MTOR
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- MeSH
- imunosupresiva * škodlivé účinky MeSH
- inhibitory kalcineurinu terapeutické užití MeSH
- lidé MeSH
- mTOR inhibitory MeSH
- nádory kůže prevence a kontrola MeSH
- randomizované kontrolované studie jako téma MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory terapeutické užití MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
WHAT IS KNOWN AND OBJECTIVES: mTOR inhibitors possess narrow therapeutic range and substantial pharmacokinetic variability and the consequences from suboptimal dosing are serious. The aim of this review is to summarize the current knowledge about the factors influencing mTOR inhibitors pharmacokinetics and the possibility of using these relationships in order to improve its therapy individualization in solid organ transplanted patients. METHODS: Literature search from Pubmed and Web of Science databases were performed using Boolean search operators in order to identify relevant studies. RESULTS AND DISCUSSION: A total of 701 reports were identified from the initial literature search. Out of which 40 studies dealt with relationships between various factors and pharmacokinetics of mTOR inhibitors and with relevance of these associations for dosage optimization. WHAT IS NEW AND CONCLUSION: The overview of the current covariates for pharmacokinetic variability of mTOR inhibitors has been provided on the level of absorption, distribution and elimination, and consequences of these relationships for dosing optimization has been summarized.
- MeSH
- imunosupresiva MeSH
- lidé MeSH
- mTOR inhibitory MeSH
- sirolimus * farmakokinetika terapeutické užití MeSH
- TOR serin-threoninkinasy MeSH
- transplantace orgánů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Až u třech čtvrtin pacientek s nově diagnostikovaným karcinomem prsu je nacházena pozitivita hormonálních (HR), tj. estrogenových (ER) či progesteronových receptorů (PR). Podle doporučení ESMO by převážná většina pacientek s metastatickým HR-pozitivním karcinomem prsu měla být v 1. linii léčena hormonální léčbou, v praxi se však poměrně často setkáváme s primární či získanou rezistencí na tuto terapii. Slibným mechanismem k obnovení citlivosti nádorových buněk k hormonální léčbě se v preklinických studiích ukázala být blokáda dráhy mTOR – v klinických studiích byly následně zkoušeny sirolimus, temsirolimus i everolimus, přičemž jako nejvhodnější se z této trojice jeví everolimus. Ve studii BOLERO-2, do níž bylo zařazeno celkem 724 pacientek s ER-pozitivním HER2-negativním karcinomem prsu po selhání předchozí léčby nesteroidním inhibitorem aromatázy, vedla terapie everolimem v kombinaci s exemestanem ve srovnání se samotným exemestanem k signifikantnímu prodloužení přežití bez progrese onemocnění, pozorován byl i trend k prodloužení celkového přežití. Lze očekávat, že kombinace hormonální a cílené léčby inhibitorem mTOR se v budoucnu stane standardem léčby pacientek s metastatickým HR-pozitivním HER2-negativním karcinomem prsu.
Up to three fourth of patients newly diagnosed with breast cancer present with positive hormone receptors (HR), i. e. estrogen (ER) or progesterone receptors (PR). According to ESMO guidelines, the vast majority of patients with metastatic HR-positive breast cancer should receive hormonal therapy as first-line treatment, but primary or acquired resistance to this therapy has been a relatively common observation in practice. A mechanism to restore tumour cell sensitivity to hormonal treatment that has shown promise in preclinical trials is the blockade of the mTOR pathway – subsequent clinical trials tested sirolimus, temsirolimus as well as everolimus, with the most suitable of this trio being everolimus. The BOLERO-2 study that included a total of 724 patients with ER-positive HER2- -negative breast cancer after previous failure of non- -steroidal aromatase inhibitor found that therapy with everolimus combined with exemestane compared with exemestane alone resulted in significantly extended progression-free survival, and observed also a trend to extended overall survival. It may be expected that the combination of hormonal and targeted therapy with an mTOR inhibitor will become standard treatment in patients with metastatic HR-positive HER2-negative breast cancer.
- MeSH
- chemorezistence MeSH
- hodnocení léčiv MeSH
- imunosupresiva MeSH
- inhibitory aromatasy terapeutické užití MeSH
- klinické zkoušky, fáze II jako téma MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kombinovaná farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- nádory prsu * farmakoterapie MeSH
- neúspěšná terapie MeSH
- postmenopauza MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- senioři MeSH
- sirolimus * analogy a deriváty aplikace a dávkování farmakokinetika terapeutické užití toxicita MeSH
- TOR serin-threoninkinasy * antagonisté a inhibitory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
Tuberózní skleróza (komplex tuberózní sklerózy, TSC) je neurokutánní syndrom vznikající na podkladě zárodečné mutace genu TSC1 nebo TSC2. Výskyt TSC je přibližně 1 : 6000 narozených dětí. Pro TSC je charakteristický nález hamartogenních a nádorových lézí v centrální nervové soustavě a dalších orgánových systémech. V tumorigenezi subependymálního obrovskobuněčného astrocytomu (SEGA) i angiomyolipomu ledvin (AML) u pacientů s tuberózní sklerózou hraje klíčovou roli patologická aktivace proteinového komplexu mTORC1. Blokáda této signální dráhy užitím mTOR inhibitoru (everolimus) se ve studiích fáze 3 ukázala jako vysoce účinná léčba vedoucí ke zmenšení objemu SEGA i renálních AML. Filosofií dlouhodobého sledování osob s TSC je časná terapeutická intervence snižující morbiditu a mortalitu z důvodu přidružených symptomů a zvyšující kvalitu života.
Tuberous sclerosis (tuberous sclerosis complex, TSC) is a neurocutaneous syndrome that results from a germline mutation in TSC1 or TSC2 genes. An incidence of TSC is approximately 1 in 6000 live births. TSC is characterized by involvement of central nervous tissues and other organ systems. The pathogenic activation of mTORC1 leads to the development of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in TSC patients. Blocking this pathway using mTOR inhibitors has the potential to reduce the volume of SEGA and AML as documented in phase 3 studies. Long term follow-up and early therapeutical intervention should lead to the reduction of mortality and morbidity and quality of life improvement in TSC patients.
- MeSH
- angiomyolipom diagnóza farmakoterapie genetika MeSH
- astrocytom diagnóza farmakoterapie genetika MeSH
- dítě MeSH
- lidé MeSH
- neurokutánní syndromy farmakoterapie genetika komplikace MeSH
- protinádorové látky terapeutické užití MeSH
- sirolimus analogy a deriváty terapeutické užití MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory farmakologie MeSH
- tuberózní skleróza * diagnóza farmakoterapie komplikace MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Mechanistic target of rapamycin (mTOR) is a highly conserved protein kinase acting as a central regulator of cell functions. The kinase forms two distinct mTOR complexes termed as mTORC1 and mTORC2. Dysregulation of mTOR activity is associated with various pathological conditions. Inhibition of overactivated mTOR represent a rational approach in the treatment of numerous human diseases. Rapamycin is a potent natural inhibitor of mTOR exhibiting significant antitumor and immunosuppressive activity. Derivatization of rapamycin provided rapalogs, the first generation of mTOR inhibitors that selectively inhibit mTORC1 activity. Further interest of research community resulted in creation of the second generation of mTOR inhibitors involving both, mTOR kinase inhibitors and dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitors. Recently, combining advances of first and second generation of mTOR inhibitors yielded in the third generation of inhibitors termed as rapalinks. Nowadays, novel inhibitors belonging to all of the three generations are still under development. These inhibitors help us better to understand role of mTOR in mTOR signaling pathway as well as in diverse human diseases. In this review, we summarize recent reported mTOR inhibitors or methods of use thereof in the treatment of various diseases.
- MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy farmakologie MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- mTOR inhibitory * MeSH
- mTORC1 metabolismus MeSH
- proliferace buněk MeSH
- sirolimus farmakologie MeSH
- TOR serin-threoninkinasy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Tuberózní skleróza je neurokutánní syndrom vznikající na podkladě zárodečné mutace genu TSC1 nebo TSC2. Patologická aktivace proteinového komplexu mTORC1 má u pacientů s tuberózní sklerózou klíčovou úlohu v tumorigenezi subependymálního obrovskobuněčného astrocytomu. Blokáda deregulované signální dráhy užitím mTOR inhibitorů má potenciál vést ke zmenšení objemu tohoto nádoru mozku o nízkém stupni malignity. V přehledném článku jsou shrnuty současné poznatky o farmakologické léčbě subependymálního obrovskobuněčného astrocytomu. Dlouhodobé sledování a včasná léčebná opatření snižují morbiditu a mortalitu a zlepšují kvalitu života pacientů s nádory spjatými s tuberózní sklerózou.
Tuberous sclerosis complex is a neurocutaneous syndrome that results from a germline mutation in TSC1 or TSC2 genes. The pathogenic activation of mTORC1 leads to the development of subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Blocking of the dysregulated pathway with mTOR inhibitors has the potential to reduce the volume of this low‑grade brain tumor. This article reviews the current knowledge on the pharmacological treatment of subependymal giant cell astrocytomas. A long‑term follow‑up and early therapeutic intervention should lead to mortality and morbidity reduction and quality of life improvement in patients with tuberous sclerosis complex associated tumors. Key words: subependymal giant cell astrocytoma − tuberous sclerosis complex – mTOR – everolimus This study was supported by the European Regional Development Fund as well as by the State Budget of the Czech Republic: project RECAMO CZ.1.05/2.1.00/03.0101 and the project CEB CZ.1.07/2.3.00/20.0183. The author has received honoraria from Novartis for the lecture with the article-related topic. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 18. 11. 2014 Accepted: 20. 11. 2014
- MeSH
- astrocytom * diagnóza etiologie farmakoterapie MeSH
- dítě MeSH
- dospělí MeSH
- everolimus MeSH
- imunosupresiva škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- nádory mozku diagnóza etiologie farmakoterapie MeSH
- protinádorové látky škodlivé účinky terapeutické užití MeSH
- sirolimus * analogy a deriváty škodlivé účinky terapeutické užití MeSH
- TOR serin-threoninkinasy antagonisté a inhibitory MeSH
- tuberózní skleróza * komplikace patofyziologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- angiomyolipom farmakoterapie MeSH
- imunosupresiva farmakokinetika škodlivé účinky MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- polycystická choroba ledvin farmakoterapie MeSH
- TOR serin-threoninkinasy * antagonisté a inhibitory farmakokinetika terapeutické užití MeSH
- transplantace orgánů MeSH
- tuberózní skleróza farmakoterapie MeSH
- Check Tag
- lidé MeSH
Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.
- MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy farmakologie terapeutické užití MeSH
- inhibitory proteinkinas farmakologie chemie terapeutické užití MeSH
- lidé MeSH
- mTOR inhibitory farmakologie terapeutické užití MeSH
- protinádorové látky * farmakologie chemie terapeutické užití MeSH
- protoonkogenní proteiny c-akt * metabolismus antagonisté a inhibitory MeSH
- sarkom * farmakoterapie metabolismus patologie MeSH
- signální transdukce * účinky léků MeSH
- TOR serin-threoninkinasy * antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The mechanistic target of rapamycin (mTOR) is a crucial regulator of cell metabolic activity. It forms part of several distinct protein complexes, particularly mTORC1 and mTORC2. The lack of specific inhibitors still hampers the attribution of mTOR functions to these complexes. JR-AB2-011 has been reported as a specific mTORC2 inhibitor preventing mTOR binding to RICTOR, a unique component of mTORC2. We aimed to describe the effects of JR-AB2-011 in leukemia/lymphoma cells, where the mTOR pathway is often aberrantly activated. METHODS: The impact of JR-AB2-011 on leukemia/lymphoma cell metabolism was analyzed using the Seahorse platform. AKT phosphorylation at Ser473 was used as a marker of mTORC2 activity. mTOR binding to RICTOR was assessed by co-immunoprecipitation. RICTOR-null cells were derived from the Karpas-299 cell line using CRISPR/Cas9 gene editing. RESULTS: In leukemia/lymphoma cell lines, JR-AB2-011 induced a rapid drop in the cell respiration rate, which was variably compensated by an increased glycolytic rate. In contrast, an increase in the respiration rate due to JR-AB2-011 treatment was observed in primary leukemia cells. Unexpectedly, JR-AB2-011 did not affect AKT Ser473 phosphorylation. In addition, mTOR did not dissociate from RICTOR in cells treated with JR-AB2-011 under the experimental conditions used in this study. The effect of JR-AB2-011 on cell respiration was retained in RICTOR-null cells. CONCLUSION: JR-AB2-011 affects leukemia/lymphoma cell metabolism via a mechanism independent of mTORC2.
- MeSH
- fosforylace účinky léků MeSH
- leukemie * farmakoterapie metabolismus MeSH
- lidé MeSH
- mTOR inhibitory farmakologie MeSH
- mTORC2 * metabolismus MeSH
- nádorové buněčné linie MeSH
- protein RICTOR * metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In the present work, a library of 239 frentizole derivatives formerly synthesized by our research group were virtually screened on the FRB domain of mTOR in a search of potential binders for further experimental evaluation. 39 compounds from this library were virtually selected and classified in 7 groups according to their structural features. 9 representative compounds of these 7 groups were further submitted to rounds of MD simulation and MM-PBSA calculations. Analysis of our results pointed to the most promising among these groups as binders to the FRB domain of mTOR. We believe that they structurally represent a priority portion of the original library for further experimental evaluation.
- MeSH
- simulace molekulární dynamiky * MeSH
- TOR serin-threoninkinasy * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH