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Cancer Research May 2024Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have...
Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the posttherapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by posttranslational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multiomics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of posttreatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.
Topics: Humans; Glioblastoma; Proteogenomics; Brain Neoplasms; Animals; Proto-Oncogene Proteins B-raf; Neoplasm Recurrence, Local; Mice; Temozolomide
PubMed: 38330148
DOI: 10.1158/0008-5472.CAN-24-0452 -
Molecular Oncology Sep 2023Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients...
Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. The standard treatment achieves a median overall survival for GBM patients of only 15 months. Hence, novel therapies based on an increased understanding of the mechanistic underpinnings of GBM are desperately needed. In this study, we show that elevated expression of 28S rRNA (cytosine-C(5))-methyltransferase NSUN5, which methylates cytosine 3782 of 28S rRNA in GBM cells, is strongly associated with the poor survival of GBM patients. Moreover, we demonstrate that overexpression of NSUN5 increases protein synthesis in GBM cells. NSUN5 knockdown decreased protein synthesis, cell proliferation, sphere formation, migration, and resistance to temozolomide in GBM cell lines. NSUN5 knockdown also decreased the number and size of GBM neurospheres in vitro. As a corollary, mice harboring U251 tumors wherein NSUN5 was knocked down survived longer than mice harboring control tumors. Taken together, our results suggest that NSUN5 plays a protumorigenic role in GBM by enabling the enhanced protein synthesis requisite for tumor progression. Accordingly, NSUN5 may be a hitherto unappreciated target for the treatment of GBM.
Topics: Animals; Mice; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Methyltransferases; RNA; RNA, Ribosomal, 28S; Temozolomide; Humans
PubMed: 37057706
DOI: 10.1002/1878-0261.13434 -
British Journal of Cancer Oct 2023Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ...
BACKGROUND
Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ).
METHODS
DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data.
RESULTS
Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets.
CONCLUSION
GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.
Topics: Humans; Temozolomide; Glioblastoma; Dacarbazine; Drug Evaluation, Preclinical; Glioma; Biomarkers; DNA; Brain Neoplasms; Drug Resistance, Neoplasm; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37620410
DOI: 10.1038/s41416-023-02402-y -
Scandinavian Journal of Clinical and... Dec 2023The aim of this study was to develop a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying dacarbazine levels in the plasma of...
The aim of this study was to develop a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying dacarbazine levels in the plasma of advanced melanoma patients, followed by an assessment of its analytical capabilities. The research encompassed the design of a high-performance liquid chromatography (HPLC) system, with the quantitative analysis performed using the multiple reaction monitoring (MRM) techniques and specific ion transition: 181.0 > 152.5 for dacarbazine and 187.1 > 158.6 for the internal standard (IS), dacarbazine-D6. The validation of the method involved an evaluation of parameters including linearity, detection limit, precision, and accuracy. Notably, the linear range extended from 10 to 1,000 µg/L for dacarbazine, and the method exhibited a detection limit of 10 µg/L. The method's precision, indicated by within-run and between-run coefficients of variation (CV), both being ≤4.2% and ≤8.3%, respectively. Furthermore, the accuracy of measurements, ranging from 86.1% to 99.4%, underscored the method's reliability. In clinical application, the dacarbazine levels of healthy control ( = 20) were 0.6 ± 0.02 μg/L; 770.9 ± 203.2 μg/mL in early-stage-melanoma patients ( = 22), and 588.7 ± 153.2 μg/mL in advanced melanoma patients ( = 25). The results serve as clinical evidence showing that long-term dacarbazine treatment affects the metabolism of dacarbazine.
Topics: Humans; Chromatography, Liquid; Melanoma; Tandem Mass Spectrometry; Dacarbazine; Reproducibility of Results; Chromatography, High Pressure Liquid
PubMed: 38145313
DOI: 10.1080/00365513.2023.2297356 -
Scientific Reports Aug 2023GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and...
GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.
Topics: Mice; Animals; Proto-Oncogene Proteins c-akt; Drug Resistance, Neoplasm; Temozolomide; Glioblastoma; Apoptosis; Mitogen-Activated Protein Kinase Kinases; Cell Line, Tumor; Brain Neoplasms
PubMed: 37528172
DOI: 10.1038/s41598-023-32983-w -
Cells Feb 2024Glioblastoma (GB) is a rare but extremely aggressive brain tumor that significantly impacts patient outcomes, affecting both duration and quality of life. The protocol... (Review)
Review
Glioblastoma (GB) is a rare but extremely aggressive brain tumor that significantly impacts patient outcomes, affecting both duration and quality of life. The protocol established by Stupp and colleagues in 2005, based on radiotherapy and chemotherapy with Temozolomide, following maximum safe surgical resection remains the gold standard for GB treatment; however, it is evident nowadays that the extreme intratumoral and intertumoral heterogeneity, as well as the invasiveness and tendency to recur, of GB are not compatible with a routine and unfortunately ineffective treatment. This review article summarizes the main challenges in the search for new valuable therapies for GB and focuses on the impact that extracellular vesicle (EV) research and exploitation may have in the field. EVs are natural particles delimited by a lipidic bilayer and filled with functional cellular content that are released and uptaken by cells as key means of cell communication. Furthermore, EVs are stable in body fluids and well tolerated by the immune system, and are able to cross physiological, interspecies, and interkingdom barriers and to target specific cells, releasing inherent or externally loaded functionally active molecules. Therefore, EVs have the potential to be ideal allies in the fight against GB and to improve the prognosis for GB patients. The present work describes the main preclinical results obtained so far on the use of EVs for GB treatment, focusing on both the EV sources and molecular cargo used in the various functional studies, primarily in vivo. Finally, a SWOT analysis is performed, highlighting the main advantages and pitfalls of developing EV-based GB therapeutic strategies. The analysis also suggests the main directions to explore to realize the possibility of exploiting EVs for the treatment of GB.
Topics: Humans; Glioblastoma; Quality of Life; Neoplasm Recurrence, Local; Temozolomide; Extracellular Vesicles
PubMed: 38391949
DOI: 10.3390/cells13040336 -
Frontiers in Endocrinology 2023Current guidelines recommend temozolomide as the first-line chemotherapy for aggressive pituitary neuroendocrine tumours. However, no clinical trials have been conducted...
Current guidelines recommend temozolomide as the first-line chemotherapy for aggressive pituitary neuroendocrine tumours. However, no clinical trials have been conducted to date and clinical experience is quite limited. We retrospectively analyzed 28 patients (9 women and 19 men), aged 46.6 + 16.9, with aggressive pituitary tumours (4 pituitary carcinomas and 24 aggressive adenomas) treated with temozolomide in 10 Spanish pituitary reference centres. Four patients had Cushing's disease, 9 prolactinomas and 15 clinically non-functioning pituitary tumours (seven silent corticotroph, three silent somatotroph, one silent lactotroph, one silent gondotroph and three null-cell tumours). Median size at diagnosis was 10.5 cm3 (IQR 4.7-22.5), with cavernous sinus invasion in 88% and no metastases. Pre-temozolomide treatment, these data were 5.2 cm3 (IQR 1.9-12.3), 89.3% and 14.3% (2 intracranial and 2 spinal metastases). All patients had undergone surgery (1-5 surgeries), 25 (89.3%) had received radiotherapy (7 of them reirradiated) and 13(46.4%) had received cabergoline. One patient interrupted temozolomide prematurely. The remaining 27 patients received a median of 13 cycles (range 3-66) of 5 days every 28 days, with a mean initial dose of 265 ± 73 mg when administered alone and of 133 ± 15 mg when co-administered with radiotherapy. Eight patients (29.6%) had a significant reduction (>30%) in tumour volume and 14 (51.9%) attained tumour stabilization. After a median follow-up of 29 months (IQR 10-55), 8 out of these 22 showed disease progression. A longer progression-free survival was found in the five patients who received concomitant radiotherapy. Seven patients (25%) died (all of them because of tumour progression or complications of treatments) at 77 months (IQR 42-136) after diagnosis and 29 months (IQR 16-55) after the first dose of temozolomide. Adverse effects occurred in 18 patients (14 mild and 4 moderate or severe). In conclusion, temozolomide is an effective medical treatment for aggressive pitNET and pituitary carcinomas but is sometimes followed by tumour progression. Co-administration with radiotherapy may increase progression-free survival.
Topics: Male; Humans; Female; Pituitary Neoplasms; Temozolomide; Neuroendocrine Tumors; Spain; Retrospective Studies; Pituitary Diseases
PubMed: 37720528
DOI: 10.3389/fendo.2023.1204206 -
Cancer Medicine Jan 2024Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease...
BACKGROUND
Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma.
METHODS
The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays.
RESULTS
α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability.
CONCLUSION
α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.
PubMed: 38189631
DOI: 10.1002/cam4.6900 -
Aging Dec 2023Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature...
Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature with infiltration of immunosuppressive cells and the expression levels of cytokines. Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. Efferocytosis plays a noticeable function in the formation of immunosuppressive environment. This study aimed to develop an efferocytosis-related prognostic model for GBM. The bioinformatic methods were utilized to analyze the transcriptomic data of GBM and normal samples. Clinical and RNA-seq data were sourced from TCGA database comprising 167 tumor samples and 5 normal samples, and 167 tumor samples for which survival information was available. Transcriptomic data of 1034 normal samples were collected from the Genotype-Tissue Expression (GTEx) database as a control sample supplement to the TCGA database. In the end, 167 tumor samples and 1039 normal samples were obtained for transcriptome analysis. Efferocytosis-related differentially expressed genes (ERDEGs) were obtained by intersecting 7487 differentially expressed genes (DEGs) between GBM and normal samples along with 1189 hub genes. Functional enrichment analyses revealed that ERDEGs were mainly involved in cytokine-mediated immune responses. Moreover, 9 prognosis-related genes (PRGs) were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis, and a prognostic model was therefore developed. The nomogram combining age and risk score could effectively predict GBM patients' prognosis. GBM patients in the high-risk group had higher immune infiltration, invasion, epithelial-mesenchymal transition, angiogenesis scores and poorer tumor purity. In addition, the high-risk group exhibited higher half maximal inhibitory concentration (IC50) values for temozolomide, carmustine, and vincristine. Expression analysis indicated that PRGs were overexpressed in GBM cells. PDIA4 knockdown reduced efferocytosis . In summary, the proposed prognostic model for GBM based on efferocytosis-related genes exhibited a robust performance.
Topics: Humans; Glioblastoma; Prognosis; Efferocytosis; Carmustine; Temozolomide; Cytokines; Tumor Microenvironment
PubMed: 38159261
DOI: 10.18632/aging.205422 -
Seminars in Neurology Dec 2023Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase...
Primary brain tumors underwent reclassification in the 2021 World Health Organization update, relying on molecular findings (especially isocitrate dehydrogenase mutations and chromosomal changes in 1p, 19q, gain of chromosome 7 and loss of chromosome 10). Newer entities have also been described including histone 3 mutant midline gliomas. These updated pathologic classifications improve prognostication and reliable diagnosis, but may confuse interpretation of prior clinical trials and require reclassification of patients diagnosed in the past. For patients over seventy, multiple studies have now confirmed the utility of shorter courses of radiation, and the risk of post-operative delirium. Ongoing studies are comparing proton to photon radiation. Long term follow up of prior clinical trials have confirmed the roles and length of chemotherapy (mainly temozolomide) in different tumors, as well as the wearable novottf device. New oral isocitrate dehydrogenase inhibitors have also shown efficacy in clinical trials.
Topics: Humans; Brain Neoplasms; Isocitrate Dehydrogenase; Glioma; Mutation; Temozolomide
PubMed: 38096849
DOI: 10.1055/s-0043-1776764