Supratentorial High-Grade Astrocytoma and Diffuse Brainstem Glioma: Two Challenges for the Pediatric Oncologist

Broniscer, Alberto; Gajjar, Amar

doi:10.1634/theoncologist.9-2-197

Cited by 208 publications

(180 citation statements)

References 45 publications

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“…1 Therefore, novel therapeutic strategies for the treatment of this tumor, including the use of small-molecule inhibitors and novel drug delivery methods, continue to be investigated. Although innovative methods of drug delivery have been tested successfully in animals only, 26 several pediatric trials are already testing the efficacy or activity of novel biologic agents in children with newly diagnosed or progressive diffuse brainstem glioma.…”

Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

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100

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BACKGROUNDThe role of chemotherapy in the treatment of children with newly diagnosed diffuse brainstem glioma is uncertain. In the current study, the authors tested the efficacy of temozolomide treatment after radiotherapy (RT) in this setting.METHODSPatients ages 3–21 years were eligible for the current multiinstitutional study. An optional window therapy regimen consisting of 2 cycles of intravenous irinotecan (10 doses of 20 mg/m2 per day separated by 2 days of rest per cycle) was delivered over 6 weeks and was followed by conventionally fractionated RT. The 5‐day schedule of temozolomide (200 mg/m2 per day) was initiated 4 weeks after RT and was continued for a total of 6 cycles. The pharmacokinetics of temozolomide and its active metabolite, 5‐(3‐methyltriazen‐1‐yl)imidazole‐4‐carboxamide (MTIC), were analyzed during Cycles 1 and 3.RESULTSThirty‐three patients (median age at diagnosis, 6.4 years) were enrolled. Of the 16 patients who received window therapy, 6 had irinotecan treatment discontinued due to clinical progression (n = 5) or toxicity (n = 1); the remaining 10 experienced disease stabilization after 2 cycles. All patients completed RT (median dose, 55.8 gray). Twenty‐nine patients received a combined total of 125 cycles of temozolomide. Grade 3/4 neutropenia and thrombocytopenia occurred in 33% and 29% of all temozolomide cycles, respectively. In approximately one‐third of the cycles, dose reduction was required due to myelosuppression. No correlation was demonstrated between temozolomide/MTIC exposure and myelosuppression at the conclusion of Cycle 1. All patients died of disease progression (median survival, 12 months). The estimated 1‐year survival rate was 48% (standard error, 8%).CONCLUSIONSThe administration of temozolomide after RT did not alter the poor prognosis associated with newly diagnosed diffuse brainstem glioma in children. Cancer 2005. © 2004 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Broniscer

Iacono

Chintagumpala

et al. 2004

Cancer

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100

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“…Dysregulation of EGFR and downstream signaling events is found in a multitude of tumor types (3)(4)(5)(6). Therefore, targeting the tyrosine kinase activity of EGFR with small molecule inhibitors or targeting EGFR with antibodies has been a focus in the treatment of several tumors, including brain (glioblastoma), cervical, lung, and head and neck (squamous cell carcinoma).…”

Section: Receptor (Egfr) Egfr Is a Member Of The Receptor Tyrosine Kmentioning

confidence: 99%

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Duex

Comeau

Sorkin

et al. 2011

Journal of Biological Chemistry

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Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3-untranslated region (3-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects. We found that Usp18 depletion elevates miR-7 levels in several cancer cell lines because of a transcriptional activation and/or mRNA stabilization of miR-7 host genes and that miR-7 acts downstream of Usp18 to regulate EGFR mRNA translation via the 3-UTR. Also, depletion of Usp18 led to a decrease in protein levels of other known oncogenic targets of miR-7, reduced cell proliferation and soft agar colony formation, and increased apoptosis. Notably, all of these phenotypes were reversed by a specific inhibitor of miR-7. Thus, our findings support a model in which Usp18 inhibition promotes upregulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells.Despite advances in cancer treatments, improvement of overall patient survival remains poor. One of the primary reasons for this low success is the inherent complexity of oncogenic pathways such as those driven by the epidermal growth factor (EGF) 5 receptor (EGFR). EGFR is a member of the receptor tyrosine kinase (RTK) family. Upon binding of ligand, EGFR autophosphorylates at tyrosine residues and triggers an intracellular signal transduction cascade, which ultimately promotes cellular survival and division (1, 2). Dysregulation of EGFR and downstream signaling events is found in a multitude of tumor types (3-6). Therefore, targeting the tyrosine kinase activity of EGFR with small molecule inhibitors or targeting EGFR with antibodies has been a focus in the treatment of several tumors, including brain (glioblastoma), cervical, lung, and head and neck (squamous cell carcinoma). However, this strategy has resulted in minimal success. A major limitation of these approaches is that tumor cells eventually develop resistance to the current therapeutics. The resistance develops through increased ligand expression, additional somatic mutations in the EGFR tyrosine kinase domain, and increased heterodimerization with other RTKs (3, 7-9).As an alternative to developing approaches to directly inhibit EGFR signaling, our recent efforts focused on identifying allosteric modulators of EGFR protein levels. Inhibition of these modulators has the potential to significantly decrease EGFR protein levels irrespective of ligand levels or EGFR mutational status. Using a library of small interfering RNAs (siRNAs) that target deubiquitinase enzymes (DUBs), a class of proteins known to regulate receptor trafficking and expression (10 -12), we identified a number of candidate proteins which regulate EGFR prote...

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“…Thus far, the only consistent prognostic variable includes the total tumor removal independent of tumor location, patient age, and adjuvant treatment. [1][2][3] In order to optimize treatment strategies for pediatric glioblastoma patients, a more precise understanding of the cellular and molecular basis of this disease is clearly necessary. Over the past several years, a variety of numerical chromosomal abnormalities have been described in adult glioblastomas, including gain of chromosome 7, and deletions involving chromosomes 1, 9, 10 and 19.…”

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confidence: 99%

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

et al. 2005

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Astrocytic gliomas are the most common pediatric brain tumors; however, nonbrainstem glioblastomas are extremely rare compared with their adult counterparts. Little information is available on the clinical significance of various molecular markers in pediatric grade IV astrocytomas. The current study was focused on the molecular analysis and clinico-pathological correlations in a set of 44 tumor samples obtained from pediatric patients with nonbrainstem glioblastomas. Fluorescence in situ hybridization (FISH) with a set of 10 commercial chromosome probes (1p36, 1q25, centromere (CEP)7, EGFR, CEP9, 9p21/p16, CEP10, 10q23/PTEN, 19p13, and 19q13) was performed. Disclosed molecular abnormalities, in descending order of frequency, included polysomy 7 (72%), loss of 10q23 (61%), loss of 9p21 (52%), loss of 1p36 (41%), gain of 1q25 (25%), polysomy 9 (16%), EGFR amplification (9%), loss of 19q13 (5%), polysomy 19 (5%), and codeletion 1p36/19q13 (2%). The overall survival time was markedly shorter only for those patients whose lesions harbored deletion of 10q23/ PTEN locus (log-rank test; P ¼ 0.00007). By multivariate analysis, only loss of 10q23 locus reached an independent level of prognostic value (hazard ratio ¼ 2.88; P ¼ 0.01). There were no significant differences in patient survival for other molecular abnormalities. In conclusion, a FISH analysis of 10q23 dosage should be recommended as an ancillary laboratory method that allows further clinical subdivision of pediatric glioblastomas.

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Supratentorial High-Grade Astrocytoma and Diffuse Brainstem Glioma: Two Challenges for the Pediatric Oncologist

Cited by 208 publications

References 45 publications

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

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