Pediatric Low-Grade Gliomas

Brain tumors constitute the largest source of oncologic mortality in children and low-grade gliomas are among most common pediatric central nervous system tumors. Pediatric low-grade gliomas differ from their counterparts in the adult population in their histopathology, genetics, and standard of care. Over the past decade, an increasingly detailed understanding of the molecular and genetic characteristics of pediatric brain tumors led to tailored therapy directed by integrated phenotypic and genotypic parameters and the availability of an increasing array of molecular-directed therapies. Advances in neuroimaging, conformal radiation therapy, and conventional chemotherapy further improved treatment outcomes. This article reviews the current classification of pediatric low-grade gliomas, their histopathologic and radiographic features, state-of-the-art surgical and adjuvant therapies, and emerging therapies currently under study in clinical trials

Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells

Background: Src family kinases (SFK) collectively regulate a variety of cellular functions in many cancer types, including proliferation, invasion, motility, survival, differentiation, and angiogenesis. Although Dasatinib (BMS-354825), an ATP-competitive, small molecule tyrosine kinase inhibitor, suppresses the activity of SFKs at nanomolar concentrations, IC50 values for antiproliferative effects in glioma cell lines were well above the clinically achievable range, suggesting the need to interfere with other components of receptor-induced downstream signaling in order to achieve an optimal therapeutic effect. Materials and Methods: The cytotoxic effects of combining Src and STAT3 inhibition on glioma cell lines were evaluated using assays to measure cell proliferation, apoptosis and migration. Western blotting and immunocytochemistry was used to monitor its effects on cell signaling and morphology. Results: Silencing Src and STAT3 expression each partially inhibited cell proliferation and migration. In addition, JSI - 124 significantly enhanced the efficacy of dasatinib in vitro. Combination of dasatinib and JSI - 124 achieved significant inhibition of migration in all cell lines, which correlated with the inhibition of Src and downstream mediators of adhesion (e.g. focal adhesion kinase). Cells exposed to dasatinib and JSI-124 exhibited morphological changes that were consistent with an upstream role for Src in regulating focal adhesion complexes. Conclusions: Targeting the Src and STAT pathways may contribute to the treatment of cancers that demonstrate increased levels of these signaling mediators, including malignant human glioma. Clinical studies in these tumor types are warranted

Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

Medulloblastoma, the most common pediatric malignant brain tumor, continues to have a high rate of morbidity and mortality in childhood. Recent advances in cancer genomics, single-cell sequencing, and sophisticated tumor models have revolutionized the characterization and stratification of medulloblastoma. In this review, we discuss heterogeneity associated with four major subgroups of medulloblastoma (WNT, SHH, Group 3, and Group 4) on the molecular and cellular levels, including histological features, genetic and epigenetic alterations, proteomic landscape, cell-of-origin, tumor microenvironment, and therapeutic approaches. The intratumoral molecular heterogeneity and intertumoral cellular diversity clearly underlie the divergent biology and clinical behavior of these lesions and highlight the future role of precision treatment in this devastating brain tumor in children

ABT-737 Synergizes with Bortezomib to Induce Apoptosis, Mediated by Bid Cleavage, Bax Activation, and Mitochondrial Dysfunction in an Akt-Dependent Context in Malignant Human Glioma Cell Lines

ABSTRACT We observed that glioma cells are differentially sensitive t

Planetary dynamics in stellar clusters

We investigate how the formation and evolution of extrasolar planetary systems can be affected by stellar encounters that occur in the crowded conditions of a stellar cluster. Using plausible estimates of cluster evolution, we show how planet formation may be supressed in globular clusters while planets wider than 0.1 AU that do form in such environments can be ejected from their stellar system. Less crowded systems such as open clusters have a much reduced effect on any planetary system. Planet formation is unaffected in open clusters and only the wider planetary systems will be disrupted during the cluster's lifetime. The potential for free-floating planets in these environments is also discussed.Comment: 8, pages, 6 figures. accepted by MNRA

Promise and challenges of peptide-poly: ICLC vaccines for adult and pediatric gliomas

We currently run phase I studies of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes emulsified in Montanide-ISA-51 and intramuscular administration of poly-ICLC in HLA-A2+ adult and pediatric patients with gliomas. Primary endpoints were safety and CD8+ T-cell responses against vaccine-targeted GAAs: IL-13Rα2, EphA2, Survivin and WT1 (WT1 in adults only). Adults with WHO grade 2 low-grade glioma (LGG) have an extremely high risk for transformation to high-grade glioma (HGG), and most patients eventually die of the disease. Because patients with LGGs may not be as immuno-compromised as patients with HGG, they may exhibit greater immunological response to and benefit from the vaccines. We conducted a phase I vaccine study with: newly diagnosed high-risk LGG without prior radiation therapy (RT) (Cohort 1); newly diagnosed high-risk LGG with prior RT (Cohort 2); or recurrent LGG (Cohort 3). Cohorts 1, 2, and 3 have enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity has been encountered except for one case with Grade 3 fever (Cohort 1). Cohort 1 patients demonstrated significantly higher magnitude of IFN-γ ELISPOT responses than Cohort 3 patients for all 4 GAA epitopes, suggesting that newly diagnosed patients may have better vaccine-responsiveness than recurrent patients. The magnitude of the IFN-γ ELISPOT responses in this study is significantly higher than that observed in our previous phase I/II study in HGG patients. Median progression-free survival (PFS) periods are 21 months (Cohort 1; range 10-44) and 12 months (Cohort 3; range 3-28). In Cohort 1, 3 patients are still progression-free (32, 33 and 44 months to date). The only patient with large astrocytoma in Cohort 2 has been progression-free for over 54 months since diagnosis. There was a positive trend for IFN-γ ELISPOT responses and PFS. Diffuse brainstem gliomas (BSGs) and other HGGs of childhood carry a dismal prognosis. To date, 24 children were enrolled, 14 with newly diagnosed BSG treated with RT, and 10 with newly diagnosed BSG or HGG treated with RT and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to corticosteroids and was associated with prolonged survival. Nineteen had stable disease for > 2 cycles, 2 had partial responses, and 1 had prolonged disease-free status after surgery. Median survival among the BSG cohort exceeded 13 months. ELISPOT analysis in 15 children showed GAA responses in 12, to IL-13Rα2 in 9, EphA2 in 7, and survivin in 7. Careful monitoring and management of pseudoprogression is warranted