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Carfilzomib

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https://www.readbyqxmd.com/read/28545322/cardiovascular-events-during-carfilzomib-therapy-for-relapsed-myeloma-practical-management-aspects-from-two-case-studies
#1
Andrzej J Jakubowiak, Jeanne M DeCara, Khalid Mezzi
Objectives and importance: Patients with multiple myeloma (MM) have an increased risk of cardiovascular comorbidities due to disease burden and treatment-related risk factors. Proteasome inhibitors, including bortezomib and carfilzomib, are effective and generally well tolerated anti-MM agents. However, cardiovascular-related toxicities have been reported with this class of agents, the mechanisms of which are not fully understood. We discuss the practical management of cardiovascular events during carfilzomib therapy for relapsed MM...
May 25, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28537897/mek-inhibitors-cobimetinib-and-trametinib-regressed-a-gemcitabine-resistant-pancreatic-cancer-patient-derived-orthotopic-xenograft-pdox
#2
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Thinzar M Lwin, Ho Kyoung Hwang, Jonathan C Delong, Bryan M Clary, Michael Bouvet, Michiaki Unno, Robert M Hoffman
A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p...
May 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28509582/tariquidar-sensitizes-multiple-myeloma-cells-to-proteasome-inhibitors-via-reduction-of-hypoxia-induced-p-gp-mediated-drug-resistance
#3
Barbara Muz, Hubert D Kusdono, Feda Azab, Pilar de la Puente, Cinzia Federico, Mark Fiala, Ravi Vij, Noha N Salama, Abdel Kareem Azab
Multiple myeloma (MM) presents a poor prognosis and high lethality of patients due to development of drug resistance. P-glycoprotein (P-gp), a drug-efflux transporter, is upregulated in MM patients post-chemotherapy and is involved in the development of drug resistance since many anti-myeloma drugs (including proteasome inhibitors) are P-gp substrates. Hypoxia develops in the bone marrow niche during MM progression and has long been linked to chemoresistance. Additionally, hypoxia-inducible transcription factor (HIF-1α) was demonstrated to directly regulate P-gp expression...
May 16, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28504554/how-is-patient-care-for-multiple-myeloma-advancing
#4
Sonja Genadieva Stavric, Francesca Bonello, Sara Bringhen, Mario Boccadoro, Alessandra Larocca
Treatment of multiple myeloma has undergone profound changes in the past years thanks to the increased understanding of the biology of the disease and the new treatment options. New drugs and effective approaches are currently available for the treatment of multiple myeloma, including immunomodulatory agents, proteasome inhibitors and autologous stem cell transplantation. Areas covered. We have described the recent updated criteria to start treatment in multiple myeloma and summarized clinical data from major studies including most recent agents...
May 15, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28500557/cellular-effect-and-efficacy-of-carfilzomib-depends-on-cellular-net-concentration-gradient
#5
Julia Schäfer, Lukas Welti, Anja Seckinger, Jürgen Burhenne, Dirk Theile, Johanna Weiss
PURPOSE: The cellular interrelation between intracellular concentrations of unbound carfilzomib, a second-generation proteasome inhibitor, and subsequent proteasome inhibition and effect on cell viability are unknown and were evaluated for two different exposure regimens: A high dose bolus regime of 500 nM for 1 h followed by 47 h in drug-free media vs. 48-h continuous exposure to 10 nM. METHODS: Eight multiple myeloma cell lines were exposed to either one of the two exposure regimens...
May 12, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28488026/carfilzomib-and-lenalidomide-response-related-to-vegf-and-vegfr2-germline-polymorphisms
#6
Tristan M Sissung, Cody J Peer, Neha Korde, Sham Mailankody, Dickran Kazandjian, David J Venzon, Ola Landgren, William D Figg
The combination of carfilzomib, lenalidomide, and dexamethasone (CRd) has induced deep responses in patients with newly diagnosed multiple myeloma. While vascular endothelial growth factor (VEGF) pathway polymorphisms have been associated with clinical outcomes for antiangiogenesis agents, we explored associations between such polymorphisms and CRd clinical response. The VEGF-1498C>T (rs833061) and VEGFR2 V297I (rs2305948) were associated with CRd response (OR ≤ 0.10, P ≤ 0.009), whereas VEGF-1498C>T and VEGFR2 Q472H (rs1870377) were associated with minimum residual disease negativity (P ≤ 0...
May 9, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28474745/daratumumab-monotherapy-compared-with-historical-control-data-in-heavily-pretreated-and-highly-refractory-patients-with-multiple-myeloma-an-adjusted-treatment-comparison
#7
Saad Z Usmani, Joris Diels, Tetsuro Ito, Maneesha Mehra, Imran Khan, Annette Lam
Daratumumab is a human CD38-directed monoclonal antibody approved in the United States as monotherapy for patients with multiple myeloma (MM) who have received ≥3 prior lines of therapy (LOTs), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) or who are double refractory to a PI and an IMiD, and in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone for patients with MM who have received ≥1 prior LOT. This study compared the efficacy of daratumumab monotherapy versus historical controls through adjusted treatment comparison...
May 5, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28439109/efficacy-and-safety-of-carfilzomib-regimens-in-multiple-myeloma-patients-relapsing-after-autologous-stem-cell-transplant-aspire-and-endeavor-outcomes
#8
P Hari, M-V Mateos, R Abonour, S Knop, W Bensinger, H Ludwig, K Song, R Hajek, P Moreau, D S Siegel, S Feng, M Obreja, S K Aggarwal, K Iskander, H Goldschmidt
Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib-lenalidomide-dexamethasone; ENDEAVOR, carfilzomib-dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide-dexamethasone; ENDEAVOR, bortezomib-dexamethasone)...
April 25, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28435528/discovery-of-highly-selective-inhibitors-of-the-immunoproteasome-low-molecular-mass-polypeptide-2-lmp2-subunit
#9
Henry W B Johnson, Janet L Anderl, Erin K Bradley, John Bui, Jeffrey Jones, Shirin Arastu-Kapur, Lisa M Kelly, Eric Lowe, David C Moebius, Tony Muchamuel, Christopher Kirk, Zhengping Wang, Dustin McMinn
Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition in vivo...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28430175/carfilzomib-lenalidomide-dexamethasone-vs-lenalidomide-dexamethasone-in-relapsed-multiple-myeloma-by-previous-treatment
#10
M A Dimopoulos, A K Stewart, T Masszi, I Špička, A Oriol, R Hájek, L Rosiñol, D Siegel, G G Mihaylov, V Goranova-Marinova, P Rajnics, A Suvorov, R Niesvizky, A Jakubowiak, J San-Miguel, H Ludwig, S Ro, S Aggarwal, P Moreau, A Palumbo
Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide...
April 21, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28424963/pharmacokinetics-and-safety-of-carfilzomib-in-patients-with-relapsed-multiple-myeloma-and-end-stage-renal-disease-esrd-an-open-label-single-arm-phase-i-study
#11
Hang Quach, Darrell White, Andrew Spencer, P Joy Ho, Divaya Bhutani, Mike White, Sandeep Inamdar, Chris Morris, Ying Ou, Martin Gyger
PURPOSE: The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m(2). This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m(2) in normal renal function and ESRD patients. METHODS: Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m(2) (cycle 1 day 1-2), escalated to 27 mg/m(2) on cycle 1 day 8; if tolerated, 56 mg/m(2) starting cycle 2 day 1...
June 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28415782/glutaminase-inhibitor-cb-839-synergizes-with-carfilzomib-in-resistant-multiple-myeloma-cells
#12
Ravyn M Thompson, Dominik Dytfeld, Leticia Reyes, Reeder M Robinson, Brittany Smith, Yefim Manevich, Andrzej Jakubowiak, Mieczyslaw Komarnicki, Anna Przybylowicz-Chalecka, Tomasz Szczepaniak, Amit K Mitra, Brian G Van Ness, Magdalena Luczak, Nathan G Dolloff
Curative responses in the treatment of multiple myeloma (MM) are limited by the emergence of therapeutic resistance. To address this problem, we set out to identify druggable mechanisms that convey resistance to proteasome inhibitors (PIs; e.g., bortezomib), which are cornerstone agents in the treatment of MM. In isogenic pairs of PI sensitive and resistant cells, we observed stark differences in cellular bioenergetics between the divergent phenotypes. PI resistant cells exhibited increased mitochondrial respiration driven by glutamine as the principle fuel source...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404519/proteasome-inhibitors-to-alleviate-aberrant-ikbkap-mrna-splicing-and-low-ikap-help1-synthesis-in-familial-dysautonomia
#13
Mylène Hervé, El Chérif Ibrahim
FD is a rare neurodegenerative disorder caused by a mutation of the IKBKAP gene, which induces low expression levels of the Elongator subunit IKAP/hELP1 protein. A rational strategy for FD treatment could be to identify drugs increasing IKAP/hELP1 expression levels by blocking protein degradation pathways such as the 26S proteasome. Proteasome inhibitors are promising molecules emerging in cancer treatment and could thus constitute an enticing pharmaceutical strategy for FD treatment. Therefore, we tested three proteasome inhibitors on FD human olfactory ecto-mesenchymal stem cells (hOE-MSCs): two approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), bortezomib and carfilzomib, as well as epoxomicin...
April 9, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28393136/development-of-%C3%AE-hairpin-peptides-for-the-measurement-of-scf-family-e3-ligase-activity-in-vitro-via-ornithine-ubiquitination
#14
Kaiulani M Houston, Adam T Melvin, Gregery S Woss, Effrat L Fayer, Marcey L Waters, Nancy L Allbritton
Regulation of the ubiquitin-proteasome system (UPS) to treat select types of cancer has become a popular area of drug discovery research. The FDA approval of proteasome inhibitors Bortezomib and Carfilzomib in the treatment of multiple myeloma has led to an increased need for chemical reporters capable of detecting and quantifying protein ubiquitination and the activity of members of the UPS including E3 ubiquitin ligases and the proteasome in the tumor cells of the patients. One limitation of peptide-based reporters is their rapid degradation in the cellular environment by cytosolic peptidases...
March 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28388244/which-therapies-will-move-to-the-front-line-for-multiple-myeloma
#15
María J Cejalvo, Javier de la Rubia
Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM...
April 24, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28357173/status-epilepticus-and-blindness-in-a-patient-with-carfilzomib-associated-posterior-reversible-encephalopathy-syndrome
#16
Salam Kadhem, Rawaa Ebrahem, Scott Cooper, Emily Manlove, Ricky Lee
Posterior reversible encephalopathy syndrome (PRES) is a neurological condition characterized by headaches, visual disturbances, and seizures. A magnetic resonance imaging (MRI) scan of an affected brain typically shows symmetrical white matter edema in the posterior cerebral hemispheres. The onset of PRES can constitute a medical emergency, especially when accompanied by status epilepticus. If promptly recognized and treated, the clinical syndrome and associated radiological findings are usually resolved in a matter of weeks or months...
February 19, 2017: Curēus
https://www.readbyqxmd.com/read/28340282/carfilzomib-induces-leukaemia-cell-apoptosis-via-inhibiting-elk1-kiaa1524-elk-1-cip2a-and-activating-pp2a-not-related-to-proteasome-inhibition
#17
Chun-Yu Liu, Feng-Shu Hsieh, Pei-Yi Chu, Wen-Chun Tsai, Chun-Teng Huang, Yuan-Bin Yu, Tzu-Ting Huang, Po-Shen Ko, Man-Hsin Hung, Wan-Lun Wang, Chung-Wai Shiau, Kuen-Feng Chen
Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib...
June 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28333868/proteasome-inhibitor-induced-gastrointestinal-toxicity
#18
Romany L Stansborough, Rachel J Gibson
PURPOSE OF REVIEW: Gastrointestinal toxicities are commonly reported following treatment with proteasome inhibitors. The first-generation proteasome inhibitor, bortezomib, induces significant gastrointestinal side effects including nausea, vomiting, diarrhoea, and constipation, occurring in up to 84% of patients. Despite the development of safer proteasome inhibitors, such as carfilzomib, gastrointestinal toxicities remain some of the most common side effects. This review aims to summarize the previous literature on proteasome inhibitor-induced gastrointestinal toxicities, report on recent updates in the field, and investigate possible mechanisms of this toxicity...
June 2017: Current Opinion in Supportive and Palliative Care
https://www.readbyqxmd.com/read/28325256/how-have-evolutions-in-strategies-for-the-treatment-of-relapsed-refractory-multiple-myeloma-translated-into-improved-outcomes-for-patients
#19
REVIEW
Pieter Sonneveld, Edwin De Wit, Philippe Moreau
Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28318679/treatment-with-carfilzomib-should-these-patients-be-admitted-in-the-intensive-care-unit
#20
R Rodríguez-García, M J Espina, L Viña, I Astola, L López-Amor, D Escudero
No abstract text is available yet for this article.
March 16, 2017: Medicina Intensiva
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