scholarly journals NCCN Task Force Report: mTOR Inhibition in Solid Tumors

2008 ◽  
Vol 6 (S5) ◽  
pp. S-1-S-20 ◽  
Author(s):  
Robert A. Figlin ◽  
Elizabeth Brown ◽  
Andrew J. Armstrong ◽  
Wallace Akerley ◽  
Al B. Benson ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Intracellular Signaling ◽  
Cell Cycle Progression ◽  
Task Force ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Current Status ◽  
Mtor Inhibition ◽  
Task Force Report ◽  
Complex Functions

The mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation, and angiogenesis. These pathways are frequently dysregulated in cancer, and therefore mTOR inhibition is a potentially important antitumor target. Commercially available mTOR inhibitors include rapamycin (i.e., sirolimus) and temsirolimus. Other agents under investigation include everolimus and deforolimus. mTOR inhibition has been studied in various solid tumors, including breast, gynecologic, gastrointestinal, prostate, lung, and head and neck cancers. Studies have focused on mTOR inhibition as a monotherapy or in combination with other drugs based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance. Temsirolimus is currently the only mTOR inhibitor that is specifically labeled for treatment of solid tumors. However, preclinical studies and early-phase trials are rapidly evolving. Additionally, research is further defining the complicated mTOR pathways and how they may be disordered in specific malignancies. To address these issues, NCCN convened a task force to review the underlying physiology of mTOR and related cellular pathways, and to review the current status of research of mTOR inhibition in solid tumors. (JNCCN 2008;6[Suppl 5]:S1—S20)

scholarly journals mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3

2018 ◽  
Vol 115 (43) ◽  
pp. E10069-E10078 ◽  
Author(s):  
Guoli Shi ◽  
Stosh Ozog ◽  
Bruce E. Torbett ◽  
Alex A. Compton
Keyword(s):  
Influenza A ◽  
Lentiviral Vector ◽  
Sendai Virus ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Endosomal Trafficking ◽  
Mtor Inhibition ◽  
Rapamycin Treatment ◽  
Endosomal Sorting ◽  
Basal Expression

Rapamycin and its derivatives are specific inhibitors of mammalian target of rapamycin (mTOR) kinase and, as a result, are well-established immunosuppressants and antitumorigenic agents. Additionally, this class of drug promotes gene delivery by facilitating lentiviral vector entry into cells, revealing its potential to improve gene therapy efforts. However, the precise mechanism was unknown. Here, we report that mTOR inhibitor treatment results in down-regulation of the IFN-induced transmembrane (IFITM) proteins. IFITM proteins, especially IFITM3, are potent inhibitors of virus–cell fusion and are broadly active against a range of pathogenic viruses. We found that the effect of rapamycin treatment on lentiviral transduction is diminished upon IFITM silencing or knockout in primary and transformed cells, and the extent of transduction enhancement depends on basal expression of IFITM proteins, with a major contribution from IFITM3. The effect of rapamycin treatment on IFITM3 manifests at the level of protein, but not mRNA, and is selective, as many other endosome-associated transmembrane proteins are unaffected. Rapamycin-mediated degradation of IFITM3 requires endosomal trafficking, ubiquitination, endosomal sorting complex required for transport (ESCRT) machinery, and lysosomal acidification. Since IFITM proteins exhibit broad antiviral activity, we show that mTOR inhibition also promotes infection by another IFITM-sensitive virus, Influenza A virus, but not infection by Sendai virus, which is IFITM-resistant. Our results identify the molecular basis by which mTOR inhibitors enhance virus entry into cells and reveal a previously unrecognized immunosuppressive feature of these clinically important drugs. In addition, this study uncovers a functional convergence between the mTOR pathway and IFITM proteins at endolysosomal membranes.

scholarly journals PLASMA BIOMARKERS OF AD EMERGING AS ESSENTIAL TOOLS FOR DRUG DEVELOPMENT: AN EU/US CTAD TASK FORCE REPORT

2019 ◽  
pp. 1-5
Author(s):  
R.J. Bateman ◽  
K. Blennow ◽  
R. Doody ◽  
S. Hendrix ◽  
S. Lovestone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Task Force ◽  
Accurate Estimate ◽  
Current Status ◽  
The European Union ◽  
Neurofilament Light ◽  
Stakeholder Collaboration ◽  
Task Force Report

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer’s disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer’s Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.

Preliminary results of a phase I study of bevacizumab (BV) in combination with everolimus (E) in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3097-3097 ◽  
Author(s):  
Y. Zafar ◽  
J. Bendell ◽  
J. Lager ◽  
D. Yu ◽  
D. George ◽  
...  
Keyword(s):  
Side Effects ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Mammalian Target Of Rapamycin ◽  
Organ Transplant ◽  
Mtor Inhibitors ◽  
Clinical Activity ◽  
Solid Organ ◽  
Advanced Solid Tumors

3097 Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity. E is an mTOR (mammalian target of rapamycin) inhibitor in development for cancer and solid organ transplant therapy. VEGF and mTOR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination anti-angiogenesis therapy, we evaluated BV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: BV was dosed at 10mg/kg IV q14d. E was dosed at 5mg PO QD, escalating to 10mg QD. Cycle length was 28 days. DLT was defined as any grade 4 heme or grade 3/4 non-heme event in Cycle 1 related to treatment. Pts had advanced solid tumors, adequate organ function, and no increased risks for class-related toxicities. Serial blood samples were collected for PK studies of E. Dermal wound angiogenesis assays were performed pre and on treatment for phospho VEGFR2, AKT, mTOR, and S6K. Results: 14 pts have been enrolled (8 F, 6 M), 12 evaluable for toxicity, 14 for efficacy. Median age is 58y (range 29–73). At dose level 1 (BV 10mg/E 5mg) there were no DLT’s in 5 pts. At dose level 2 (BV 10mg/E 10mg), no DLT’s were noted in the initial 3 pts and the cohort was expanded to 9 pts. Side effects were primarily grade 1–2: pain (10/14), mucositis (9/14), anorexia (8/14), rash (7/14), bleeding (7/14), hyperlipidemia (6/14), fatigue (6/14), and HTN (4/14). 1 pt had a myocardial infarction at day 72 and one pt developed nephrotic syndrome at day 70. 7/14 pts had stable disease as best response (70–278d). Conclusions: BV + E is generally well-tolerated. Preliminary clinical activity and class-related side effects were noted. The recommended phase II dose is BV 10mg/kg IV q14d and E 10mg PO QD. [Table: see text]

scholarly journals Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro

2009 ◽  
Vol 16 (3) ◽  
pp. 1017-1027 ◽  
Author(s):  
Alexander Gorshtein ◽  
Hadara Rubinfeld ◽  
Efrat Kendler ◽  
Marily Theodoropoulou ◽  
Vesna Cerovac ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cyclin D1 ◽  
Pituitary Adenomas ◽  
Pituitary Tumor ◽  
Mammalian Target Of Rapamycin ◽  
Pituitary Tumors ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Gh3 Cells ◽  
Mtor Inhibition

The effect of mammalian target of rapamycin (mTOR) inhibitors on pituitary tumors is unknown. Akt overexpression was demonstrated in pituitary adenomas, which may render them sensitive to the anti-proliferative effects of these drugs. The objective of the study was to evaluate the anti-proliferative efficacy of the mTOR inhibitor, rapamycin, and its orally bioavailable analog RAD001 on the GH-secreting pituitary tumor GH3 and MtT/S cells and in human GH-secreting pituitary adenomas (GH-omas) in primary cell cultures. Treatment with rapamycin or RAD001 significantly decreased the number of viable cells and cell proliferation in a dose- and time-dependent manner. This was reflected by decreased phosphorylation levels of the downstream mTOR target p70S6K. Rapamycin treatment of GH3 cells induced G0/G1 cell cycle arrest. In other tumor cell types, this was attributed to a decrease in cyclin D1 levels. However, rapamycin did not affect cyclin D1 protein levels in GH3 cells. By contrast, it decreased cyclin D3 and p21/CIP, which stabilizes cyclin D/cyclin-dependent kinase 4 (cdk4) complexes. Rapamycin inhibited FCS-induced retinoblastoma phosphorylation and subsequent E2F-transcriptional activity. In response to decreased E2F activity, the expression of the E2F-regulated genes cyclin E and cdk2 was reduced. Our results showed that mTOR inhibitors potently inhibit pituitary cell proliferation, suggesting that mTOR inhibition may be a promising anti-proliferative therapy for pituitary adenomas. This therapeutic manipulation may have beneficial effects particularly for patients harboring invasive pituitary tumors resistant to current treatments.

scholarly journals Inhibition of mammalian target of rapamycin decreases intrarenal oxygen availability and alters glomerular permeability

2018 ◽  
Vol 314 (5) ◽  
pp. F864-F872 ◽  
Author(s):  
Ebba Sivertsson ◽  
Malou Friederich-Persson ◽  
Carl M. Öberg ◽  
Angelica Fasching ◽  
Peter Hansell ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Oxygen Consumption ◽  
Kidney Disease ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Oxygen Availability ◽  
Common Pathway ◽  
Glomerular Permeability ◽  
Mtor Inhibition ◽  
Large Molecules

An increased kidney oxygen consumption causing tissue hypoxia has been suggested to be a common pathway toward chronic kidney disease. The mammalian target of rapamycin (mTOR) regulates cell proliferation and mitochondrial function. mTOR inhibitors (e.g., rapamycin) are used clinically to prevent graft rejection. mTOR has been identified as a key player in diabetes, which has stimulated the use of mTOR inhibitors to counter diabetic nephropathy. However, the effect of mTOR inhibition on kidney oxygen consumption is unknown. Therefore, we investigated the effects of mTOR inhibition on in vivo kidney function, oxygen homeostasis, and glomerular permeability. Control and streptozotocin-induced diabetic rats were chronically treated with rapamycin, and the functional consequences were studied 14 days thereafter. In both groups, mTOR inhibition induced mitochondrial uncoupling, resulting in increased total kidney oxygen consumption and decreased intrarenal oxygen availability. Concomitantly, mTOR inhibition induced tubular injury, as estimated from urinary excretion of kidney injury molecule-1 (KIM-1) and reduced urinary protein excretion. The latter corresponded to reduced sieving coefficient for large molecules. In conclusion, mTOR inhibition induces mitochondrial dysfunction leading to decreased oxygen availability in normal and diabetic kidneys, which translates into increased KIM-1 in the urine. Reduced proteinuria after mTOR inhibition is an effect of reduced glomerular permeability for large molecules. Since hypoxia has been suggested as a common pathway in the development of chronic kidney disease, mTOR inhibition to patients with preexisting nephropathy should be used with caution, since it may accelerate the progression of the disease.

scholarly journals Inhibition of Mammalian Target of Rapamycin Induces Phosphatidylinositol 3-Kinase-Dependent and Mnk-Mediated Eukaryotic Translation Initiation Factor 4E Phosphorylation

2007 ◽  
Vol 27 (21) ◽  
pp. 7405-7413 ◽  
Author(s):  
Xuerong Wang ◽  
Ping Yue ◽  
Chi-Bun Chan ◽  
Keqiang Ye ◽  
Takeshi Ueda ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Mtor Inhibition ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

ABSTRACT The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors’ effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.

scholarly journals Inhibition of mammalian target of rapamycin (mTOR) improves neurobehavioral deficit and modulates inflammatory response after traumatic brain injury

2020 ◽  
Author(s):  
Irene Paterniti ◽  
Michela Campolo ◽  
Giovanna Casili ◽  
Marika Lanza ◽  
Alessia Filippone ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Function ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Brain Parenchyma ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Secondary Damage ◽  
Effective Therapeutic Strategy

Abstract Traumatic brain injury (TBI) induce primary and secondary damage on endothelium and brain parenchyma, leading neurons die rapidly by necrosis. The mammalian target of rapamycin signalling pathway (mTOR) mediates many aspects of cell growth and regeneration and is up-regulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signalling event for recovery of brain function is presently unclear, here we used two different selective inhibitors of mTOR activity to explore the functional role of mTOR inhibition in an validated model of TBI, the controlled cortical impact injury (CCI). We treated animals withKU0063794, a dual mTORC1 and mTORC2 inhibitor, and with rapamycin a well-known inhibitor of mTOR, 1 and 4 hours after TBI. Our results demonstrated that mTOR inhibitors, especially KU0063794, significantly improve motor and cognitive recovery after TBI as well as reduce lesion volumes. Moreover we observed that mTOR inhibitors treatment ameliorate the neuroinflammation associated to TBI and showed that this acute treatment significantly diminished the extent of neuronal death, astrogliosis and apoptotic process after trauma. Our findings suggest that the neuronal mTORC1/2 activity after TBI is deleterious to brain function and acute intervention with selective mTORC1/2 inhibitor may represent an effective therapeutic strategy to improve recovery after brain trauma.

scholarly journals Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hernán Trimarchi ◽  
Mariano Forrester ◽  
Fernando Lombi ◽  
Vanesa Pomeranz ◽  
Romina Iriarte ◽  
...  
Keyword(s):  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Primary Glomerulonephritis ◽  
Glomerular Proteinuria ◽  
Mesangioproliferative Glomerulonephritis ◽  
Stage Renal Disease ◽  
End Stage

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.

scholarly journals Hormone Therapy plus mTOR Inhibitors in the Treatment of Endometrial Carcinoma

2010 ◽  
Vol 9 (1) ◽  
pp. 18
Author(s):  
Erica M Stringer ◽  
Gini F Fleming ◽  
◽  
Keyword(s):  
Endometrial Cancer ◽  
Hormonal Therapy ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Hormonal Treatment ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Mtor Inhibition ◽  
Hormonal Therapies ◽  
Progestin Therapy

Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised that mTOR inhibition would enhance sensitivity to hormonal therapy.

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