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https://www.readbyqxmd.com/read/28314474/sulforaphane-as-an-adjunctive-to-everolimus-counteracts-everolimus-resistance-in-renal-cancer-cell-lines
#1
Eva Juengel, Stephanie Euler, Sebastian Maxeiner, Jochen Rutz, Saira Justin, Frederik Roos, Wael Khoder, Karen Nelson, Wolf O Bechstein, Roman A Blaheta
BACKGROUND: The mechanistic target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, have widened therapeutic options to treat renal cell carcinoma (RCC). However, chronic treatment with these inhibitors often induces resistance, leading to therapeutic failure. PURPOSE: The natural compound, sulforaphane (SFN), was added to an everolimus based regime in vitro in the hopes of preventing resistance development. METHODS: A panel of RCC cell lines (A498, Caki-1, KTCTL-26) was treated with everolimus or SFN or with an everolimus-SFN-combination, either short- (24h) or long-term (8 weeks), and cell growth, proliferation, apoptosis, and cell cycle phases were measured...
April 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28302097/objective-response-to-mtor-inhibition-in-a-metastatic-collision-tumor-of-the-liver-composed-of-melanoma-and-adenocarcinoma-with-tsc1-loss-a-case-report
#2
Munveer S Bhangoo, Jenny Y Zhou, Siraj M Ali, Russell Madison, Alexa B Schrock, Carrie Costantini
BACKGROUND: Collision tumors are uncommon but well described clinical entities composed of distinct tumor histologies occurring within the same anatomic site. Optimal management of patients with collision tumors remains highly variable and depends on clinical characteristics such as the involved tumor types, predominant histology, as well as the extent of disease. Comprehensive genomic profiling is a means of identifying genomic alterations to suggest benefit from targeted therapy. CASE PRESENTATION: A 78-year-old woman presented to medical oncology with liver metastases occurring within the background of a 1-year history of uveal melanoma...
March 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28295182/a-phase-1-trial-of-temsirolimus-and-intensive-re-induction-chemotherapy-for-2nd-or-greater-relapse-of-acute-lymphoblastic-leukaemia-a-children-s-oncology-group-study-advl1114
#3
Susan R Rheingold, Sarah J Tasian, James A Whitlock, David T Teachey, Michael J Borowitz, Xiaowei Liu, Charles G Minard, Elizabeth Fox, Brenda J Weigel, Susan M Blaney
The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m(2) weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m(2) weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m(2) weekly × 2 doses (DL-1)...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28276433/renal-cell-carcinoma
#4
REVIEW
James J Hsieh, Mark P Purdue, Sabina Signoretti, Charles Swanton, Laurence Albiges, Manuela Schmidinger, Daniel Y Heng, James Larkin, Vincenzo Ficarra
Renal cell carcinoma (RCC) denotes cancer originated from the renal epithelium and accounts for >90% of cancers in the kidney. The disease encompasses >10 histological and molecular subtypes, of which clear cell RCC (ccRCC) is most common and accounts for most cancer-related deaths. Although somatic VHL mutations have been described for some time, more-recent cancer genomic studies have identified mutations in epigenetic regulatory genes and demonstrated marked intra-tumour heterogeneity, which could have prognostic, predictive and therapeutic relevance...
March 9, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28263222/mtor-and-cardiovascular-diseases-diabetes-mellitus
#5
Bruno Vergès
The mammalian targets of rapamycin (mTOR) inhibitors are potent immunosuppressors used for prevention of acute rejection following transplantation and have been more recently used as anticancer drugs. mTOR inhibitors have a significant impact on glucose metabolism and induce frequently diabetes. mTOR inhibitors, when used as immunosuppressive agents (sirolimus, everolimus), can induce diabetes with an incidence which is low when used without calcineurin inhibitors (CNI) but high when used in combination with CNI (from 11...
March 4, 2017: Transplantation
https://www.readbyqxmd.com/read/28259301/effectiveness-of-antiangiogenic-drugs-in-glioblastoma-patients-a-systematic-review-and-meta-analysis-of-randomized-clinical-trials
#6
REVIEW
Giuseppe Lombardi, Ardi Pambuku, Luisa Bellu, Miriam Farina, Alessandro Della Puppa, Luca Denaro, Vittorina Zagonel
BACKGROUND: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases...
March 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28258008/high-content-screening-of-clinically-tested-anticancer-drugs-identifies-novel-inhibitors-of-human-mrp1-abcc1
#7
Brian G Peterson, Kee W Tan, Bremansu Osa-Andrews, Surtaj H Iram
Multidrug resistance protein 1 (MRP1/ABCC1), an integral transmembrane efflux transporter, belongs to the ATP-binding cassette (ABC) protein superfamily. MRP1 governs the absorption and disposition of a wide variety of endogenous and xenobiotic substrates including various drugs across organs and physiological barriers. Additionally, its overexpression has been implicated in multidrug resistance in chemotherapy of multiple cancers. Here, we describe the development of a high content imaging-based screening assay for MRP1 activity...
February 28, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28222071/combination-of-the-histone-deacetylase-inhibitor-vorinostat-with-bevacizumab-in-patients-with-clear-cell-renal-cell-carcinoma-a-multicentre-single-arm-phase-i-ii-clinical-trial
#8
Roberto Pili, Glenn Liu, Sreenivasulu Chintala, Hendrick Verheul, Shabnam Rehman, Kristopher Attwood, Martin A Lodge, Richard Wahl, James I Martin, Kiersten Marie Miles, Silvia Paesante, Remi Adelaiye, Alejandro Godoy, Serina King, James Zwiebel, Michael A Carducci
BACKGROUND: Class II histone deacetylase (HDAC) inhibitors induce hypoxia-inducible factor-1 and -2α degradation and have antitumour effects in combination with vascular endothelial growth factor (VEGF) inhibitors. In this study, we tested the safety and efficacy of the HDAC inhibitor vorinostat and the VEGF blocker bevacizumab in metastatic clear-cell renal cell carcinoma (ccRCC) patients previously treated with different drugs including sunitinib, sorafenib, axitinib, interleukin-2, interferon, and temsirolimus...
February 21, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28194539/phase-i-trial-of-mek-1-2-inhibitor-pimasertib-combined-with-mtor-inhibitor-temsirolimus-in-patients-with-advanced-solid-tumors
#9
Monica Mita, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, Alain Mita, Ronald Natale, Wei Guo, Charles Zhao, Razelle Kurzrock, Aung Naing
Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated...
February 13, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28176536/kinase-targets-in-cns-drug-discovery
#10
Hendra Gunosewoyo, Lifang Yu, Lenka Munoz, Michael Kassiou
Originally thought to be nondruggable, kinases represent attractive drug targets for pharmaceutical companies and academia. To date, there are over 40 kinase inhibitors approved by the US FDA, with 32 of these being small molecules, in addition to the three mammalian target of rapamycin inhibitor macrolides (sirolimus, temsirolimus and everolimus). Despite the rapid development of kinase inhibitors for cancer, presently none of these agents are approved for CNS indications. This mini perspective highlights selected kinase targets for CNS disorders, of which brain-permeable small-molecule inhibitors are reported, with demonstrated preclinical proof-of-concept efficacy...
February 8, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28143997/targeted-therapy-for-metastatic-renal-cell-carcinoma
#11
REVIEW
Andika Afriansyah, Agus Rizal Ah Hamid, Chaidir A Mochtar, Rainy Umbas
In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC...
October 2016: Acta Medica Indonesiana
https://www.readbyqxmd.com/read/28141932/an-expanded-portfolio-of-survival-metrics-for-assessing-anticancer-agents
#12
Jennifer Karweit, Srividya Kotapati, Samuel Wagner, James W Shaw, Steffan W Wolfe, Amy P Abernethy
OBJECTIVES: With the introduction of more effective anticancer agents that prolong survival, there is a need for new methods to define the clinical value of treatments. The objective of this preliminary qualitative and quantitative analysis was to assess the utility of an expanded portfolio of survival metrics to differentiate the value of anticancer agents. STUDY DESIGN: A literature review was conducted of phase 3 trial data, reported in regulatory submissions within the last 10 years of agents for 6 metastatic cancers (breast cancer, colorectal cancer [CRC], melanoma, non-small cell lung cancer [NSCLC], prostate cancer [PC], and renal cell cancer [RCC])...
January 2017: American Journal of Managed Care
https://www.readbyqxmd.com/read/28105206/curcumin-enhances-temsirolimus-induced-apoptosis-in-human-renal-carcinoma-cells-through-upregulation-of-yap-p53
#13
Shan Xu, Zheng Yang, Yizeng Fan, Bing Guan, Jing Jia, Yang Gao, Ke Wang, Kaijie Wu, Xinyang Wang, Pengsheng Zheng, Dalin He, Peng Guo
Curcumin has frequently been used as a therapeutic agent in the treatment of various types of disease and is known to enhance the drug sensitivity of cells. In the present study, the combined effect of curcumin and temsirolimus treatment on apoptosis in human renal cell carcinoma (RCC) cells was investigated. Temsirolimus is an inhibitor of the mechanistic target of rapamycin signaling pathway and used in the first-line treatment of metastatic RCC. It was demonstrated that curcumin combined with temsirolimus markedly induced apoptosis in RCC cells, however this effect was not observed following curcumin or temsirolimus treatment alone...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28096934/first-line-treatment-options-in-metastatic-renal-cell-cancer
#14
REVIEW
Anil Kapoor
The introduction of targeted therapy a decade ago revolutionized the treatment of metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Currently recommended first-line treatments in Canada include sunitinib, pazopanib, and temsirolimus. With the heterogeneity of mRCC disease, the choice of treatment is driven largely by prognostic factors...
November 2016: Canadian Urological Association Journal, Journal de L'Association des Urologues du Canada
https://www.readbyqxmd.com/read/28077238/patterns-of-care-and-clinical-outcomes-in-patients-with-metastatic-renal-cell-carcinoma-results-from-a-tertiary-cancer-center-in-india
#15
Anant Ramaswamy, Amit Joshi, Vanita Noronha, Vijay M Patil, Rushabh Kothari, Arvind Sahu, Ram Abhinav Kannan, Nilesh Sable, Palak Popat, Santosh Menon, Kumar Prabhash
INTRODUCTION: The current treatment of metastatic renal cell carcinoma (mRCC) revolves around targeted agents, which have resulted in a median overall survival of 22 to 26 months in registration trials. However, the outcomes in a non-trial, real-world Indian population have not yet been evaluated. MATERIALS AND METHODS: The present study was a part of a prospective Clinical Trials Registry-India-registered study, the Kidney Cancer Registry, a prospectively maintained kidney cancer registry...
October 19, 2016: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28061764/biological-toxicities-as-surrogate-markers-of-efficacy-in-patients-treated-with-mtor-inhibitors-for-metastatic-renal-cell-carcinoma
#16
M Jebali, R Elaidi, M Brizard, J Fouque, C Takouchop, B Sabatier, S Oudard, J Medioni
BACKGROUND: Metabolic toxicities of mTOR inhibitors (mTORi) are well characterized. The purpose of the study was to investigate the relationship between these metabolic toxicities and mTORi efficacy. METHODS: From 2007 to 2011, metabolic toxicities were retrospectively collected in patients treated with an mTORi (everolimus, temsirolimus) for a metastatic renal cell carcinoma (mRCC) in a single institution. Patients were eligible if they have received an mTORi for at least 28 days...
January 6, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28039705/safety-profile-of-temsirolimus-in-patients-with-metastatic-renal-cell-carcinoma
#17
Ivan Levakov, Sasa Vojinov, Goran Marusic, Milan Popov, Olivera Levakov, Mladen Popov, Dimitrije Jeremic
PURPOSE: Various targeted disease-specific therapeutics are currently approved, demonstrating a survival benefit over therapy with interferon-alpha (IFN-α) in patients with metastatic renal cell carcinoma (mRCC). Temsirolimus, a highly specific inhibitor of the mammalian target of rapamycin (mTOR), improves the overall and progression-free survival of high-risk patients with mRCC. The purpose of this study was to estimate the effects of temsirolimus on several laboratory parameters and to report the potential adverse events (AEs) in patients with mRCC...
November 2016: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
https://www.readbyqxmd.com/read/28035748/a-phase-i-study-of-perifosine-with-temsirolimus-for-recurrent-pediatric-solid-tumors
#18
Oren J Becher, Stephen W Gilheeney, Yasmin Khakoo, David C Lyden, Sofia Haque, Kevin C De Braganca, Jill M Kolesar, Jason T Huse, Shakeel Modak, Leonard H Wexler, Kim Kramer, Ivan Spasojevic, Ira J Dunkel
BACKGROUND: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. PROCEDURE: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors...
December 30, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28004284/a-phase-i-study-of-tivantinib-in-combination-with-temsirolimus-in-patients-with-advanced-solid-tumors
#19
Christos E Kyriakopoulos, Amy M Braden, Jill M Kolesar, Jens C Eickhoff, Howard H Bailey, Jennifer Heideman, Glenn Liu, Kari B Wisinski
Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination...
December 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/28000286/population-pharmacokinetics-of-temsirolimus-and-sirolimus-in-children-with-recurrent-solid-tumours-a-report-from-the-children-s-oncology-group
#20
Tomoyuki Mizuno, Tsuyoshi Fukuda, Uwe Christians, John P Perentesis, Maryam Fouladi, Alexander A Vinks
AIMS: Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Pharmacokinetic (PK) characterization of temsirolimus in children is limited and there is no paediatric temsirolimus population PK model available. The objective of this study was to simultaneously characterize the PK of temsirolimus and its metabolite sirolimus in paediatric patients with recurrent solid or central nervous system tumours and to develop a population PK model. METHODS: The PK data for temsirolimus and sirolimus were collected as a part of a Children's Oncology Group phase I clinical trial in paediatric patients with recurrent solid tumours...
November 7, 2016: British Journal of Clinical Pharmacology
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