- Novel analogs of sulfasalazine as system xc - antiporter inhibitors: Insights from the molecular modeling studies. [Journal Article]
- DDDrug Dev Res 2019 Jun 14
- System xc - (Sxc -), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases,…
System xc - (Sxc -), a cystine-glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc - . However, its pharmacological inhibition with novel and potent agents is still very much required due to potential issues, for example, potency, bioavailability, and blood-brain barrier (BBB) permeability, with the current lead molecules such as SSZ. Therefore, in this study, we report the synthesis and structure-activity relationships (SAR) of SSZ derivatives along with molecular docking and dynamics simulations using the developed homology model of xCT chain of Sxc - antiporter. The generated homology model attempted to address the limitations of previously reported comparative protein models, thereby increasing the confidence in the computational modeling studies. The main objective of the present study was to derive a suitable lead structure from SSZ eliminating its potential issues for the treatment of glioblastoma multiforme (GBM), a deadly and malignant grade IV astrocytoma. The designed compounds with favorable Sxc - inhibitory activity following in vitro Sxc - inhibition studies, showed moderately potent cytotoxicity in patient-derived human glioblastoma cells, thereby generating potential interest in these compounds. The xCT-ligand model can be further optimized in search of potent lead molecules for novel drug discovery and development studies.
- Oncogenic BRAF Alterations and Their Role in Brain Tumors. [Review]
- CCancers (Basel) 2019 Jun 08; 11(6)
- Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective…
Alterations of the v-raf murine sarcoma viral oncogene homolog B (BRAF) have been extensively studied in several tumor entities and are known to drive cell growth in several tumor entities. Effective targeted therapies with mutation-specific small molecule inhibitors have been developed and established for metastasized malignant melanoma. The BRAF V600E mutation and KIAA1549-BRAF fusion are alterations found in several brain tumors and show a distinct prognostic impact in some entities. Besides the diagnostic significance for the classification of central nervous system tumors, these alterations present possible therapy targets that may be exploitable for oncological treatments, as it has been established for malignant melanomas. In this review the different central nervous system tumors harboring BRAF alterations are presented and the diagnostic significance, prognostic role, and therapeutic potential are discussed.
- Total copy number variation as a prognostic factor in adult astrocytoma subtypes. [Journal Article]
- ANActa Neuropathol Commun 2019 Jun 10; 7(1):8
- Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade …
Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.
- Defining an Intermediate-risk Group for Low-grade Glioma: A National Cancer Database Analysis. [Journal Article]
- ARAnticancer Res 2019; 39(6):2911-2918
- CONCLUSIONS: Due to inferior OS for patients with LR-LGG with >5 cm, non-oligodendroglioma tumors, we propose an 'intermediate-risk' clinical classification for this subset.
- Clinical importance of molecular markers of adult diffuse glioma. [Journal Article]
- PNPract Neurol 2019 Jun 06
- In 2016, the WHO incorporated molecular markers, in addition to histology, into the diagnostic classification of central nervous system (CNS) tumours. This improves diagnostic accuracy and prognostic…
In 2016, the WHO incorporated molecular markers, in addition to histology, into the diagnostic classification of central nervous system (CNS) tumours. This improves diagnostic accuracy and prognostication: oligo-astrocytoma no longer exists as a clinical entity; isocitrate dehydrogenase (IDH) mutant and 1p/19q co-deleted oligodendroglioma is a smaller category with better prognosis; IDH wild-type 'low-grade' glioma has a much poorer prognosis; and glioblastoma is divided into IDH mutant (with an better prognosis than pre-2016 glioblastoma) and IDH wild type (with a poorer prognosis). Previous advice based on phenotype alone will change with respect to median survival, best management plan and response to treatment. There are implications for routine neuropathology reporting and future trial design. Cases that are difficult to classify may need more advanced molecular genetic classification through DNA methylation-based classification of CNS tumours (Heidelberg Classifier). We discuss the practical implications.
- Sensitive detection of FGFR1 N546K mosaic mutation in patient with encephalocraniocutaneous lipomatosis and pilocytic astrocytoma. [Case Reports]
- AJAm J Med Genet A 2019 Jun 07
- Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder, with only about 100 cases reported worldwide. It is characterized by congenital lesions of the eye, skin, and central ne…
Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder, with only about 100 cases reported worldwide. It is characterized by congenital lesions of the eye, skin, and central nervous system. Only recently, potential causative FGFR1 point mutations have been identified in brain tumors and cultured skin biopsies from patients with this condition. Here, we analyzed the molecular status of a patient with ECCL and a coexisting pilocytic astrocytoma with detected FGFR1 N546K mutation. The presence of the alteration in both affected and unaffected tissues has been evaluated using Sanger sequencing and droplet digital polymerase chain reaction (ddPCR) technique. The ddPCR analysis showed differential distribution of the alteration in all specimens, including unaffected and untreated samples. Therefore, we confirm that FGFR1 N546K is a plausible causative mutation of ECCL patients and could be associated with a risk of brain tumor development. We also show the usefulness of sensitive ddPCR method for detection of low levels of autosomal mosaic mutation in blood or swabs. We suggest that utilization of this method may improve the diagnostic process, especially when targeted therapies are considered.
- [The Efficacy of Everolimus for Refractory Seizures in Childhood Onset Epilepsy with Tuberous Sclerosis Complex]. [Journal Article]
- BNBrain Nerve 2019; 71(6):611-616
- Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has cytoreductive effects on subependymal giant cell astrocytoma and renal angiomyolipoma in tuberous sclerosis complex (TSC). Rece…
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has cytoreductive effects on subependymal giant cell astrocytoma and renal angiomyolipoma in tuberous sclerosis complex (TSC). Recent studies have also shown its efficacy against refractory seizures in TSC. We investigated the efficacy of everolimus in nine patients with TSC, who were admitted to the TSC clinic in Seirei Hamamatsu General Hospital and who suffered from refractory seizures. At the start of treatment, patients ranged from 1 month to 23 years of age, and were refractory to a mean of 5.4 antiepileptic agents. Main seizures were focal in six patients and generalized in three patients. After 0.5 to 4.0 years (mean=2.4 years), three patients (33%) were seizure-free and two patients (22%) experienced >90% reduction in seizures. Everolimus may therefore be effective in the treatment of refractory seizures in TSC. (Received February 20, 2019; Accepted April 2, 2019; Published June 1, 2019).
- Expression-based decision tree model reveals distinct microRNA expression pattern in pediatric neuronal and mixed neuronal-glial tumors. [Journal Article]
- BCBMC Cancer 2019 Jun 06; 19(1):544
- CONCLUSIONS: Our data showed the existence of miRNAs which expression is specific for different histological types of tumors. miRNA expression analysis may be useful in in-depth molecular diagnostic process of the tumors and could elucidate their origins and molecular background.
- PDQ Cancer Information Summaries: Childhood Astrocytomas Treatment (PDQ®): Health Professional Version [BOOK]
- BOOKNational Cancer Institute (US): Bethesda (MD)
- This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resou…
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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- Systematically characterize the clinical and biological significances of 1p19q genes in 1p/19q non-codeletion glioma. [Journal Article]
- CCarcinogenesis 2019 Jun 03
- 1p/19q codeletion, which leads to the abnormal expression of 1p19q genes in oligodendroglioma, is associated with chemosensitivity and favorable prognosis. Here, we aimed to explore the clinical impl…
1p/19q codeletion, which leads to the abnormal expression of 1p19q genes in oligodendroglioma, is associated with chemosensitivity and favorable prognosis. Here, we aimed to explore the clinical implications of 1p19q gene expression in 1p/19q non-codel gliomas. We analyzed expression of 1p19q genes in 668 1p/19q non-codel gliomas obtained from The Cancer Genome Atlas (TCGA) (n = 447) and the Chinese Glioma Genome Atlas (CGGA) (n = 221) for training and validation, respectively. The expression of 1p19q genes was significantly correlated with the clinicopathological features and overall survival (OS) of 1p/19q non-codel gliomas. Then, we derived a risk signature of 25 selected 1p19q genes that not only had prognosis value in total 1p/19q non-codel gliomas but also had prognosis value in stratified gliomas. The prognosis value of the risk signature was superior than known clinicopathological features in 1p/19q non-codel gliomas and was also highly associated with the following features: loss of CDKN2A/B copy number in mutant-IDH-astrocytoma; TERT promoter mutation, combined chromosome 7 gain / chromosome 10 loss, and EGFR amplification in wildtype-IDH-astrocytoma; Classical and Mesenchymal subtypes in glioblastoma. Furthermore, genes enriched in the biological processes of cell division, extracellular matrix, angiogenesis significantly correlated to the signature risk-score, and this is also supported by the immunohistochemistry and cell biology experiments. In conclusion, the expression profile of 1p19q genes is highly associated with the malignancy and prognosis of 1p/19q non-codel gliomas. A 25-1p19q-gene signature has powerfully predictive value for both malignant molecular pathological features and prognosis across distinct subgroups of 1p/19q non-codel gliomas.