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Molecular Biotechnology Oct 2023Glioblastoma (GBM) is a malignant cancer that is fatal even after standard therapy and the effects of current available therapeutics are not promising due its complex... (Review)
Review
Glioblastoma (GBM) is a malignant cancer that is fatal even after standard therapy and the effects of current available therapeutics are not promising due its complex and evolving epigenetic and genetic profile. The mysteries that lead to GBM intratumoral heterogeneity and subtype transitions are not entirely clear. Systems medicine is an approach to view the patient in a whole picture integrating systems biology and synthetic biology along with computational techniques. Since the GBM oncogenesis involves genetic mutations, various therapies including gene therapeutics based on CRISPR-Cas technique, MicroRNAs, and implanted synthetic cells endowed with synthetic circuits against GBM with neural stem cells and mesenchymal stem cells acting as potential vehicles carrying therapeutics via the intranasal route, avoiding the risks of invasive methods in order to reach the GBM cells in the brain are discussed and proposed in this review. Systems medicine approach is a rather novel strategy, and since the GBM of a patient is complex and unique, thus to devise an individualized treatment strategy to tailor personalized multimodal treatments for the individual patient taking into account the phenotype of the GBM, the unique body health profile of the patient and individual responses according to the systems medicine concept might show potential to achieve optimum effects.
Topics: Humans; Glioblastoma; Brain Neoplasms; MicroRNAs; Systems Biology
PubMed: 36859639
DOI: 10.1007/s12033-023-00699-x -
Nanoscale Nov 2023Glioblastoma (GBM) is a challenging problem due to the poor BBB permeability of cancer drugs, its recurrence after the treatment, and high malignancy and is difficult to... (Review)
Review
Glioblastoma (GBM) is a challenging problem due to the poor BBB permeability of cancer drugs, its recurrence after the treatment, and high malignancy and is difficult to treat with the currently available therapeutic strategies. Furthermore, the prognosis and survival rate of GBM are still poor after surgical removal conventional combination therapy. Owing to the existence of the formidable blood-brain barrier (BBB) and the aggressive, infiltrating nature of GBM growth, the diagnosis and treatment of GBM are quite challenging. Recently, liposomes and their derivatives have emerged as super cargos for the delivery of both hydrophobic and hydrophilic drugs for the treatment of glioblastoma because of their advantages, such as biocompatibility, long circulation, and ease of physical and chemical modification, which facilitate the capability of targeting specific sites, circumvention of BBB transport restrictions, and amplification of the therapeutic efficacy. Herein, we provide a timely update on the burgeoning liposome-based drug delivery systems and potential challenges in these fields for the diagnosis and treatment of brain tumors. Furthermore, we focus on the most recent liposome-based drug delivery cargos, including pH-sensitive, temperature-sensitive, and biomimetic liposomes, to enhance the multimodality in imaging and therapeutics of glioblastoma. Furthermore, we highlight the future difficulties and directions for the research and clinical translation of liposome-based drug delivery. Hopefully, this review will trigger the interest of researchers to expedite the development of liposome cargos and even their clinical translation for improving the prognosis of glioblastoma.
Topics: Humans; Liposomes; Glioblastoma; Drug Delivery Systems; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms
PubMed: 37937394
DOI: 10.1039/d3nr04241c -
JAMA Dermatology Oct 2023Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.
IMPORTANCE
Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.
OBJECTIVE
To estimate the prevalence and describe the tumor types of MAS.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023.
MAIN OUTCOMES AND MEASURES
Disease prevalence and tumor frequency.
RESULTS
Prevalence of MAS ranged from 1 in 170 503 (n = 1 case; 95% CI, 1:30 098-1:965 887) in Geisinger MyCode (n = 170 503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39 149 (n = 12 cases; 95% CI, 1:22 396-1:68 434) in UK Biobank (n = 469 789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene.
CONCLUSIONS AND RELEVANCE
This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.
Topics: Humans; Female; Middle Aged; Aged; Male; Melanoma; Neurofibromatosis 1; Retrospective Studies; Cohort Studies; Prevalence; Skin Neoplasms; Astrocytoma; Neurilemmoma; Phenotype; Brain Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Melanoma, Cutaneous Malignant
PubMed: 37585199
DOI: 10.1001/jamadermatol.2023.2621 -
Life Sciences Oct 2023Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and...
Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and strategies to improve patient outcomes. In this study, we explored the tumor microenvironment and discovered unique characteristics of microglia to interact with astrocytoma cells and promote proliferation and migration of collisions. The conditioned medium from the collisions expressed cell chemoattraction and anti-inflammatory responses. To further understand the interactions between microglia and astrocytoma cells, we used flow sorting and protein analysis found that the protein alterations were related to biogenesis in the astrocytoma cells and metabolic processes in the microglia. Both types of cells were involved in binding and activity in cell-cell interactions. Using STRING to demonstrate the protein cross-interaction between the cells. Furthermore, PHB and RDX interact with oncogenic proteins, which were significantly expressed in patients with Glioblastoma Multiforme (GBM) and low-grade glioma (LGG) according to GEPIA. To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment.
Topics: Mice; Animals; Microglia; Multiomics; Astrocytoma; Glioma; Glioblastoma; Brain; Brain Neoplasms; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37419413
DOI: 10.1016/j.lfs.2023.121855 -
Journal of Neuro-oncology Aug 2023To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in... (Meta-Analysis)
Meta-Analysis Review
Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.
PURPOSE
To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma).
METHODS
The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models.
RESULTS
The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001).
CONCLUSION
Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.
Topics: Adult; Humans; Astrocytoma; Brain Neoplasms; Disease-Free Survival; Glioblastoma; Progression-Free Survival; Retrospective Studies
PubMed: 37561356
DOI: 10.1007/s11060-023-04409-0 -
The Journal of Pathology Jul 2023Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic...
Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.
Topics: Humans; Phosphatidylinositol 3-Kinases; Mutation; Astrocytoma; Glioma; Spinal Cord; RNA-Binding Proteins
PubMed: 37114614
DOI: 10.1002/path.6084 -
Antioxidants & Redox Signaling Nov 2023Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the... (Review)
Review
Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. . 39, 942-956.
Topics: Humans; Mutation; Glioma; Astrocytoma; Glioblastoma; Brain Neoplasms; Isocitrate Dehydrogenase
PubMed: 36852494
DOI: 10.1089/ars.2022.0085 -
Neuro-oncology Mar 2024Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy.... (Review)
Review
Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy. Integration of biologically informed multimodality imaging to address the spatial and temporal heterogeneity underlying treatment resistance in glioblastoma is now possible for patient care, with evidence of safety and potential benefit. Beyond their diagnostic utility, several candidate imaging biomarkers have emerged in recent early-phase clinical trials of biologically based radiotherapy, and their definitive assessment in multicenter prospective trials is already in development. In this review, the rationale for clinical implementation of candidate advanced magnetic resonance imaging and positron emission tomography imaging biomarkers to guide personalized radiotherapy, the current landscape, and future directions for integrating imaging biomarkers into radiotherapy for glioblastoma are summarized. Moving forward, response-adaptive radiotherapy using biologically informed imaging biomarkers to address emerging treatment resistance in rational combination with novel systemic therapies may ultimately permit improvements in glioblastoma outcomes and true individualization of patient care.
Topics: Humans; Glioblastoma; Prospective Studies; Radiation Oncology; Multimodal Imaging; Biomarkers; Multicenter Studies as Topic
PubMed: 38437666
DOI: 10.1093/neuonc/noad187 -
The Lancet. Child & Adolescent Health Jul 2023Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus...
BACKGROUND
Outcomes of recurrent paediatric high-grade glioma are poor, with a median overall survival of less than 6 months. Viral immunotherapy, such as the polio-rhinovirus chimera lerapolturev, is a novel approach for treatment of recurrent paediatric high-grade glioma and has shown promise in adults with recurrent glioblastoma. The poliovirus receptor CD155 is ubiquitously expressed in malignant paediatric brain tumours and is a treatment target in paediatric high-grade glioma. We aimed to assess the safety of lerapolturev when administered as a single dose intracerebrally by convection enhanced delivery in children and young people with recurrent WHO grade 3 or grade 4 glioma, and to assess overall survival in these patients.
METHODS
This phase 1b trial was done at the Duke University Medical Center (Durham, NC, USA). Patients aged 4-21 years with recurrent high-grade malignant glioma (anaplastic astrocytoma, glioblastoma, anaplastic oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic pleomorphic xanthoastrocytoma) or anaplastic ependymoma, atypical teratoid rhabdoid tumour, or medulloblastoma with infusible disease were eligible for this study. A catheter was tunnelled beneath the scalp for a distance of at least 5 cm to aid in prevention of infection. The next day, lerapolturev at a dose of 5 × 10 median tissue culture infectious dose in 3 mL infusate loaded in a syringe was administered via a pump at a rate of 0·5 mL per h as a one-time dose. The infusion time was approximately 6·5 h to compensate for volume of the tubing. The primary endpoint was the proportion of patients with unacceptable toxic effects during the 14-day period after lerapolturev treatment. The study is registered with ClinicalTrials.gov, NCT03043391.
FINDINGS
Between Dec 5, 2017, and May 12, 2021, 12 patients (11 unique patients) were enrolled in the trial. Eight patients were treated with lerapolturev. The median patient age was 16·5 years (IQR 11·0-18·0), five (63%) of eight patients were male and three (38%) were female, and six (75%) of eight patients were White and two (25%) were Black or African American. The median number of previous chemotherapeutic regimens was 3·50 (IQR 1·25-5·00). Six of eight patients had 26 treatment-related adverse events attributable to lerapolturev. There were no irreversible (ie, persisted longer than 2 weeks) treatment-related grade 4 adverse events or deaths. Treatment-related grade 3 adverse events included headaches in two patients and seizure in one patient. Four patients received low-dose bevacizumab on-study for treatment-related peritumoural inflammation or oedema, diagnosed by both clinical symptoms plus fluid-attenuated inversion recovery MRI. The median overall survival was 4·1 months (95% CI 1·2-10·1). One patient remains alive after 22 months.
INTERPRETATION
Convection enhanced delivery of lerapolturev is safe enough in the treatment of recurrent paediatric high-grade glioma to proceed to the next phase of trial.
FUNDING
Solving Kids Cancer, B+ Foundation, Musella Foundation, and National Institutes of Health.
Topics: Adult; Humans; Child; Male; Female; Adolescent; Glioblastoma; Rhinovirus; Neoplasm Recurrence, Local; Glioma; Brain Neoplasms; Immunotherapy; Astrocytoma; Poliomyelitis; Cerebellar Neoplasms
PubMed: 37004712
DOI: 10.1016/S2352-4642(23)00031-7 -
Cancer Letters Aug 2023Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT...
Radiation therapy (RT) is essential for the management of glioblastoma (GBM). However, GBM frequently relapses within the irradiated margins, thus suggesting that RT might stimulate mechanisms of resistance that limits its efficacy. GBM is recognized for its metabolic plasticity, but whether RT-induced resistance relies on metabolic adaptation remains unclear. Here, we show in vitro and in vivo that irradiated GBM tumors switch their metabolic program to accumulate lipids, especially unsaturated fatty acids. This resulted in an increased formation of lipid droplets to prevent endoplasmic reticulum (ER) stress. The reduction of lipid accumulation with genetic suppression and pharmacological inhibition of the fatty acid synthase (FASN), one of the main lipogenic enzymes, leads to mitochondrial dysfunction and increased apoptosis of irradiated GBM cells. Combination of FASN inhibition with focal RT improved the median survival of GBM-bearing mice. Supporting the translational value of these findings, retrospective analysis of the GLASS consortium dataset of matched GBM patients revealed an enrichment in lipid metabolism signature in recurrent GBM compared to primary. Overall, these results demonstrate that RT drives GBM resistance by generating a lipogenic environment permissive to GBM survival. Targeting lipid metabolism might be required to develop more effective anti-GBM strategies.
Topics: Animals; Mice; Glioblastoma; Retrospective Studies; Cell Line, Tumor; Neoplasm Recurrence, Local; Fatty Acids, Unsaturated; Fatty Acids
PubMed: 37499741
DOI: 10.1016/j.canlet.2023.216329