bims-malgli 2024-09-29 papers

Sci Rep. 2024 09 20. 14(1): 21959

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress.

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

Keywords: Brain tumor; Cell migration; Enzyme inhibitor; Oxidative stress; Tumor metabolism

DOI: https://doi.org/10.1038/s41598-024-73051-1

Mol Oncol. 2024 Sep 26.

Rodent models of tumours of the central nervous system.

Sebastian Brandner.

Modelling of human diseases is an essential component of biomedical research, to understand their pathogenesis and ultimately, develop therapeutic approaches. Here, we will describe models of tumours of the central nervous system, with focus on intrinsic CNS tumours. Model systems for brain tumours were established as early as the 1920s, using chemical carcinogenesis, and a systematic analysis of different carcinogens, with a more refined histological analysis followed in the 1950s and 1960s. Alternative approaches at the time used retroviral carcinogenesis, allowing a more topical, organ-centred delivery. Most of the neoplasms arising from this approach were high-grade gliomas. Whilst these experimental approaches did not directly demonstrate a cell of origin, the localisation and growth pattern of the tumours already pointed to an origin in the neurogenic zones of the brain. In the 1980s, expression of oncogenes in transgenic models allowed a more targeted approach by expressing the transgene under tissue-specific promoters, whilst the constitutive inactivation of tumour suppressor genes ('knock out')-often resulted in embryonic lethality. This limitation was elegantly solved by engineering the Cre-lox system, allowing for a promoter-specific, and often also time-controlled gene inactivation. More recently, the use of the CRISPR Cas9 technology has significantly increased experimental flexibility of gene expression or gene inactivation and thus added increased value of rodent models for the study of pathogenesis and establishing preclinical models.

Keywords: CRISPR Cas9 system; Cre‐lox system; brain tumour; genetically modified mouse model; glioblastoma; medulloblastoma

DOI: https://doi.org/10.1002/1878-0261.13729

Nat Med. 2024 Sep 20.

High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity.

Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.

DOI: https://doi.org/10.1038/s41591-024-03224-y

Brain Tumor Pathol. 2024 Sep 24.

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma.

Naohide Fujita, Andrew Bondoc, Sergio Simoes, Joji Ishida, Michael S Taccone, Amanda Luck, Dilakshan Srikanthan, Robert Siddaway, Adrian Levine, Nesrin Sabha, Stacey Krumholtz, Akihide Kondo, Hajime Arai, Christian Smith, Paul McDonald, Cynthia Hawkins, Shoukat Dedhar, James Rutka.

Diffuse intrinsic pontine glioma (DIPG) remains a significant therapeutic challenge due to the lack of effective and safe treatment options. This study explores the potential of combining histone deacetylase (HDAC) and carbonic anhydrase 9 (CA9) inhibitors in treating DIPG. Analysis of RNA sequencing data and tumor tissue from patient samples for the expression of the carbonic anhydrase family and hypoxia signaling pathway activity revealed clinical relevance for targeting CA9 in DIPG. A synergy screen was conducted using CA9 inhibitor SLC-0111 and HDAC inhibitors panobinostat, vorinostat, entinostat, and pyroxamide. The combination of SLC-0111 and pyroxamide demonstrated the highest synergy and was selected for further analysis. Combining SLC-0111 and pyroxamide effectively inhibited DIPG cell proliferation, reduced cell migration and invasion potential, and enhanced histone acetylation, leading to decreased cell population in S Phase. Additionally, the combination therapy induced a greater reduction in intracellular pH than either agent alone. Data from this study suggest that the combination of SLC-0111 and pyroxamide holds promise for treating experimental DIPG, and further investigation of this combination therapy in preclinical models is warranted to evaluate its potential as a viable treatment for DIPG.

Keywords: CA9; Combination therapy; DIPG; HDAC inhibitor; Pyroxamide; SLC-0111

DOI: https://doi.org/10.1007/s10014-024-00493-w