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https://www.readbyqxmd.com/read/28952411/clinical-development-of-mtor-inhibitors-for-renal-cancer
#1
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-2-trial-of-crlx101-in-combination-with-bevacizumab-versus-standard-of-care-in-patients-with-advanced-renal-cell-carcinoma
#2
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 (NDC) enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel NDC containing camptothecin a potent inhibitor of topoisomerase I and the hypoxia-inducible factors (HIF) 1α and 2α. In a phase 1b/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase 2 trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC...
September 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28926611/activation-of-the-unfolded-protein-response-in-sarcoma-cells-treated-with-rapamycin-or-temsirolimus
#3
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/28821555/p53-nongenotoxic-activation-and-mtorc1-inhibition-lead-to-effective-combination-for-neuroblastoma-therapy
#4
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
#5
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/28590313/current-management-of-metastatic-renal-cell-carcinoma-evolving-new-therapies
#6
Ravi Kumar, Anil Kapoor
PURPOSE OF REVIEW: Targeted therapies have recently replaced cytokine treatments as the gold standard for management of metastatic renal cell carcinoma (mRCC). Currently approved treatments include the tyrosine kinase inhibitors sunitinib, pazopanib, axitinib, sorafenib, cabozantinib and lenvatinib; the vascular endothelial growth factor (VEGF) inhibitor bevacizumab; the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus; and the immunologic nivolumab. The purpose of this review is to provide an updated analysis of the clinical data supporting the use of these agents in the first-line and second-line setting...
September 2017: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/28556689/health-related-quality-of-life-data-from-a-phase-3-international-randomized-open-label-multicenter-study-in-patients-with-previously-treated-mantle-cell-lymphoma-treated-with-ibrutinib-versus-temsirolimus
#7
Georg Hess, Simon Rule, Wojciech Jurczak, Mats Jerkeman, Rodrigo Santucci Silva, Chiara Rusconi, Dolores Caballero, Cristina Joao, Mathias Witzens-Harig, Isabelle Bence-Bruckler, Seok-Goo Cho, Wenjiong Zhou, Jenna D Goldberg, Cristina Trambitas, Christopher Enny, Jessica Vermeulen, Shana Traina, Chiun-Fang Chiou, Joris Diels, Martin Dreyling
Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial...
December 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28549783/irinotecan-temozolomide-with-temsirolimus-or-dinutuximab-in-children-with-refractory-or-relapsed-neuroblastoma-cog-anbl1221-an-open-label-randomised-phase-2-trial
#8
RANDOMIZED CONTROLLED TRIAL
Rajen Mody, Arlene Naranjo, Collin Van Ryn, Alice L Yu, Wendy B London, Barry L Shulkin, Marguerite T Parisi, Sabah-E-Noor Servaes, Mitchell B Diccianni, Paul M Sondel, Julia G Bender, John M Maris, Julie R Park, Rochelle Bagatell
BACKGROUND: Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan-temozolomide in patients with relapsed or refractory neuroblastoma. METHODS: For this open-label, randomised, phase 2 selection design trial of the Children's Oncology Group (COG; ANBL1221), patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis...
July 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28504837/immunotherapy-for-metastatic-renal-cell-carcinoma
#9
REVIEW
Susanne Unverzagt, Ines Moldenhauer, Monika Nothacker, Dorothea Roßmeißl, Andreas V Hadjinicolaou, Frank Peinemann, Francesco Greco, Barbara Seliger
BACKGROUND: Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients...
May 15, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28403496/-interdisciplinary-recommendations-for-the-treatment-of-metastatic-renal-cell-carcinoma
#10
Kurt Miller, Lothar Bergmann, Christian Doehn, Jürgen Gschwend, Ulrich Keilholz
Thanks to the use of targeted therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved significantly. A median overall survival of more than 2 years is a realistic claim. These improvements are also reflected in recent discussions about 3 and more lines of therapy.Sunitinib, pazopanib, the combination of bevacizumab and interferon alpha, and temsirolimus are approved for first-line therapy of mRCC. Sunitinib and pazopanib are also approved for second-line therapy, which, for pazopanib, is confined to the use after cytokine failure...
February 2017: Aktuelle Urologie
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
#11
Susan R Rheingold, Sarah K 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)...
May 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28259301/effectiveness-of-antiangiogenic-drugs-in-glioblastoma-patients-a-systematic-review-and-meta-analysis-of-randomized-clinical-trials
#12
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
#13
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...
May 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
#14
MULTICENTER STUDY
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...
March 28, 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
#15
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/28143997/targeted-therapy-for-metastatic-renal-cell-carcinoma
#16
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
#17
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/28077238/patterns-of-care-and-clinical-outcomes-in-patients-with-metastatic-renal-cell-carcinoma-results-from-a-tertiary-cancer-center-in-india
#18
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/28000286/population-pharmacokinetics-of-temsirolimus-and-sirolimus-in-children-with-recurrent-solid-tumours-a-report-from-the-children-s-oncology-group
#19
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...
May 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27995456/current-treatment-strategies-in-relapsed-refractory-mantle-cell-lymphoma-where-are-we-now
#20
REVIEW
Erden Atilla, Pinar Ataca Atilla, Taner Demirer
The management of relapsed/refractory mantle cell lymphoma remains challenging. Patients with relapsed mantle cell lymphoma have been treated with multi-agent salvage chemotherapies; however, outcomes are poor. Although there have been studies in the relapse/refractory setting, current data indicate that autologous hematopoietic stem cell transplantation may be an especially useful approach in the front line setting in patients in first complete or partial remission following induction chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only curative option, although reduced intensity conditioning in chemo-sensitive relapse or refractory mantle cell lymphoma provides better survival rates...
March 2017: International Journal of Hematology
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