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Bulletin Du Cancer Jan 2009PI3K/AKT/mTOR is a cell signalling pathway that plays a major role in regulation of apoptosis, cell growth and cell cycle. This pathway is often disregulated in human... (Review)
Review
PI3K/AKT/mTOR is a cell signalling pathway that plays a major role in regulation of apoptosis, cell growth and cell cycle. This pathway is often disregulated in human cancers, and constitutes an interesting target for antitumor therapy. Rapamycin is an inhibitor of mTOR that has first been developed for its immunosuppressive characteristics, as a preventive treatment of graft rejection. More recently, three rapamycin analogs have been developed, resulting in interesting results in preclinical studies on cancer cell lines : temsirolimus, everolimus, and deforolimus. These molecules are being tested in clinical studies, and both temsirolimus and everolimus have demonstrated efficacy in metastatic renal cancers. In contrast, perfosin, an AKT inhibitor, did not prove to be active in clinical studies. Many ongoing studies explore next indications of these drugs, given alone or in combination with chemotherapy or with other targeted therapy. Identification of predictive factors for sensibility to treatment represents another way of research.
Topics: Antineoplastic Agents; Cell Proliferation; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 19211363
DOI: 10.1684/bdc.2009.0807 -
The Oncologist Aug 2007Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival.... (Review)
Review
Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article.
Topics: Clinical Trials as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 17766661
DOI: 10.1634/theoncologist.12-8-1007 -
The Oncologist Feb 2008The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a... (Review)
Review
The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a critical role in regulating basic cellular functions including cellular growth and proliferation. Currently, the mTOR inhibitor rapamycin and its analogues (CCI-779, RAD001, AP23573), which induce cell-cycle arrest in the G(1) phase, are being evaluated in cancer clinical trials. The mTOR inhibitors appear to be well tolerated, with skin reactions, stomatitis, myelosuppression, and metabolic abnormalities the most common toxicities seen. These adverse events are transient and reversible with interruption of dosing. Several pieces of evidence suggest a certain antitumor activity, including tumor regressions and prolonged stable disease, which has been reported among patients with a variety of malignancies, including non-small cell lung cancer (NSCLC). These promising preliminary clinical data have stimulated further research in this setting. Here, we review the basic structure of the pathway together with current results and future developments of mTOR inhibitors in the treatment of NSCLC patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Disease Progression; ErbB Receptors; Everolimus; Humans; Immunosuppressive Agents; Lung Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 18305058
DOI: 10.1634/theoncologist.2007-0171 -
Frontiers in Pharmacology 2022Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block...
Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew ().
Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.5, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) of temsirolimus in the least shrew. Temsirolimus caused a bell-shaped and dose-dependent increase in both the mean vomit frequency and the number of shrews vomiting with maximal efficacy at 10 mg/kg ( < 0.05 and < 0.02, respectively). Its larger doses (20 or 40 mg/kg) had no significant emetic effect. We also evaluated the emetic potential of its analogs (5, 10, and 20 mg/kg, i.p.), all of which exhibited a similar emetic profile. Our observational studies indicated that temsirolimus can reduce the shrew motor activity at 40 mg/kg, and subsequently, we examined the motor effects of its lower doses. At 10 and 20 mg/kg, it did not affect the spontaneous locomotor activity (distance moved) but attenuated the mean rearing frequency in a U-shaped manner at 10 mg/kg ( < 0.05). We then determined the broad-spectrum antiemetic potential of a 20 mg/kg (i.p.) dose of temsirolimus against diverse emetogens, including selective and nonselective agonists of 1) dopaminergic D receptors (apomorphine and quinpirole); 2) serotonergic 5-HT receptors [5-HT (serotonin) and 2-methyl-5-HT]; 3) cholinergic M receptors (pilocarpine and McN-A-343); 4) substance P neurokinin NK receptors (GR73632); 5) the L-type calcium (Ca) channel (LTCC) (FPL64176); 6) the sarcoplasmic endoplasmic reticulum Ca ATPase inhibitor, thapsigargin; 7) the CB receptor inverse agonist/antagonist, SR141716A; and 8) the chemotherapeutic cisplatin. Temsirolimus prevented vomiting evoked by the aforementioned emetogens with varying degrees. The mechanisms underlying the pro- and antiemetic effects of temsirolimus evaluated by immunochemistry for c-fos expression demonstrated a c-fos induction in the AP and NTS, but not DMNX with the 10 mg/kg emetic dose of temsirolimus, whereas its larger antiemetic dose (20 mg/kg) had no significant effect. Our study is the first to provide preclinical evidence demonstrating the promising antiemetic potential of high doses of temsirolimus and possibly its analogs in least shrews.
PubMed: 35444553
DOI: 10.3389/fphar.2022.848673 -
Breast Cancer (Dove Medical Press) 2014Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2)... (Review)
Review
Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR) inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus). This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus) are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease). Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is impossible to select patients not benefiting from addition of everolimus to exemestane. Side effects and impact on quality of life are other important issues discussed in this review. Second-generation mTOR inhibitors and dual mTOR-phosphatidylinositol-3-kinase inhibitors are currently being evaluated in clinical trials.
PubMed: 24833916
DOI: 10.2147/BCTT.S38679 -
Oncotarget Sep 2015In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion)....
In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned.
Topics: Aging; Animals; Blood Proteins; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Humans; Immunoblotting; Indoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Multiprotein Complexes; Purines; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 26177051
DOI: 10.18632/oncotarget.4836 -
Tomography (Ann Arbor, Mich.) Dec 2019Tumor microenvironments expose cancer cells to heterogeneous, dynamic environments by shifting availability of nutrients, growth factors, and metabolites. Cells...
Tumor microenvironments expose cancer cells to heterogeneous, dynamic environments by shifting availability of nutrients, growth factors, and metabolites. Cells integrate various inputs to generate cellular memory that determines trajectories of subsequent phenotypes. Here we report that short-term exposure of triple-negative breast cancer cells to growth factors or targeted inhibitors regulates subsequent tumor initiation. Using breast cancer cells with different driver mutations, we conditioned cells lines with various stimuli for 4 hours before implanting these cells as tumor xenografts and quantifying tumor progression by means of bioluminescence imaging. In the orthotopic model, conditioning a low number of cancer cells with fetal bovine serum led to enhancement of tumor-initiating potential, tumor volume, and liver metastases. Epidermal growth factor and the mTORC1 inhibitor ridaforolimus produced similar but relatively reduced effects on tumorigenic potential. These data show that a short-term stimulus increases tumorigenic phenotypes based on cellular memory. Conditioning regimens failed to alter proliferation or adhesion of cancer cells in vitro or kinase signaling through Akt and ERK measured by multiphoton microscopy in vivo, suggesting that other mechanisms enhanced tumorigenesis. Given the dynamic nature of the tumor environment and time-varying concentrations of small-molecule drugs, this work highlights how variable conditions in tumor environments shape tumor formation, metastasis, and response to therapy.
Topics: Animals; Carcinogenesis; Cell Adhesion; Cell Count; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Disease Progression; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Luminescent Measurements; Mechanistic Target of Rapamycin Complex 1; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; Serum Albumin, Bovine; Sirolimus; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 31893233
DOI: 10.18383/j.tom.2019.00019 -
EuroIntervention : Journal of EuroPCR... May 2018The aim of this study was to evaluate the efficacy and safety of the BioNIR stent compared with the Resolute Integrity stent for the treatment of coronary artery disease. (Randomized Controlled Trial)
Randomized Controlled Trial
A prospective randomised trial comparing the novel ridaforolimus-eluting BioNIR stent to the zotarolimus-eluting Resolute stent: six-month angiographic and one-year clinical results of the NIREUS trial.
AIMS
The aim of this study was to evaluate the efficacy and safety of the BioNIR stent compared with the Resolute Integrity stent for the treatment of coronary artery disease.
METHODS AND RESULTS
This first-in-human, multicentre, single-blind randomised non-inferiority trial was performed in Europe and Israel. Patients with stable coronary artery disease or acute coronary syndromes were randomly assigned to treatment with BioNIR or Resolute Integrity stents in a 2:1 fashion. The primary endpoint was angiographic in-stent late lumen loss (LLL) at six months. Three hundred and two patients were randomised, of whom 261 (86.0%) underwent six-month angiographic follow-up. The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of in-stent LLL at six months (0.04±0.30 mm vs. 0.03±0.31 mm, respectively, pnoninferiority<0.0001). At 12-month follow-up, target lesion failure occurred in 3.4% in the BioNIR group and 5.9% in the Resolute Integrity group (p=0.22). Rates of MACE were similar between the BioNIR and Resolute Integrity groups (4.3% vs. 5.9%, respectively, p=0.45).
CONCLUSIONS
The BioNIR stent was non-inferior to the Resolute Integrity stent for the primary endpoint of angiographic in-stent LLL at six months. Clinical outcomes at one year were comparable between the two groups.
Topics: Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prospective Studies; Sirolimus; Treatment Outcome
PubMed: 29537374
DOI: 10.4244/EIJ-D-17-00890 -
Annals of Oncology : Official Journal... Jun 2010The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus)...
BACKGROUND
The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol).
MATERIALS AND METHODS
Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m(2), both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out.
RESULTS
Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m(2) PTX and 12.5 mg/80 mg/m(2). Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease > or =4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively.
CONCLUSION
Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.
Topics: Adult; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Drug Interactions; Female; Humans; Injections, Intravenous; Intracellular Signaling Peptides and Proteins; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Paclitaxel; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 19901013
DOI: 10.1093/annonc/mdp504 -
JACC. Cardiovascular Interventions Dec 2018The authors sought to investigate the impact of diabetes mellitus (DM) on outcomes following contemporary drug-eluting stent (DES) implantation in the BIONICS (BioNIR... (Comparative Study)
Comparative Study
OBJECTIVES
The authors sought to investigate the impact of diabetes mellitus (DM) on outcomes following contemporary drug-eluting stent (DES) implantation in the BIONICS (BioNIR Ridaforolimus Eluting Coronary Stent System in Coronary Stenosis) trial.
BACKGROUND
Patients with DM are at increased risk for adverse events following percutaneous coronary intervention (PCI).
METHODS
A prospective, multicenter, 1:1 randomized trial was conducted to evaluate in a noninferiority design the safety and efficacy of ridaforolimus-eluting stents versus zotarolimus-eluting stents among 1,919 patients undergoing PCI. Randomization was stratified to the presence of medically treated DM, and a pre-specified analysis compared outcomes according to the presence or absence of DM up to 2 years.
RESULTS
The overall prevalence of DM was 29.1% (559 of 1,919). DM patients had higher body mass index, greater prevalence of hyperlipidemia and hypertension, and smaller reference vessel diameter. One-year target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) was significantly higher among diabetic patients (7.8% vs. 4.2%; p = 0.002), mainly due to higher target lesion revascularization (4.5% vs. 2.0%; p = 0.002). Rates of cardiac death, myocardial infarction, and stent thrombosis did not statistically vary. Among 158 patients undergoing 13-month angiographic follow-up, restenosis rates were 3 times higher in diabetic patients compared with nondiabetic patients (15.2% vs. 4.7%; p = 0.01). Clinical and angiographic outcomes were similar between ridaforolimus-eluting stent- and zotarolimus-eluting stent-treated patients.
CONCLUSIONS
Despite advances in interventional therapies, and the implementation of new-generation DES, diabetic patients still have worse angiographic and clinical outcomes compared with nondiabetic patients undergoing PCI.
Topics: Aged; Cardiovascular Agents; Coronary Artery Disease; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Diabetes Mellitus; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prevalence; Prospective Studies; Prosthesis Design; Risk Factors; Single-Blind Method; Sirolimus; Time Factors; Treatment Outcome
PubMed: 30573057
DOI: 10.1016/j.jcin.2018.09.033