Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma.

Preclinical analysis of MTOR complex 1/2 inhibition in diffuse intrinsic pontine glioma. Oncol Rep. 2017 Nov 29;: Authors: Flannery PC, DeSisto JA, Amani V, Venkataraman S, Lemma RT, Prince EW, Donson A, Moroze EE, Hoffman L, Levy JMM, Foreman N, Vibhakar R, Green AL Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy. We assessed the effects of each compound on the AKT pathway. Finally, we measured the efficacy of AZD2014 in combination with radiation therapy (RT) and a panel of FDA-approved chemotherapy drugs. While everolimus showed minimal antitumor efficacy, AZD2014 revealed IC50 levels of 410-552 nM and IC90 levels of 1.30-8.86 µM in the three cell lines. AZD2014 demonstrated increased inhibition of cell self-renewal compared to everolimus. AZD2014 decreased expression of phospho-AKT, while no such effect was noted with everolimus. Direct AKT inhibition showed si...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research

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Low-grade gliomas represent an important class of primary brain tumors. They account for approximately 20% of primary brain tumors and typically present in the fourth decade of life. Standard management gliomas involves observation, surgery, chemotherapy, and/or radiotherapy. Treatment decisions are based on many factors including prognostic molecular markers, potential benefits of increased progression-free survival, and potential long-term treatment complications. Recent studies have improved our understanding regarding therapeutic interventions. This review provides an overview of low-grade glioma and discusses the role...
Source: Neurosurgery Clinics of North America - Category: Neurosurgery Authors: Source Type: research
Publication date: Available online 24 October 2018Source: Interdisciplinary NeurosurgeryAuthor(s): Ryan Khanna, Bledi Brahimaj, Konstantin Tchalukov, Kayla Byrne, Owoicho Adogwa, Miral Jhaveri, Richard ByrneAbstractThe authors present the case of a patient who after undergoing craniotomy for glioblastoma resection was found to have gliosarcoma recurrence in the subdural space without intraparenchymal recurrence. A 74-year old man originally presented with the first seizure of his life and was found to have a right temporal glioblastoma multiforme. He underwent craniotomy and adjuvant chemotherapy and radiation therapy. Fiv...
Source: Interdisciplinary Neurosurgery - Category: Neurosurgery Source Type: research
CONCLUSIONS: This study establishes normative data for a model exploiting dogs with naturally occurring glioma, which can be used to test novel therapies prior to translation to human trials. Further work will focus on the effects of different therapies, including chemotherapy, radiation therapy, and immunotherapy. PMID: 30234401 [PubMed - as supplied by publisher]
Source: Cancer Investigation - Category: Cancer & Oncology Tags: Cancer Invest Source Type: research
ConclusionTrametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.
Source: Journal of Neuro-Oncology - Category: Cancer & Oncology Source Type: research
Authors: Puduvalli VK, Hoang N Abstract Malignant gliomas have been historically considered unresponsive to chemotherapy due to their intrinsic resistance to conventional anticancer medications and the role of the blood-brain barrier in preventing access of the cytotoxic agents to the tumor. However, recent studies have demonstrated the efficacy of specific drugs in subsets of patients with high-grade astrocytomas that has revived the enthusiasm for the role of systemic chemotherapy against these neoplasms. Temozolomide, a monofunctional alkylator, was the first chemotherapeutic agent to definitively improve surviv...
Source: Progress in Neurological Surgery - Category: Neurosurgery Tags: Prog Neurol Surg Source Type: research
Authors: Kortmann RD, Seidel C, Müller K, Hirsch FW Abstract Attainment of local control is a cornerstone in the management of brain tumors in children. Treatment of progressive low-grade and all high-grade gliomas traditionally includes resection followed by fractionated radiotherapy (FRT) or FRT alone in neoplasms not amenable to surgical removal. While in younger children chemotherapy is typically used as a first-line non-surgical management option, FRT in such patients remains the standard of salvage therapy. Recent improvements in techniques for radiation treatment planning and delivery allow conformal an...
Source: Progress in Neurological Surgery - Category: Neurosurgery Tags: Prog Neurol Surg Source Type: research
CONCLUSION Cognitive impairment can affect daily functioning, quality of life, and capacity to work in patients with cancer and those in remission. Consequently, cognitive assessment is now an important and necessary part of a comprehensive oncological care plan. Cancer-related cognitive impairment might be due to the direct effects of the cancer itself, nonspecific factors, or comorbid conditions that are independent of the disease and/or due to the adverse effects of the treatment or combination of treatments given for the disease. The prevalence and extent of cognitive impairment associated with cancer is recognized but...
Source: Innovations in Clinical Neuroscience - Category: Neuroscience Authors: Tags: Cognition Current Issue Neuro oncology Neurology Review cancer chemotherapy cognitive impairment neuropsychological assessment treatment Source Type: research
Brain tumors are common, requiring general medical providers to have a basic understanding of their diagnosis and management. The most prevalent brain tumors are intracranial metastases from systemic cancers, meningiomas, and gliomas, specifically, glioblastoma. Central nervous system metastases may occur anywhere along the neuroaxis, and require complex multidisciplinary care with neurosurgery, radiation oncology, and medical oncology. Meningiomas are tumors of the meninges, mostly benign and often managed by surgical resection, with radiation therapy and chemotherapy reserved for high-risk or refractory disease.
Source: The American Journal of Medicine - Category: General Medicine Authors: Tags: Review Source Type: research
Downregulation of miR‑205 is associated with glioblastoma cell migration, invasion, and the epithelial-mesenchymal transition, by targeting ZEB1 via the Akt/mTOR signaling pathway. Int J Oncol. 2018 Feb;52(2):485-495 Authors: Chen W, Kong KK, Xu XK, Chen C, Li H, Wang FY, Peng XF, Zhang Z, Li P, Li JL, Li FC Abstract Glioblastoma (GBM) is the most common type of malignant brain tumor. In spite of recent advancements in surgical techniques, chemotherapy, and radiation therapy, patients with GBM often face a dire prognosis. MicroRNAs have been shown to modulate the aggressiveness of various cancers, a...
Source: International Journal of Oncology - Category: Cancer & Oncology Authors: Tags: Int J Oncol Source Type: research
Purpose of Review: Low-grade gliomas present vexing management issues for neuro-oncologists. The relatively long survival compared to other brain tumors makes consideration of treatment toxicity, and thus timing of potentially damaging interventions such as surgery, radiation, and chemotherapy, crucial. Moreover, the rarity of these tumors makes clinical trials to ascertain optimal care challenging. Recent Findings: The discovery that most low-grade gliomas harbor isocitrate dehydrogenase (IDH) mutations that confer a favorable prognosis has improved diagnosis and risk stratification of these tumors. Although Level 1 evid...
Source: CONTINUUM: Lifelong Learning in Neurology - Category: Neurology Tags: Review Articles Source Type: research
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