The therapeutic potential of repurposed mebendazole, alone and in synergistic combination with ONC201, in the treatment of diffuse midline glioma.

H3K27-altered diffuse midline glioma (DMG) is a universally fatal disease with no available therapeutic strategies apart from palliative radiotherapy. Repurposing marketed non-cancer drugs in oncology is emerging as a fast-tracking approach to speed up the development of new treatment options, urgently needed for DMG. Repurposed anthelmintic mebendazole (MBZ) is in the spotlight against brain tumors, because it joins promising anticancer properties with high neuropenetrance, favorable pharmacokinetic and safety profile.

Spatial Analysis Identifies CD147 as a Novel Marker of High-Grade Childhood Posterior Fossa Ependymoma.

Ependymoma (EPN) is the third most common malignant tumor of the central nervous system in children. The spatial and temporal heterogeneity of cancer cell populations can impact the ability of EPN to overcome microenvironmental constraints. Data set analysis revealed that CD147 expression is increased in glioma, and its expression correlates with detrimental survival and higher mutational burden.

Drug Repurposing in Pediatric Brain Tumors: Posterior Fossa Ependymoma and Diffuse Midline Glioma under the Looking Glass.

Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research is needed to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. Increased attention is being paid to the repositioning of already-approved drugs for new anticancer indications as a fast-tracking strategy for identifying new and more effective therapies.

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma.

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states.

The BET Inhibitor OTX015 Exhibits In Vitro and In Vivo Antitumor Activity in Pediatric Ependymoma Stem Cell Models.

Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes.

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies.

Novel - Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens.

The basis for molecular and cellular heterogeneity in ependymomas of the central nervous system is not understood. This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI).

Ependymoma stem cells are highly sensitive to temozolomide in vitro and in orthotopic models.

Background: Ependymoma management remains challenging because of the inherent chemoresistance of this tumor. To determine whether ependymoma stem cells (SCs) might contribute to therapy resistance, we investigated the sensitivity of ependymoma SCs to temozolomide and etoposide.

Methods: The efficacies of the two DNA damaging agents were explored in two ependymoma SC lines in vitro and in vivo models.

Epigenetic Silencing of DKK3 in medulloblastoma.

Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK) 1-4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.

Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma.

The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small-cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia.

Effects of epidermal growth factor receptor blockade on ependymoma stem cells in vitro and in orthotopic mouse models.

Some lines of evidence suggest that tumors, including ependymoma, might arise from a subpopulation of cells, termed cancer stem cells (CSCs), with self-renewal and tumor-initiation properties. Given the strict dependence of CSCs on epidermal growth factor (EGF) through EGF receptor (EGFR), we investigated the effects of EGFR inhibitors in ependymoma-stem cells (SCs) in vitro and in orthotopic mouse models. We established two ependymoma-SC lines from two recurrent pediatric ependymoma.

Chromosome 9q and 16q loss identified by genome-wide pooled-analysis are associated with tumor aggressiveness in patients with classic medulloblastoma.

Medulloblastoma (MB) is one of the most aggressive pediatric brain tumor. We report genome-wide pooled-analysis of classic MB variant of patients over 3 years of age at diagnosis. We combined array comparative genomic hybridization (aCGH) results from experimental analysis (31 cases) with two public databases (55 cases) in a final evaluation of 86 MBs.

Dual Inhibitor AEE788 Reduces Tumor Growth in Preclinical Models of Medulloblastoma.

Medulloblastoma is the most frequent malignant pediatric brain tumor with a dismal prognosis in 30% of cases. We examined the activity of AEE788, a dual inhibitor of human epidermal receptor (HER) 1/2 and vascular endothelial growth factor receptor (VEGFR) 1/2, in medulloblastoma preclinical models. Established lines (Daoy and D283), chemoresistant (Daoy(Pt)), and ectopically HER2-overexpressing (Daoy(HER2)) cells expressed diverse levels of total and activated AEE788 target receptors.

Antitumor activity and pharmacokinetics of oral gimatecan on pediatric cancer xenografts.

Purpose: This study compared the antitumor activity and the pharmacological profile of gimatecan given orally and irinotecan (CPT-11) on pediatric tumor xenografts.

Experimental Design: Gimatecan was tested in two neuroblastoma cell lines (SK-N-DZ and SK-N-(BE)2c) and on TE-671 rhabdomyosarcoma cells using two different schedules. We characterized its pharmacokinetic profile in nude mice bearing human SK-N-DZ and TE-671 cell lines.

Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo.

The effects of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on cell growth and signaling were evaluated in three medulloblastoma (MB) cell lines (D283, D341, Daoy), one supratentorial primitive neuroectodermal tumor cell line (PFSK), and four MB primary cultures. Cell lines showed diverse expression of EGFR and human epidermal receptor 2 (HER2), with high levels of constitutively activated HER2 in the HER2-overexpressing D341 and D283 cells. Gefitinib sensitivity varied across lines and was not related to expression of HER receptors or receptor baseline activation.

Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib.

Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival.

Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation.

The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells.

Neprilysin participates in skeletal muscle regeneration and is accumulated in abnormal muscle fibres of inclusion body myositis.

Neprilysin (NEP, EP24.11), a metallopeptidase originally shown to modulate signalling events by degrading small regulatory peptides, is also an amyloid-beta- (Abeta) degrading enzyme. We investigated a possible role of NEP in inclusion body myositis (IBM) and other acquired and hereditary muscle disorders and found that in all myopathies NEP expression was directly associated with the degree of muscle fibre regeneration.

Antitumor activity of imatinib mesylate in neuroblastoma xenografts.

Imatinib mesylate has antitumor activity in vitro and in vivo against neuroblastoma cell lines and xenografts characterized by a different expression of receptor tyrosine kinases. In this article, we report that imatinib tumor concentration can be independent of the administered dose and does not correlate with the antitumor effect. In xenografts, high-dose administration does not improve imatinib efficacy.

The cellular response to PPARgamma ligands is related to the phenotype of neuroblastoma cell lines.

Neuroblastoma (NB) is a phenotypically heterogeneous tumor, displaying cells of neuronal, melanocytic, or glial/schwannian lineage. This cellular heterogeneity is also present in vitro, where cells of neuroblastic (N)- or stromal (S)-type may be identified. Ligands of peroxisome proliferator-activated receptor gamma (PPARgamma) have been shown to inhibit growth in different tumor cell lines.

The PPARgamma ligands PGJ2 and rosiglitazone show a differential ability to inhibit proliferation and to induce apoptosis and differentiation of human glioblastoma cell lines.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the control of cell proliferation, apoptosis and differentiation in various tumor cells. Among PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (PGJ2), the ultimate metabolite of PGD2, plays a role in the biology of brain tumors. It is still unclear to which extent the anti-proliferative and differentiation-promoting activity of PGJ2 is mediated through PPARgamma.

The protein tyrosine phosphatase SHP-2 negatively regulates ciliary neurotrophic factor induction of gene expression.

Ciliary neurotrophic factor, along with other neuropoietic cytokines, signals through the shared receptor subunit gp130 [1-3], leading to the tyrosine phosphorylation of a number of substrates [4,5], including the transcription factors STAT1 and STAT3 and the protein tyrosine phosphatase SHP-2 [6,7] [8]. SHP-2 (also known as PTP1D, SHPTP2, Syp and PTP2C) is a positive regulatory molecule required for the activation of the mitogen-activated protein kinase pathway and the stimulation of gene expression in response to epidermal growth factor, insulin and platelet-derived growth factor stimulation [9-11]. We have previously shown that cytokines that signal via the gp130 receptor subunit activate transcription of the vasoactive intestinal peptide (VIP) gene through a 180 bp cytokine response element (CyRE) [12,13].