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BioImpacts : BI 2024Neuroglioma, a classification encompassing tumors arising from glial cells, exhibits variable aggressiveness and depends on tumor grade and stage. Unraveling the EGFR...
INTRODUCTION
Neuroglioma, a classification encompassing tumors arising from glial cells, exhibits variable aggressiveness and depends on tumor grade and stage. Unraveling the EGFR gene alterations, including amplifications (unaltered), deletions, and missense mutations (altered), is emerging in glioma. However, the precise understanding of emerging EGFR mutations and their role in neuroglioma remains limited. This study aims to identify specific EGFR mutations prevalent in neuroglioma patients and investigate their potential as therapeutic targets using FDA-approved drugs for repurposing approach.
METHODS
Neuroglioma patient's data were analyzed to identify the various mutations and survival rates. High throughput virtual screening (HTVS) of FDA-approved (1615) drugs using molecular docking and simulation was executed to determine the potential hits.
RESULTS
Neuroglioma patient samples (n=4251) analysis reveals 19% EGFR alterations with most missense mutations at V774M in exon 19. The Kaplan-Meier plots show that the overall survival rate was higher in the unaltered group than in the altered group. Docking studies resulted the best hits based on each target's higher docking score, minimum free energy (MMGBSA), minimum kd, ki, and IC50 values. MD simulations and their trajectories show that compounds ZINC000011679756 target unaltered EGFR and ZINC000003978005 targets altered EGFR, whereas ZINC000012503187 (Conivaptan, Benzazepine) and ZINC000068153186 (Dabrafenib, aminopyrimidine) target both the EGFRs. The shortlisted compounds demonstrate favorable residual interactions with their respective targets, forming highly stable complexes. Moreover, these shortlisted compounds have drug- like properties as assessed by ADMET profiling.
CONCLUSION
Therefore, compounds (ZINC000012503187 and ZINC000068153186) can effectively target both the unaltered/altered EGFRs as multi-target therapeutic repurposing drugs towards neuroglioma.
PubMed: 38938756
DOI: 10.34172/bi.2023.28876 -
International Journal of Cancer Jun 2024Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance...
K channel targeting impairs DNA repair and invasiveness of patient-derived glioblastoma stem cells in culture and orthotopic mouse xenografts which only in part is predictable by K expression levels.
Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IK and BK Ca-activated K channels. Therefore, we analyzed here the effect of IK- and BK-targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K channel targeting. As a result, the IK- and BK-blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IK- and BK-expressing pGSC cultures, respectively. In addition, BK- but not IK-blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that K-blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy.
PubMed: 38938062
DOI: 10.1002/ijc.35064 -
Cancer Cell International Jun 2024Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes,...
BACKGROUND
Glioma is considered the most common primary malignant tumor of the central nervous system. Although traditional treatments have not achieved satisfactory outcomes, recently, targeted therapies for glioma have shown promising efficacy. However, due to the single-target nature of targeted therapy, traditional targeted therapies are ineffective; thus, novel therapeutic targets are urgently needed.
METHODS
The gene expression data for glioma patients were derived from the GEO (GSE4290, GSE50161), TCGA and CGGA databases. Next, the upregulated genes obtained from the above databases were cross-analyzed, finally, 10 overlapping genes (BIRC5, FOXM1, EZH2, CDK1, KIF11, KIF4A, NDC80, PBK, RRM2, and TOP2A) were ultimately screened and only KIF4A expression has the strongest correlation with clinical characteristics in glioma patients. Futher, the TCGA and CGGA database were utilized to explore the correlation of KIF4A expression with glioma prognosis. Then, qRT-PCR and Western blot was used to detect the KIF4A mRNA and protein expression level in glioma cells, respectively. And WZ-3146, the small molecule inhibitor targeting KIF4A, were screened by Cmap analysis. Subsequently, the effect of KIF4A knockdown or WZ-3146 treatment on glioma was measured by the MTT, EdU, Colony formation assay and Transwell assay. Ultimately, GSEA enrichment analysis was performed to find that the apoptotic pathway could be regulated by KIF4A in glioma, in addition, the effect of WZ-3146 on glioma apoptosis was detected by flow cytometry and Western blot.
RESULTS
In the present study, we confirmed that KIF4A is abnormally overexpressed in glioma. In addition, KIF4A overexpression is a key indicator of glioma prognosis; moreover, suppressing KIF4A expression can inhibit glioma progression. We also discovered that WZ-3146, a small molecule inhibitor of KIF4A, can induce apoptosis in glioma cells and exhibit antiglioma effects.
CONCLUSION
In conclusion, these observations demonstrated that targeting KIF4A can inhibit glioma progression. With further research, WZ-3146, a small molecule inhibitor of KIF4A, could be combined with other molecular targeted drugs to cooperatively inhibit glioma progression.
PubMed: 38937742
DOI: 10.1186/s12935-024-03409-y -
Cell Death & Disease Jun 2024Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of...
Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor's deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients' survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.
Topics: Glioblastoma; Humans; Tumor Suppressor Protein p53; Cellular Senescence; Cell Proliferation; Mutation; Cell Line, Tumor; Apoptosis; Brain Neoplasms; Temozolomide
PubMed: 38937431
DOI: 10.1038/s41419-024-06769-5 -
Journal of Neuro-oncology Jun 2024Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in...
PURPOSE
Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations.
METHODS
We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases.
RESULTS
Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations.
CONCLUSION
DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.
PubMed: 38937309
DOI: 10.1007/s11060-024-04733-z -
AJNR. American Journal of Neuroradiology Jun 2024Visually Accessible Rembrandt (Repository for Molecular Brain Neoplasia Data) Images (VASARI) features, a vocabulary to establish reproducible terminology for glioma...
BACKGROUND
Visually Accessible Rembrandt (Repository for Molecular Brain Neoplasia Data) Images (VASARI) features, a vocabulary to establish reproducible terminology for glioma reporting, have been applied for a decade, but a systematic performance evaluation is lacking.
PURPOSE
Our aim was to conduct a systematic review and meta-analysis of the performance of the VASARI features set for glioma assessment.
DATA SOURCES
MEDLINE, Web of Science, EMBASE, and the Cochrane Library were systematically searched until September 26, 2023.
STUDY SELECTION
Original articles predicting diagnosis, progression, and survival in patients with glioma were included.
DATA ANALYSIS
The modified Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was applied to evaluate the risk-of-bias. The meta-analysis used a random effects model and forest plot visualizations, if ≥5 comparable studies with a low or medium risk of bias were provided.
DATA SYNTHESIS
Thirty-five studies (3304 patients) were included. Risk-of-bias scores were medium ( = 33) and low ( = 2). Recurring objectives were overall survival ( = 18) and isocitrate dehydrogenase mutation (; = 12) prediction. Progression-free survival was examined in 7 studies. In 4 studies (glioblastoma = 2, grade 2/3 glioma = 1, grade 3 glioma = 1), a significant association was found between progression-free survival and single VASARI features. The single features predicting overall survival with the highest pooled hazard ratios were multifocality (hazard ratio = 1.80; 95%-CI, 1.21-2.67; I = 53%), ependymal invasion (hazard ratio = 1.73; 95% CI, 1.45-2.05; I = 0%), and enhancing tumor crossing the midline (hazard ratio = 2.08; 95% CI, 1.35-3.18; I = 52%). mutation-predicting models combining VASARI features rendered a pooled area under the receiver operating characteristic curve of 0.82 (95% CI, 0.76-0.88) at considerable heterogeneity (I = 100%). Combined input models using VASARI plus clinical and/or radiomics features outperformed single data-type models in all relevant studies ( = 17).
LIMITATIONS
Studies were heterogeneously designed and often with a small sample size. Several studies used The Cancer Imaging Archive database, with likely overlapping cohorts. The meta-analysis for was limited due to a high study heterogeneity.
CONCLUSIONS
Some VASARI features perform well in predicting overall survival and mutation status, but combined models outperform single features. More studies with less heterogeneity are needed to increase the evidence level.
PubMed: 38937115
DOI: 10.3174/ajnr.A8274 -
In Vivo (Athens, Greece) 2024Prognostic factors can facilitate treatment personalization in patients with glioblastoma multiforme (GBM). This study investigated different Glasgow prognostic scores...
BACKGROUND/AIM
Prognostic factors can facilitate treatment personalization in patients with glioblastoma multiforme (GBM). This study investigated different Glasgow prognostic scores (GPS) and the LabBM score in patients with GBM receiving chemoradiation following resection or biopsy.
PATIENTS AND METHODS
Four GPS versions, LabBM score, and 10 other factors were retrospectively investigated for progression-free survival (PFS) and overall survival (OS) in 86 patients. GPS versions included original GPS (oGPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), and high-sensitivity oGPS (HS-oGPS).
RESULTS
On multivariate analysis, higher oGPS was significantly associated with worse OS (p=0.006). On univariate analyses, trends were found for associations between higher mGPS and worse OS (p=0.098) and between higher LabBM scores and worse PFS (p=0.059).
CONCLUSION
The oGPS was an independent predictor of OS in patients receiving chemoradiation for GBM and can help personalizing the treatment for these patients. The LabBM score may be useful for predicting PFS.
Topics: Humans; Glioblastoma; Female; Male; Prognosis; Middle Aged; Chemoradiotherapy; Aged; Adult; Brain Neoplasms; Retrospective Studies; Aged, 80 and over; Treatment Outcome
PubMed: 38936935
DOI: 10.21873/invivo.13632 -
In Vivo (Athens, Greece) 2024Gliomas are highly heterogeneous malignancies originating from diverse cell types within the brain. Although their precise etiology is frequently unknown, risk factors,...
BACKGROUND/AIM
Gliomas are highly heterogeneous malignancies originating from diverse cell types within the brain. Although their precise etiology is frequently unknown, risk factors, such as chemical exposure, radiation, and specific uncommon genetic disorders have been identified. Diagnosis typically entails imaging tests, such as magnetic resonance imaging and computed tomography, complemented by a biopsy for confirmation, which may be further validated through genetic testing.
CASE REPORT
Next-generation sequencing technology revealed germline co-deletion deletion of cyclin-dependent kinase inhibitor 2 A and B genes (CDKN2A and CDKN2B) in a patient diagnosed with pleomorphic xanthoastrocytoma based on the tumor's molecular characteristics. Following this result, we performed focused genetic analysis with use of multiplex ligation-dependent probe amplification technology for the mother that revealed the same co-deletion. Moreover, due to the father's neuroendocrine pancreatic cancer, application of the NGS technology detected a pathogenic variant in the BRCA1-interacting helicase 1 (BRIP1) gene. Comprehensive multi-gene testing conducted within the familial context, marked by a varied spectrum of cancer type, revealed a constellation of genetic predispositions.
CONCLUSION
This case study underscores the critical importance of molecular testing for tumor characterization and highlights the pivotal role of genetic testing in facilitating early intervention and screening for at-risk family members. Furthermore, the identification of germline co-deletions in cancer lays the foundation for the development of targeted therapeutic strategies aimed at restoring normal cellular regulation and improving patient management.
Topics: Humans; Cyclin-Dependent Kinase Inhibitor p16; Astrocytoma; Cyclin-Dependent Kinase Inhibitor p15; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Genetic Predisposition to Disease; Male; Female; Adult; Brain Neoplasms; Pedigree; Magnetic Resonance Imaging; Gene Deletion
PubMed: 38936911
DOI: 10.21873/invivo.13617 -
European Journal of Cancer (Oxford,... Jun 2024Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric... (Review)
Review
Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.
PubMed: 38936103
DOI: 10.1016/j.ejca.2024.114145 -
JCO Precision Oncology Jun 2024The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II...
Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
PURPOSE
The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor.
METHODS
As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS).
RESULTS
Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with -altered CNS tumors achieved stable disease >6 months.
CONCLUSION
Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
Topics: Humans; Adolescent; Child; Female; Male; Young Adult; Child, Preschool; Neoplasms; Infant; United States; Mitogen-Activated Protein Kinases; National Cancer Institute (U.S.); MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38935895
DOI: 10.1200/PO.24.00103