial and functional isolation within individual cells. Based on current translational efforts and ongoing clinical trials, we propose the Alcatraz‐Strategy as a promising framework to tackle the harmful effects of cellular brain tumour networks. This review introduces the ‘Alcatraz‐Strategy’ for malignant brain tumours, drawing parallels to Alcatraz's isolating barriers. By disrupting cellular tumour networks through supramarginal resection and targeted pharmacological therapy, it aims to decouple tumour cells, akin to the prison's spatial and functional inmate isolation. This approach offers a promising framework to counteract the malignant connectivity of brain tumour networks.

Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti‐proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U‐ 13 C‐glucose and U‐ 13 C‐glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up‐regulates pro‐apoptotic Noxa in an ATF4‐dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient‐derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies. Synopsis Liver‐X‐receptor agonists display limited anti‐tumor activity. The present study uncovers the synthetic lethality triggered by combining activation of liver‐X‐receptor and Bcl‐xL inhibition. Activation of LXR‐receptors resulted in suppression of gene‐sets related to mitochondrial translation, metabolism, transcription and regulators of intrinsic apoptosis associated, with an increase in cholesterol efflux signature. In the TCGA datasets, high levels of the LXR target ABCA1 correlated with low levels of group of genes related to mitochondrial transcription, translation and metabolism. Liver‐X‐receptors activation led to early reprogramming of oxidative energy metabolism, resulting in energy deprivation and solid tumor cells sensitization to glucose withdrawal. Suppression of the electron transport chain by LXRβ activation lowered the apoptotic threshold and sensitized solid tumor cells to the cytotoxic effects of BH3‐mimetics. The combination treatment of ABT263 and LXR623 reduced tumor growth in patient‐derived xenograft model systems. Graphical Abstract Liver‐X‐receptor agonists display limited anti‐tumor activity. The present study uncovers the synthetic lethality triggered by combining activation of liver‐X‐receptor and Bcl‐xL inhibition.

Vaccines are doubtlessly one of the most crucial life-saving medical interventions to date. However, perplexingly, they court more public controversy than their objectively excellent safety profile warrants. While doubts about the safety of vaccines, as well as opposition to vaccine policies, can be traced back at least to the mid-19th century, the modern anti-vaccine movement has come in 3 distinct waves, or generations, each precipitating around distinct key events. Here, we describe the first 2 generations and trace the origins of an emerging third generation anti-vaccine movement. Currently, this third generation is an integral part of the larger anti-COVID movement and in this more libertarian environment propagates the idea of individualism superseding the responsibility for community health. We highlight the need for a better science education of the young, as well as the general public to further enhance overall science literacy and suggests strategies to achieve these goals.

Glioblastoma cells rely on connexin 43 (Cx43)‐based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood–brain‐barrier‐penetrating drug with GJ‐inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence‐guided measurements of calcein cell‐to‐cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide‐stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR/Cas9‐mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3′ mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ‐mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO‐mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide‐induced cell death. CRISPR/Cas9 Cx43‐knockout revealed similar results, indicating that TO‐mediated inhibitory effects rely on the inhibition of Cx43‐based GJs. Gene set enrichment analyses found that GJ‐mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM‐based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ‐targeted therapeutic approach from bench to bedside. Tonabersat (TO) inhibits Cx43‐based gap junctions (GJs) in glioblastoma, leading to both functional and morphological breakdown of malignant cell‐to‐cell connectivity. This increases sensitivity to temozolomide (TMZ)‐induced cell death, reduces tumor cell proliferation, and enhances TMZ‐activated molecular pathways that drive growth arrest and apoptosis. TO's potential as a clinically feasible drug holds promise for advancing new therapeutic approaches in glioblastoma treatment.

Tumor organoid models have emerged as a promising tool in cancer research. By preserving intra- and intertumoral heterogeneity and structural integrity they provide a physiologically relevant platform for drug-response studies. However, valid methodological approaches for cell death analyses applying flow cytometry, particularly in complex, large organoids, are lacking. Using glioblastoma organoids (GBOs), we developed a flow cytometry protocol to quantify cell death as an important readout in cancer research. Human GBOs were generated out of tumor material from six patients. Temozolomide (TMZ) and lomustine (CCNU) were used as cytotoxic agents commonly employed in glioblastoma therapy. After treatment for 144 and 288 hours, single cell suspensions from densely-packed GBOs were generated through a combined approach of enzymatic and mechanical dissociation. Cells were permeabilized with Triton X and subsequently stained with propidium iodide (PI). PI staining labels fragmented nuclear DNA, yielding a hypodiploid sub-G1 peak in flow cytometry that markes cell death. After treatment for 288 hours with physiologically-relevant concentrations of TMZ and CCNU cell death rates reached up to 63% in our GBO model. Across three GBO populations, the impact of CCNU at the given concentration was more pronounced compared to that observed with TMZ and the cell death rates of treatment for 288 hours surpassed that of the 144-hour treatment. Both biological and technical replicates showed low variability. Hoechst 33258 staining on the same samples confirmed trends in cell death rates obtained from PI-based analysis. We further validated the treatment-induced effect using a plate-based lactate dehydrogenase release assay and measurements of GBO diameter. Our single-stain flow-cytometry protocol scales to large, dense organoids and provides a practical balance of performance, hands-on time, cost, specificity, and throughput. This protocol could support development and evaluation of subtype-specific therapeutic strategies in translational cancer research.