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Anti-cancer Agents in Medicinal... 2022mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1 and mTORC2. It plays a crucial role in various... (Review)
Review
mTOR (mammalian target of rapamycin) is a catalytic subunit composed of two multi-protein complexes that indicate mTORC1 and mTORC2. It plays a crucial role in various fundamental cell processes like cell proliferation, metabolism, survival, cell growth, etc. Various first line mTOR inhibitors such as Rapamycin, Temsirolimus, Everolimus, Ridaforolimus, Umirolimus, and Zotarolimus have been used popularly. In contrast, several mTOR inhibitors such as Gedatolisib (PF-05212384) are under phase 2 clinical trials studies for the treatment of triple-negative breast cancer. The mTOR inhibitors bearing heterocyclic moieties such as quinazoline, thiophene, morpholine, imidazole, pyrazine, furan, quinoline are under investigation against various cancer cell lines (U87MG, PC-3, MCF-7, A549, MDA-231). In this review, we summarized updated research related to mTOR inhibitors and their structure-activity relationship, which may help scientists develop potent inhibitors against cancer.
Topics: Cell Proliferation; Everolimus; Humans; MTOR Inhibitors; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 34288843
DOI: 10.2174/1871520621666210720121403 -
Pharmacological Research Jul 2021Osteosarcoma, a highly malignant tumor, is characterized by widespread and recurrent chromosomal and genetic abnormalities. In recent years, a number of elaborated... (Review)
Review
Osteosarcoma, a highly malignant tumor, is characterized by widespread and recurrent chromosomal and genetic abnormalities. In recent years, a number of elaborated sequencing analyses have made it possible to cluster the osteosarcoma based on the identification of candidate driver genes and develop targeted therapy. Here, we reviewed recent next-generation genome sequencing studies and advances in targeted therapies for osteosarcoma based on molecular classification. First, we stratified osteosarcomas into ten molecular subtypes based on genetic changes. And we analyzed potential targeted therapies for osteosarcoma based on the identified molecular subtypes. Finally, the development of targeted therapies for osteosarcoma investigated in clinical trials were further summarized and discussed. Therefore, we indicated the importance of molecular classification on the targeted therapy for osteosarcoma. And the stratification of patients based on the genetic characteristics of osteosarcoma will help to obtain a better therapeutic response to targeted therapies, bringing us closer to the era of personalized medicine.
Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Genes, Neoplasm; Humans; Molecular Targeted Therapy; Osteosarcoma
PubMed: 34022396
DOI: 10.1016/j.phrs.2021.105684 -
BioRxiv : the Preprint Server For... Aug 2022SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs,...
SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.
PubMed: 33880473
DOI: 10.1101/2021.04.15.440067 -
Cardiovascular Revascularization... Apr 2021Treatment of lesions in small coronary vessels is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI).We... (Randomized Controlled Trial)
Randomized Controlled Trial
Incidence and Predictors of Target Lesion Failure in Patients With Lesions in Small Vessels Undergoing PCI With Contemporary Drug-Eluting Stents: Insights From the BIONICS Study.
Treatment of lesions in small coronary vessels is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI).We aimed to evaluate the outcomes of patients undergoing small-vessel PCI in the BIONICS trial and to identify predictors of stent failure. 1910 patients were randomized to treatment with the EluNIR™ ridaforolimus-eluting stent (RES) or Resolute™ zotarolimus-eluting stent (ZES). Small vessels were defined as reference vessel diameters (RVD) ≤2.5 mm. A Cox proportional hazards model was used to identify predictors of target lesion failure (TLF) through 2 years. Patients undergoing small vessel disease PCI had a higher frequency of diabetes, prior myocardial infarction (MI), and prior PCI. 2 year TLF was higher among patients with small vessels (9.7% vs. 5.9%, HR 1.7 [95% CI 1.22-2.37], p < 0.01), driven by increased rates of target vessel-MI and target lesion revascularization (TLR). Stent thrombosis at 2 years was higher among patients with small vessel disease (1.4% vs. 0.3%, HR 5.25 [95% CI 1.47-18.8], p < 0.01). 2 year TLF rates were similar in the RES and ZES patient groups (P 0.86). In conclusion, patients undergoing PCI in small vessels have significantly worse outcomes despite the use of contemporary stents.
Topics: Bionics; Cardiovascular Agents; Drug-Eluting Stents; Humans; Incidence; Percutaneous Coronary Intervention; Prosthesis Design; Risk Factors; Time Factors; Treatment Outcome
PubMed: 33168433
DOI: 10.1016/j.carrev.2020.10.018 -
Cardiovascular Intervention and... Jul 2021Japanese patients have shown improved outcomes after treatment with drug eluting stents compared with Western patients. Outcomes with the ridaforolimus-eluting EluNIR... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Japanese patients have shown improved outcomes after treatment with drug eluting stents compared with Western patients. Outcomes with the ridaforolimus-eluting EluNIR stent in Japanese patients are unknown.
METHODS AND RESULTS
This was a multi-center trial in Japanese patients undergoing PCI with the ridaforolimus eluting EluNIR stent. A propensity-score matched analysis was performed with the EluNIR arm of the BIONICS trial. The matched cohort was compared with the Japanese patients for the primary endpoint of target lesion failure (TLF) in a non-inferiority study. 104 Japanese patients were compared with 410 matched patients from BIONICS. Baseline characteristics were similar except for more frequent multi-vessel disease in the BIONICS cohort. Post dilation was more likely in Japanese patients (90.4% vs. 64.6%, p < 0.001). TLF at 12 months was met by 2 patients (1.9%) in the JNIR study compared with 5.3% in the BIONICS group (Pnoninf = 0.0028). Rates of MI (0% vs. 4.7%, p = 0.03), target vessel MI (0% vs. 3.7%, p = 0.04), MACE (1.0% vs. 6.2%, p = 0.03) and TVF (1.0% vs. 6.9%, p = 0.02) were all significantly lower among Japanese patients.
CONCLUSION
Treatment of Japanese patients with the EluNIR stent is associated with very low rates of adverse events, significantly fewer than seen in the BIONICS trial.
Topics: Aged; Coronary Angiography; Coronary Artery Disease; Drug-Eluting Stents; Female; Follow-Up Studies; Humans; Japan; Male; Morbidity; Percutaneous Coronary Intervention; Propensity Score; Prospective Studies; Prosthesis Design; Risk Factors; Sirolimus; Time Factors; Treatment Outcome
PubMed: 32592082
DOI: 10.1007/s12928-020-00680-4 -
The American Journal of Cardiology Jul 2020Treatment of bifurcation lesions is technically challenging and has been associated with an increased risk of adverse events. We sought to evaluate the clinical and... (Randomized Controlled Trial)
Randomized Controlled Trial
Treatment of bifurcation lesions is technically challenging and has been associated with an increased risk of adverse events. We sought to evaluate the clinical and angiographic outcomes of patients who underwent bifurcation lesion provisional treatment in the BioNIR Ridaforolimus Eluting Coronary Stent System in Coronary Stenosis trial. A prospective, multicenter, 1:1 randomized trial was conducted to evaluate the safety and efficacy of ridaforolimus-eluting stents (RES) versus zotarolimus-eluting stents (ZES). Enrollment of bifurcation lesions treated with a provisional 1-stent technique was allowed. Bifurcation lesions were analyzed by an angiographic core laboratory. Outcomes were analyzed according to the presence of a bifurcation lesion treatment. Study population included 686 (35.8%) patients with and 1,228 (64.2%) patients without bifurcation lesion treatment. Procedural success was high and similar between groups. In 2 years, there was no difference in the rate of target lesion failure between the bifurcation and nonbifurcation groups (7.6% vs 7.3%, respectively, p = 0.81) regardless of the presence of side branch stenosis ≥50%. In 159 patients with angiographic follow-up, there was no difference in the rate of binary restenosis between groups (9.0% vs 9.2%, p = 0.96). Rates of target lesion failure at 1-year were similar with ZES and RES, and consistent in patients with and without bifurcation lesions (p = 0.61). In conclusion, patients with bifurcation lesions treated and a provisional strategy experienced similar outcomes as those with nonbifurcation lesions. RES performed as well as ZES in bifurcation and nonbifurcation lesions.
Topics: Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Prospective Studies; Sirolimus
PubMed: 32317100
DOI: 10.1016/j.amjcard.2020.04.002 -
EuroIntervention : Journal of EuroPCR... Jun 2021The relative thrombogenicity and albumin adsorption and retention of different durable polymers used in coronary stents has not been tested.
BACKGROUND
The relative thrombogenicity and albumin adsorption and retention of different durable polymers used in coronary stents has not been tested.
AIMS
This study sought to compare the thromboresistance and albumin binding capacity of different durable polymer drug-eluting stents (DES) using dedicated preclinical and in vitro models.
METHODS
In an ex vivo swine arteriovenous shunt model, a fluoropolymer everolimus-eluting stent (FP-EES) (n=14) was compared with two durable polymer DES, the BioLinx polymer-coated zotarolimus-eluting stent (BL-ZES) (n=9) and a CarboSil elastomer polymer-coated ridaforolimus-eluting stent (EP-RES) (n=6), and bare metal stents (BMS) (n=10). Stents underwent immunostaining using a cocktail of antiplatelet antibodies and a marker for inflammation and were then evaluated by confocal microscopy (CM). Albumin retention was assessed using a flow loop model with labelled human serum albumin (FP-EES [n=8], BL-ZES [n=4], EP-RES [n=4], and BMS [n=7]), and scanned by CM.
RESULTS
The area of platelet adherence (normalised to total stent surface area) was lower in the order FP-EES (9.8%), BL-ZES (32.7%), EP-RES (87.6%) and BMS (202.0%), and inflammatory cell density was least for FP-EES
CONCLUSIONS
These results suggest that thromboresistance and albumin retention vary by polymer type and that these differences might result in different suitability for short-term dual antiplatelet therapy.
Topics: Adsorption; Albumins; Animals; Drug-Eluting Stents; Everolimus; Percutaneous Coronary Intervention; Polymers; Prosthesis Design; Stents; Swine; Treatment Outcome
PubMed: 32149708
DOI: 10.4244/EIJ-D-19-00938 -
JACC. Cardiovascular Interventions Jan 2020
Topics: Bionics; Sirolimus; Treatment Outcome
PubMed: 31918947
DOI: 10.1016/j.jcin.2019.09.003 -
JACC. Cardiovascular Interventions Jan 2020This study sought to determine clinical outcomes between treatment groups over long-term follow-up.
OBJECTIVES
This study sought to determine clinical outcomes between treatment groups over long-term follow-up.
BACKGROUND
The safety and efficacy of a ridaforolimus-eluting stent (RES) was evaluated in the BIONICS (BioNIR Ridaforolimus-Eluting Coronary Stent System in Coronary Stenosis) and NIREUS (BioNIR Ridaforolimus Eluting Coronary Stent System [BioNIR] European Angiography Study) trials, demonstrating noninferiority of RES in comparison with a zotarolimus-eluting stent (ZES) regarding 1-year target lesion failure (TLF) and 6-month angiographic late lumen loss, respectively.
METHODS
Patient-level data from the BIONICS (N = 1,919) and NIREUS (N = 302) randomized trials were pooled, and outcomes in patients implanted with RES and ZES compared. Broad inclusion criteria allowed enrollment of patients with acute coronary syndromes and complex lesions. The primary endpoint was the 2-year rate of TLF or clinically driven target lesion revascularization.
RESULTS
A total of 2,221 patients (age 63.2 ± 10.3 years; 79.7% men) undergoing percutaneous coronary intervention with RES (n = 1,159) or ZES (n = 1,062) were included. Clinical and angiographic characteristics were similar between groups. At 2 years, the primary endpoint of TLF was similar among patients implanted with RES and ZES (7.0% vs. 7.2%; p = 0.94). Rates of target lesion revascularization (4.8% RES vs. 4.1% ZES; p = 0.41) and target vessel-related myocardial infarction (3.1% RES vs. 3.8% ZES; p = 0.52) did not differ between groups. The overall rate of stent thrombosis was also similar (0.5% RES vs. 0.9% ZES; p = 0.39).
CONCLUSIONS
In a pooled analysis of 2 randomized trials, 2-year clinical outcomes were similar between patients undergoing percutaneous coronary intervention with RES and ZES. These results support the long-term safety and efficacy of RES for the treatment of a broad population of patients with coronary artery disease.
Topics: Aged; Cardiovascular Agents; Coronary Angiography; Coronary Artery Disease; Coronary Thrombosis; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Prosthesis Design; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Time Factors; Treatment Outcome
PubMed: 31918946
DOI: 10.1016/j.jcin.2019.08.019 -
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