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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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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
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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
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Source: CONTINUUM: Lifelong Learning in Neurology - Category: Neurology Tags: Review Articles Source Type: research
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Source: Annals of Nuclear Medicine - Category: Nuclear Medicine Source Type: research
Authors: Hashizume R Abstract Diffuse intrinsic pontine glioma (DIPG) is a rare but uniformly fatal cancer of the brain, with peak incidence in children of 5-7 years of age. In contrast to most types of human cancer, there has been no significant improvement in treatment outcomes for patients with DIPG. Since DIPG occurs in the brainstem, a vital region of the brain, there are no surgical options for providing relief to patients, and chemotherapy as well as radiation therapy provide palliative relief at best. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemothera...
Source: Neurologia Medico-Chirurgica - Category: Neurosurgery Tags: Neurol Med Chir (Tokyo) Source Type: research
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Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
Abstract Glioblastoma multiforme (GBM) is the deadliest form of heterogeneous brain cancer. It affects an enormous number of patients every year and the survival is approximately 8 to 15 months. GBM has driven by complex signaling pathways and considered as a most challenging to treat. Standard treatment of GBM includes surgery, radiation therapy, chemotherapy and also the combined treatment. This review article described inter and intra- tumor heterogeneity of GMB. In addition, recent chemotherapeutic agents, with their mechanism of action have been defined. FDA-approved drugs also been focused over here and most...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
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