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https://www.readbyqxmd.com/read/29118224/exceptional-response-to-temsirolimus-in-a-metastatic-clear-cell-renal-cell-carcinoma-with-an-early-novel-mtor-activating-mutation
#1
Juan Francisco Rodríguez-Moreno, María Apellaniz-Ruiz, Juan María Roldan-Romero, Ignacio Durán, Luis Beltrán, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Jesus García-Donas, Cristina Rodríguez-Antona
mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment...
November 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29103764/additive-cytotoxic-effects-of-radiation-and-mtor-inhibitors-in-a-cervical-cancer-cell-line
#2
Daniele Xavier Assad, Gabriel Alvares Borges, Samuel Ramalho Avelino, Eliete Neves Silva Guerra
The PI3K/AKT/mTOR signaling pathway is frequently activated in HPV-positive cervical squamous cell cancer (CC). This study investigated the biological effects of mTOR inhibitors associated with radiotherapy in a CC cell line (HeLa). A human keratinocyte cell line (HaCaT) was used as control. Temsirolimus, everolimus, resveratrol, curcumin and epigallocatechin gallate (EGCG) were the mTOR inhibitors assessed. The 50% cell cytotoxicity rate (CC50) for each treatment was determined by MTT cell viability assay...
November 2, 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#3
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29074560/a-network-meta-analysis-of-short-term-efficacy-of-different-single-drug-targeted-therapies-in-the-treatment-of-renal-cell-carcinoma
#4
Hong-Ling He, Wan-Xia Yao
The network meta-analysis was conducted to compare the short-term efficacy of different single-drug targeted therapies in the treatment of renal cell carcinoma (RCC). We initially searched databases for randomized controlled trials (RCTs) on different single-drug targeted therapies in treating RCC. The meta-analysis combined the direct and indirect evidence to calculate the pooled odds ratios (OR) and draw surface under the cumulative ranking curves (SUCRA). A total of 14 eligible RCTs were ultimately selected...
October 26, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28961834/a-phase-ii-study-of-temsirolimus-added-to-low-dose-weekly-carboplatin-and-paclitaxel-for-patients-with-recurrent-and-or-metastatic-r-m-head-and-neck-squamous-cell-carcinoma-hnscc
#5
L A Dunn, M G Fury, H Xiao, S S Baxi, E J Sherman, S Korte, C Pfister, S Haque, N Katabi, A L Ho, D G Pfister
Background: Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy. Patients and methods: In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC...
October 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28952411/clinical-development-of-mtor-inhibitors-for-renal-cancer
#6
REVIEW
Michele Ghidini, Fausto Petrelli, Antonio Ghidini, Gianluca Tomasello, Jens Claus Hahne, Rodolfo Passalacqua, Sandro Barni
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28950297/a-randomized-phase-ii-trial-of-crlx101-in-combination-with-bevacizumab-versus-standard-of-care-in-patients-with-advanced-renal-cell-carcinoma
#7
M H Voss, A Hussain, N Vogelzang, J L Lee, B Keam, S Y Rha, U Vaishampayan, W B Harris, S Richey, J M Randall, D Shaffer, A Cohn, T Crowell, J Li, A Senderowicz, E Stone, R Figlin, R J Motzer, N B Haas, T Hutson
Background: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28941151/recurrent-desmoplastic-small-round-cell-tumor-responding-to-an-mtor-inhibitor-containing-regimen
#8
Nidale Tarek, Andrea Hayes-Jordan, Laura Salvador, Mary F McAleer, Cynthia E Herzog, Winston W Huh
Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multimodal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. We report our experience with five patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range 4-14 courses), and partial response was observed in all patients. Median time to progression or relapse was 8...
September 22, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28932277/a-retrospective-review-of-the-multidisciplinary-management-of-medullary-thyroid-cancer-eligibility-for-systemic-therapy
#9
Georgia Geller, Janessa Laskin, Winson Y Cheung, Cheryl Ho
BACKGROUND: Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid cancers. The clinical course of metastatic disease can be indolent. Our aim was to characterize the natural history of disease to evaluate the true proportion of patients who would be eligible for the currently available systemic therapies. METHODS: The British Columbia Cancer Agency (BCCA) provides cancer care to a population of 4.6 million. A retrospective chart review was conducted of all patients with MTC referred to the BCCA from 1991 to 2013...
2017: Thyroid Research
https://www.readbyqxmd.com/read/28926611/activation-of-the-unfolded-protein-response-in-sarcoma-cells-treated-with-rapamycin-or-temsirolimus
#10
Joseph W Briggs, Ling Ren, Kristi R Chakrabarti, Yien Che Tsai, Allan M Weissman, Ryan J Hansen, Daniel L Gustafson, Yousuf A Khan, Jonathan D Dinman, Chand Khanna
Activation of the unfolded protein response (UPR) in eukaryotic cells represents an evolutionarily conserved response to physiological stress. Here, we report that the mTOR inhibitors rapamycin (sirolimus) and structurally related temsirolimus are capable of inducing UPR in sarcoma cells. However, this effect appears to be distinct from the classical role for these drugs as mTOR inhibitors. Instead, we detected these compounds to be associated with ribosomes isolated from treated cells. Specifically, temsirolimus treatment resulted in protection from chemical modification of several rRNA residues previously shown to bind rapamycin in prokaryotic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28901501/mtor-inhibition-reduces-growth-and-adhesion-of-hepatocellular-carcinoma-cells-in%C3%A2-vitro
#11
Tobias Engl, Jochen Rutz, Sebastian Maxeiner, Eva Juengel, Frederik Roos, Wael Khoder, Wolf O Bechstein, Karen Nelson, Igor Tsaur, Axel Haferkamp, Roman A Blaheta
Mechanistic target of rapamycin (mTOR) signaling is typically increased in hepatocellular carcinoma (HCC). A panel of HCC cell lines (HepG2, Hep3B and HuH6) was exposed to various concentrations of the mTOR inhibitors, everolimus and temsirolimus, in order to investigate their effects on cell growth, clonal formation, cell cycle progression, and adhesion and chemotactic migration using MTT and clonal cell growth assays, fluorometric detection of cell cycle phases and a Boyden chamber assay. In addition, integrin α and β adhesion receptors were analyzed by flow cytometry and blocking studies using function blocking monoclonal antibodies were conducted to explore functional relevance...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28840097/a-case-of-delayed-exacerbation-of-interstitial-lung-disease-after-discontinuation-of-temsirolimus
#12
Rei Matsuki, Kenichi Okuda, Akihisa Mitani, Yasuhiro Yamauchi, Goh Tanaka, Haruki Kume, Yukio Homma, Munetoshi Hinata, Akimasa Hayashi, Junji Shibahara, Masashi Fukayama, Takahide Nagase
Temsirolimus is an inhibitor of mammalian target of rapamycin and interstitial lung disease (ILD) is known to be one of the adverse events associated with temsirolimus, which usually improves rapidly after discontinuation of the drug and rarely worsens thereafter. Herein, we report a case of delayed exacerbation of ILD after discontinuation of temsirolimus for metastatic renal cell carcinoma in an 86-year-old male with chronic ILD. The patient developed gradually worsening dyspnea five weeks after an initiation of temsirolimus and was admitted to our facility...
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28821555/p53-nongenotoxic-activation-and-mtorc1-inhibition-lead-to-effective-combination-for-neuroblastoma-therapy
#13
Myrthala Moreno-Smith, Anna Lakoma, Zaowen Chen, Ling Tao, Kathleen A Scorsone, Linda Schild, Kevin Aviles-Padilla, Rana Nikzad, Yankai Zhang, Rikhia Chakraborty, Jan J Molenaar, Sanjeev A Vasudevan, Vivien Sheehan, Eugene S Kim, Silke Paust, Jason M Shohet, Eveline Barbieri
Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy; however, they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling.Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the antitumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first- and second-generation MDM2 inhibitors to reactivate p53...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28811872/current-and-emerging-treatment-options-for-mantle-cell-lymphoma
#14
REVIEW
Bita Fakhri, Brad Kahl
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with typically aggressive behavior. The genetic signature is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. Asymptomatic newly diagnosed MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Although MCL classically responds to upfront chemotherapy, it remains incurable with standard approaches. For patients in need of frontline therapy, the initial decision is whether to proceed with an intensive treatment strategy or a non-intensive treatment strategy...
August 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28793293/triggering-of-eryptosis-the-suicidal-erythrocyte-death-by-mammalian-target-of-rapamycin-mtor-inhibitor-temsirolimus
#15
A Al Mamun Bhuyan, Hang Cao, Florian Lang
BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is utilized for the treatment of malignancy. Temsirolimus is at least in part effective by triggering suicidal tumor cell death. The most common side effect of temsirolimus treatment is anemia. At least in theory, the anemia following temsirolimus treatment could result from stimulation of eryptosis, the suicidal erythrocyte death. Hallmarks of eryptosis include cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28777104/mood-stabilizing-effects-of-rapamycin-and-its-analog-temsirolimus-relevance-to-autophagy
#16
Nirit Z Kara, Shlomit Flaisher-Grinberg, Grant W Anderson, Galila Agam, Haim Einat
Accumulated data support a relationship between mood disorders and cellular plasticity and resilience, some suggesting relevance to autophagy. Our previous data show that pharmacological enhancement of autophagy results in antidepressant-like effects in mice. The current study was designed to further examine the effects of autophagy enhancement on mood by testing the effects of subchronic treatment with the mammalian target of rapamycin inhibitors and autophagy enhancers rapamycin and temsirolimus in a model for mania and in a model for antidepressant action, respectively...
August 2, 2017: Behavioural Pharmacology
https://www.readbyqxmd.com/read/28772211/autophagy-as-a-potential-therapeutic-target-during-epithelial-to-mesenchymal-transition-in-renal-cell-carcinoma-an-in-vitro-study
#17
Mamta Singla, Shalmoli Bhattacharyya
Cancer progression toward invasive and metastatic disease is aided by reactivation of epithelial-mesenchymal transition (EMT), involving transdifferentiation of epithelial cells into mesenchymal phenotype. This leads to increased migratory and stem cell-like features in the cells. These EMT cells are more resistant to chemotherapy and it is hypothesized that the phenomenon of autophagy induces resistance, providing a survival strategy for cells. In the present study, we induced EMT-like phenotype in renal carcinoma cells and identified corresponding higher autophagy flux in these cells...
October 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28768446/comparison-of-two-doses-of-intravenous-temsirolimus-in-patients-with-relapsed-refractory-mantle-cell-lymphoma
#18
Wojciech Jurczak, Sundra Ramanathan, Pratyush Giri, Alessandra Romano, Heidi Mocikova, Jill Clancy, Mariajose Lechuga, Michelle Casey, Joseph Boni, Agnieszka Giza, Georg Hess
Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression...
August 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28761748/new-treatment-options-for-metastatic-renal-cell-carcinoma
#19
REVIEW
Alejo Rodriguez-Vida, Thomas E Hutson, Joaquim Bellmunt, Michiel H Strijbos
During the last decade, the treatment of advanced or metastatic renal cell carcinoma (RCC) was revolutionised with the advent of antiangiogenic drugs and tyrosine-kinase inhibitors. Several agents targeting the vascular endothelial growth factor (VEGF) pathway (sunitinib, bevacizumab, pazopanib, axitinib) or the mammalian target of rapamycin pathway (temsirolimus, everolimus) were since then progressively approved for first-line or later-line use in the treatment of patients with advanced RCC and became the new standard of care...
2017: ESMO Open
https://www.readbyqxmd.com/read/28759157/mtor-notch3-signaling-mediates-pulmonary-hypertension-in-hypoxia-exposed-neonatal-rats-independent-of-changes-in-autophagy
#20
Julijana Ivanovska, Sparsh Shah, Mathew J Wong, Crystal Kantores, Amish Jain, Martin Post, Behzad Yeganeh, Robert P Jankov
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) is a pivotal regulator of cell proliferation, survival, and autophagy. Autophagy is increased in adult experimental chronic pulmonary hypertension (PHT), but its contributory role to pulmonary vascular disease remains uncertain and has yet to be explored in the neonatal animal. Notch is a major pro-proliferative pathway activated by mTOR. A direct relationship between autophagy and Notch signaling has not been previously explored. Our aim was to examine changes in mTOR-, Notch-, and autophagy-related pathways and the therapeutic effects of autophagy modulators in experimental chronic neonatal PHT secondary to chronic hypoxia...
November 2017: Pediatric Pulmonology
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