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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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ABSTRACT 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 L...
Source: CONTINUUM: Lifelong Learning in Neurology - Category: Neurology Tags: Review Articles Source Type: research
AbstractBrain neoplasms constitute a group of tumors with discrete differentiation grades, and therefore, course of disease and prognosis. Magnetic resonance imaging (MRI) remains the gold standard method for the investigation of central nervous system tumors. However, MRI suffers certain limitations, especially if radiation therapy or chemotherapy has been previously applied. On the other hand, given the development of newer radiopharmaceuticals, positron emission tomography (PET) aims to a better investigation of brain tumors, assisting in the clinical management of the patients. In the present review, the potential cont...
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
Publication date: August 2017 Source:Biomedicine & Pharmacotherapy, Volume 92 Author(s): Komal Anjum, Bibi Ibtesam Shagufta, Syed Qamar Abbas, Seema Patel, Ishrat Khan, Sayed Asmat Ali Shah, Najeeb Akhter, Syed Shams ul Hassan 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...
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
CONCLUSIONS: Since the last version of this review, no new studies have been identified for inclusion and currently there are no RCTs or CCTs available on which to base definitive clinical decisions. Therefore, physicians must approach each case individually and weigh the risks and benefits of each intervention until further evidence is available. Some retrospective studies and non-randomized prospective studies do seem to suggest improved OS and seizure control correlating to higher extent of resection. Future research could focus on RCTs to determine outcomes benefits for biopsy versus resection. PMID: 28447767 [Pub...
Source: Cochrane Database of Systematic Reviews - Category: Journals (General) Authors: Tags: Cochrane Database Syst Rev Source Type: research
Abstract Malignant glioma is one of the most challenging central nervous system diseases to treat, and has high rates of recurrence and mortality. The current therapies include surgery, radiation therapy, and chemotherapy, although these approaches often failed to control tumor progression or improve patient survival. Sonodynamic therapy is a developing cancer treatment that uses ultrasound combined with a sonosensitizer to synergistically kill tumor cells, and has provided impressive results in both in vitro and in vivo studies. The ultrasound waves can penetrate deep tissues and reversibly open the blood-brain b...
Source: Ultrasonics Sonochemistry - Category: Chemistry Authors: Tags: Ultrason Sonochem Source Type: research
We examined outcomes of glioblastoma in patients
Source: Neurology - Category: Neurology Authors: Tags: Neuro-oncology: Gliomas I Source Type: research
CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM. PMID: 27903197 [PubMed - in process]
Source: Journal of Neurosurgery - Category: Neurosurgery Authors: Tags: J Neurosurg Source Type: research
Cancer remains one of the leading causes of death worldwide. Amongst other treatment methods, such as surgery and chemotherapy, the use of radiation in the treatment of cancer remains the most prominent and successful modality [1]. The sensitive treatment of brain tumours (such as inoperable gliomas), with wide, and unsegmented radiotherapeutic beams, impart unavoidable yet clinically unacceptable damage to vital central nervous system (CNS) tissues [2,3]. Microbeam radiation therapy (MRT) may provide a solution to achieve tumour control and normal tissue sparing.
Source: Physica Medica: European Journal of Medical Physics - Category: Journals (General) Authors: Tags: Original paper Source Type: research
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