HIGH GRADE GLIOMAS AND DIPG
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ABSTRACT:
SUBMITTER: Classen C
PROVIDER: S-EPMC4046287 | biostudies-literature | 2014 Jun
REPOSITORIES: biostudies-literature
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Project description:Abstract Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. The objective of this study was to evaluate the suitability of DNX-2401 as treatment for pHGG/DIPGs. Our results showed that DNX-2401 exerts a potent antitumor effect in pHGG (n=5) and DIPG (n=6) cell lines in vitro and in vivo. Our clinical trial experience with DNX-2401 in adult glioblastoma underscored the importance of the immune system in durable responses observed in patients. DNX-2401 administration in two DIPG immunocompent models was safe and without toxicity. DNX-2401 prolonged the overall survival, leading 20% to 80% of long-term survivors. Histologic examination showed that DNX-2401 stimulated T-cell infiltration (CD3+, CD4+ and CD8+; p<0.001) within the tumor. Esplenocytes from DNX-2401 treated-mice co-cultured with tumor cells significantly increase the IFNg production (p<0.0001). These outstanding preclinical results allowed us to open a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. Up to date 7 patients have been treated within the trial (3x1010viral particles in 1mL). The procedure was well tolerated and safe. Patients were home 3–4 days after the procedure. All the patients displayed a reduced tumor volume after combined treatment. In the next weeks, we will have information regarding the median survival. We are currently conducting molecular and functional studies to assess the response of the patients to the virus. Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumor patients.
| S-EPMC6477258 | biostudies-literature
Project description:In this issue of the Chinese Journal of Cancer, European experts review current standards, trends, and future prospects in the difficult domain of high-grade glioma. In all fields covered by the different authors, the progress has been impressive. For example, discoveries at the molecular level have already impacted imaging, surgery, radiotherapy, and systemic therapies, and they are expected to play an increasing role in the management of these cancers. The European Organization for Research and Treatment of Cancer (EORTC) has pioneered new treatment strategies and contributed to new standards. The articles in this issue will cover basic molecular biological principles applicable today, novel surgical approaches, innovations in radiotherapy planning and delivery, evidence-based standards for radiotherapy alone or combined with chemotherapy, current standards and novel approaches for systemic treatments, and the important but often neglected field of health-related quality of life. Despite the advances described in these articles, the overall prognosis of high-grade glioma, especially glioblastoma, remains poor, and more research is needed to address this problem.
| S-EPMC3905083 | biostudies-other
Project description:Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are a phenotypically diverse collection of tumours which molecular profiling studies have refined into age- and location-based subgroups driven by unique genetic and epigenetic alterations. Despite this, the rarity of these tumours means individual studies are underpowered to investigate subgroup-specific changes and to identify low frequency events recurrently targeting specific pathways. We have collated genomic data from 143 unpublished cases up to 30 years of age along with those from 18 previously published datasets in an integrated analysis comprising 1067 unique patients across all anatomical compartments of the CNS, with histone mutation status available for 893 cases (n=67 H3.3G34R/V, n=316 H3.3K27M, n=68 H3.1/H3.2K27M). Distinct clinicopathological and molecular subgroups are defined by these histone mutations, with several novel co-segregating mutations identified through these aggregated analyses, including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups can be further refined by the presence of key oncogenic events (PDGFRA or EGFR amplification/mutations) or methylation profiles which molecularly more closely resemble pleomorphic xanthoastrocytoma or other low grade gliomas. The burden of genomic aberrations decreases with age, highlighting the infant population as biologically and clinically distinct. Across the whole cohort, we identify novel previously unrecognised pathway dysregulation in small subsets of tumours (e.g. splicing, WNT, immune response) which make up the umbrella classification of paediatric diffusely infiltrating gliomas. The integrated dataset helps to further define the molecular diversity of the disease, opening up novel avenues for biological study and providing a basis for functionally defined future treatment stratification.
| EGAS00001002314 | EGA
Project description:High-grade gliomas, including glioblastoma, are the most common malignant brain tumors in adults. Despite intensive efforts to develop new therapies for these diseases, treatment options remain limited and prognosis is poor. Recently, there have been important advances in our understanding of the molecular basis of glioma, leading to refinements in our diagnostic and management approach. There is new evidence to guide the treatment of elderly patients. A multitude of new agents have been investigated, including targeted therapies, immunotherapeutics and tumor-treating fields. This review summarizes the key findings from this research, and presents a perspective on future opportunities to advance the field.
| S-EPMC6001673 | biostudies-literature
Project description:BackgroundLower-grade gliomas may be indolent for many years before developing malignant behavior. The mechanisms underlying malignant progression remain unclear.MethodsWe collected blocks of live human brain tissue donated by people undergoing glioma resection. The tissue blocks extended through the peritumoral cortex and into the glioma. The living human brain tissue was cut into ex vivo brain slices and bathed in 5-aminolevulinic acid (5-ALA). High-grade glioma cells avidly take up 5-ALA and accumulate high levels of the fluorescent metabolite, Protoporphyrin IX (PpIX). We exploited the PpIX fluorescence emitted by higher-grade glioma cells to investigate the earliest stages of malignant progression in lower-grade gliomas.ResultsWe found sparsely distributed "hot-spots" of PpIX-positive cells in living lower-grade glioma tissue. Glioma cells and endothelial cells formed part of the PpIX hotspots. Glioma cells in PpIX hotspots were IDH1 mutant and expressed nestin suggesting they had acquired stem-like properties. Spatial analysis with 5-ALA-conjugated quantum dots indicated that these glioma cells replicated adjacent to blood vessels. PpIX hotspots were formed in the absence of angiogenesis.ConclusionOur data show that PpIX hotspots represent microdomains of cells with high-grade potential within lower-grade gliomas and identify locations where malignant progression could start.
| S-EPMC8082133 | biostudies-literature
Project description:Glioblastoma (GBM) is the most common and fatal primary adult brain tumor. To date, various promising chemotherapeutic regimens have been trialed for use in GBM; however, temozolomide (TMZ) therapy remains the only US Food and Drug Administration-approved first-line chemotherapeutic option for newly diagnosed GBM. Despite maximal therapy with surgery and combined concurrent chemoradiation and adjuvant TMZ therapy, the median overall survival remains approximately 14 months. Given the failure of conventional chemotherapeutic strategies in GBM, there has been renewed interest in the role of immunotherapy in GBM. Dendritic cells are immune antigen-presenting cells that play a role in both the innate and adaptive immune system, thereby making them prime vehicles for immunotherapy via dendritic cell vaccinations (DCVs) in various cancers. There is great enthusiasm surrounding the use of DCVs for GBM with multiple ongoing trials. In this review, we comprehensively summarize the safety, efficacy, and quality of life results from 33 trials reporting on DCV for high-grade gliomas.
| S-EPMC6067774 | biostudies-literature
Project description:High grade gliomas represent one of the most aggressive and treatment-resistant types of human cancer, with only 1-2 years median survival rate for patients with grade IV glioma. The treatment of glioblastoma is a considerable therapeutic challenge; combination therapy targeting multiple pathways is becoming a fast growing area of research. This review offers an up-to-date perspective of the literature about current molecular therapy targets in high grade glioma, that include angiogenic signals, tyrosine kinase receptors, nodal signaling proteins and cancer stem cells related approaches. Simultaneous identification of proteomic signatures could provide biomarker panels for diagnostic and personalized treatment of different subsets of glioblastoma. Personalized medicine is starting to gain importance in clinical care, already having recorded a series of successes in several types of cancer; nonetheless, in brain tumors it is still at an early stage.
| S-EPMC3821381 | biostudies-literature
Project description:Pediatric high grade gliomas (HGG) are lethal tumors which are currently untreatable. A number of recent studies have provided much needed insights into the mutations and mechanisms which drive oncogenesis in pediatric HGGs. It is now clear that mutations in chromatin proteins, particularly H3.3 and its associated chaperone complex (ATRX), are a hallmark feature of pediatric HGGs. We review the current literature on the normal roles of the ATRX/H3.3 complex and how these functions are disrupted by oncogenic mutations. We discuss the current clinical trials and pre-clinical models that target chromatin and DNA, and how these agents fit into the ATRX/H3.3 mutation model. As chromatin mutations are a relatively new discovery in pediatric HGGs, developing clear mechanistic insights are a key step to improving therapies for these tumors.
| S-EPMC9853562 | biostudies-literature
Project description:BackgroundDespite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.MethodsUsing glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50).ResultsAmong 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).ConclusionWhile multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.
| S-EPMC10749203 | biostudies-literature
Project description:BackgroundHigh-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs.MethodsWe explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line.ResultsComparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG.ConclusionsOur results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.
| S-EPMC3895388 | biostudies-literature