Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex.
ABSTRACT Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Everolimus (starting dosage 3.0 mg/m(2)) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus. In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5 mg/m(2)) versus none of the placebo recipients (p < 0.0001) had an overall response (a reduction in the sum of all target SEGA volumes of ≥50% relative to baseline, nonworsening of non-target SEGA lesions, no new SEGA lesions, and no new/worsening hydrocephalus). Everolimus was generally well tolerated in patients with SEGA associated with TSC; most drug-related adverse reactions were mild to moderate in severity.
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ABSTRACT: Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40-60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.BioMed Research International 2015:394257. DOI:10.1155/2015/394257 · 2.71 Impact Factor
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ABSTRACT: The genetic disease tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by loss of function mutations in either TSC1 (hamartin) or TSC2 (tuberin), which serve as negative regulators of mechanistic target of rapamycin complex 1 (mTORC1) activity. TSC patients exhibit developmental brain abnormalities and tuber formations that are associated with neuropsychological and neurocognitive impairments, seizures and premature death. Mechanistically, TSC1 and TSC2 loss of function mutations result in abnormally high mTORC1 activity. Thus, the development of a strategy to inhibit abnormally high mTORC1 activity may have therapeutic value in the treatment of TSC. mTORC1 is a master regulator of growth processes, and its activity can be reduced by withdrawal of growth factors, decreased energy availability, and by the immunosuppressant rapamycin. Recently, glutamine has been shown to alter mTORC1 activity in a TSC1-TSC2 independent manner in cells cultured under amino acid- and serum-deprived conditions. Since starvation culture conditions are not physiologically relevant, we examined if glutamine can regulate mTORC1 in non-deprived cells and in a murine model of TSC. Our results show that glutamine can reduce phosphorylation of S6 and S6 kinase, surrogate indicators of mTORC1 activity, in both deprived and non-deprived cells, although higher concentrations were required for non-deprived cultures. When administered orally to TSC2 knockout mice, glutamine reduced S6 phosphorylation in the brain and significantly prolonged their lifespan. Taken together, these studies suggest that glutamine supplementation can be used as a potential treatment for TSC. Copyright © 2015. Published by Elsevier Inc.Biochemical and Biophysical Research Communications 01/2015; DOI:10.1016/j.bbrc.2015.01.039 · 2.28 Impact Factor
Article: Brain Metastases in Breast Cancer.[Show abstract] [Hide abstract]
ABSTRACT: Brain metastases are less common than bone or visceral metastases in patients with breast cancer. The overall prognosis of breast cancer patients with brain metastases remains poor, and these metastases are less responsive to systemic therapies. Brain metastasis is associated with a reduced quality of life due to progressive neurologic impairments. Recently, a trend of increased incidence of brain metastases in breast cancer has been noted. Reasons for this increased incidence include the more frequent use of sensitive detection methods such as contrast-enhanced magnetic resonance imaging and increased awareness of brain metastasis among patients and clinicians. Adjuvant and systemic therapy with drugs that have a low blood-brain barrier penetrance can lead to an increased risk of brain metastases in breast cancer patients. Molecular subtype is a predictive factor for overall survival after developing brain metastases. Patients who do not have a poor prognosis based on previously identified prognostic factors should be treated with radiation therapy to control symptoms. Whole-brain radiation therapy, stereotactic irradiation and surgery are tools for the local treatment of brain metastases. Novel molecular target therapy, including HER2-targeted therapy, has demonstrated an antitumor effect on brain metastases. In this review, we provide a practical algorithm for the treatment of breast cancer brain metastases. This review provides an overview of the incidence, risk factors, diagnosis, prognostic factors and current and potential future management strategies of breast cancer brain metastases.Japanese Journal of Clinical Oncology 10/2014; DOI:10.1093/jjco/hyu156 · 1.75 Impact Factor