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https://www.readbyqxmd.com/read/27913521/sequencing-of-nontransplant-treatments-in-multiple-myeloma-patients-with-active-disease
#1
Andrew J Yee, Noopur S Raje
The approval of several different classes of drugs in recent years has resulted in a dramatic expansion of treatment options for multiple myeloma patients, improving both survival and quality of life. Lenalidomide and bortezomib are now core components of treatment both at time of diagnosis and at relapse. Next-generation immunomodulatory drugs, like pomalidomide, and newer proteasome inhibitors like carfilzomib and ixazomib are available for use at relapse. Drugs with novel mechanisms of action such as the histone deacetylase inhibitor panobinostat and the monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) are significant steps forward...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27911437/the-role-of-the-proteasome-in-aml
#2
REVIEW
C M Csizmar, D-H Kim, Z Sachs
Acute myeloid leukemia (AML) is deadly hematologic malignancy. Despite a well-characterized genetic and molecular landscape, targeted therapies for AML have failed to significantly improve clinical outcomes. Over the past decade, proteasome inhibition has been demonstrated to be an effective therapeutic strategy in several hematologic malignancies. Proteasome inhibitors, such as bortezomib and carfilzomib, have become mainstays of treatment for multiple myeloma and mantle cell lymphoma. In light of this success, there has been a surge of literature exploring both the role of the proteasome and the effects of proteasome inhibition in AML...
December 2, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27904737/a-clinical-update-on-the-role-of-carfilzomib-in-the-treatment-of-relapsed-or-refractory-multiple-myeloma
#3
REVIEW
B Franken, N W C J van de Donk, J C Cloos, S Zweegman, H M Lokhorst
Even though the prognosis of patients with multiple myeloma is continuing to improve, all patients eventually develop relapsed refractory disease. Several novel therapeutics have been developed in the last few years including the second-generation proteasome inhibitor carfilzomib which has been approved for patients with relapsed and refractory multiple myeloma in the United States since 2012. Recently data from several phase III studies have become available showing the promising efficacy of carfilzomib in combination with lenalidomide, which led to the renewed approval of carfilzomib in combination with lenalidomide and dexamethasone for relapsed myeloma in 2015...
December 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27900802/therapeutic-potential-of-carfilzomib-an-irreversible-proteasome-inhibitor-against-acetaminophen-induced-hepatotoxicity-in-mice
#4
Abdulrazaq Alanazi, Saleh G Algfeley, Khaled A Al-Hosaini, Hesham M Korashy, Faisal Imam, Mahmoud N Nagi
Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis...
November 30, 2016: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/27894203/management-of-adverse-events-induced-by-next-generation-immunomodulatory-drug-and-proteasome-inhibitors-in-multiple-myeloma
#5
Marco Salvini, Francesca Bonello, Mario Boccadoro, Alessandra Larocca
In the last decade the introduction of novel agents has strongly improved multiple myeloma prognosis by doubling median overall survival. Unfortunately disease relapse is very common and patients may become refractory to previous drugs. Therefore, new therapeutic strategies are urgently needed. Areas covered. We have reviewed the available data on next generation novel agents, particularly immunomodulatory drug pomalidomide and proteasome inhibitors carfilzomib and ixazomib, the latter being the first-in-class orally available...
November 29, 2016: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/27888768/multiple-myeloma-treatment-at-relapse-after-autologous-stem-cell-transplantation-a-practical-analysis
#6
REVIEW
F Malard, J L Harousseau, M Mohty
Over the past decade, significant advances have been made in the field of multiple myeloma. Introduction of the so-called novel agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), and improved supportive care have resulted in significantly better outcome. Standard first line treatment in fit patients include PI and IMiD based induction, high dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) and consolidation/maintenance. However, despite these progresses MM remains incurable for the majority of patients and most patients will relapse...
November 15, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27875670/efficacy-of-carfilzomib-in-the-treatment-of-relapsed-and-or-refractory-multiple-myeloma-a-meta-analysis-of-data-from-clinical-trials
#7
Runzhe Chen, Baoan Chen, Xiaoping Zhang, Chong Gao
OBJECTIVE: Recently, carfilzomib has become a promising therapeutic approach for relapsed and (or) refractory multiple myeloma (RRMM), but no study has summarized the overall effect of carfilzomib in RRMM. To explore the role of carfilzomib, we performed a meta-analysis of all known prospective clinical trials to assess the efficacy of carfilzomib in patients with RRMM. METHODS AND MATERIALS: A systematic review of publications was performed on December 15, 2015...
October 2016: Discovery Medicine
https://www.readbyqxmd.com/read/27873146/comparison-of-dialysis-and-solvatofluorochromism-based-methods-to-determine-drug-release-rates-from-polymer-nanoassemblies
#8
Derek Reichel, Younsoo Bae
PURPOSE: To compare traditional dialysis- and novel solvatofluorochromism (SFC)-based methods for accurate determination of drug release profiles for nanoparticle drug carriers. METHODS: Polymer nanoassemblies (PNAs) varying in drug release patterns were prepared using poly(ethylene glycol), poly(ethylenimine), hydrophobic excipients (palmitate and deoxycholate), and model hydrophobic anticancer drugs with clinical relevance (carfilzomib and docetaxel). Nile blue (NB) was used as a model SFC dye quenching fluorescence in water yet emitting strong fluorescence in the presence of hydrophobic drugs within PNAs...
November 21, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27813130/p-glycoprotein-inhibition-sensitizes-human-breast-cancer-cells-to-proteasome-inhibitors
#9
Rahul R Deshmukh, Seongho Kim, Yasmine Elghoul, Q Ping Dou
Although effective for the treatment of hematological malignancies, the FDA approved proteasome inhibitors bortezomib and carfilzomib have limited efficacy in solid tumors including triple negative breast cancer (TNBC). Chemotherapy is the only option for treating TNBC due to the absence of specific therapeutic targets. Therefore, development of new TNBC therapeutic strategies has been warranted. We studied whether P-glycoprotein (P-gp) inhibition could sensitize TNBC cells to proteasome inhibitors. When verapamil, a P-gp inhibitor, was combined with the proteasome inhibitor MG132, bortezomib or carfilzomib, the cytotoxic effects and apoptosis in TNBC MDA-MB-231 cells were enhanced, compared to each treatment alone...
November 4, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27806331/xpo1-inhibitor-combination-therapy-with-bortezomib-or-carfilzomib-induces-nuclear-localization-of-i%C3%AE%C2%BAb%C3%AE-and-overcomes-acquired-proteasome-inhibitor-resistance-in-human-multiple-myeloma
#10
Joel G Turner, Trinayan Kashyap, Jana L Dawson, Juan Gomez, Alexis A Bauer, Steven Grant, Yun Dai, Kenneth H Shain, Mark Meads, Yosef Landesman, Daniel M Sullivan
Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays...
October 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27795518/current-treatment-of-refractory-and-relapsed-multiple-myeloma
#11
Makoto Sasaki
In the past decade, previously approved novel agents, such as proteasome inhibitors (bortezomib) and immunomodulatory drugs ([IMiDs]; e.g., lenalidomide), have led to significant improvement in the treatment of multiple myeloma in Japan. However, almost all patients will ultimately relapse, even when they have achieved a deep and prolonged therapeutic response with initial treatment. Next-generation IMiDs (pomalidomide) and deacetylase inhibitors (panobinostat) were approved for use as salvage therapy for refractory and relapsed multiple myeloma [RRMM] within the last year...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27793878/maf-protein-mediates-innate-resistance-to-proteasome-inhibition-therapy-in-multiple-myeloma
#12
Ya-Wei Qiang, Shiqiao Ye, Yu Chen, Amy F Buros, Ricky Edmonson, Frits Van Rhee, Bart Barlogie, Joshua Epstein, Gareth J Morgan, Faith E Davies
Multiple myeloma (MM) patients with the t(14;16) translocation have a poor prognosis, and unlike other molecular subgroups, their outcome has not improved with the introduction of bortezomib. The mechanism underlying innate resistance of MM to bortezomib is unknown. In the present study, we have investigated how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy (bortezomib and carfilzomib). High levels of MAF protein were found in t(14;16) cell lines, cell lines from the t(4;14) subgroup had intermediate levels, while cell lines from the other subgroups had low levels...
October 28, 2016: Blood
https://www.readbyqxmd.com/read/27790952/tethered-polymer-nanoassemblies-for-sustained-carfilzomib-release-and-prolonged-suppression-of-proteasome-activity
#13
Derek Reichel, Min Jae Lee, Wooin Lee, Kyung Bo Kim, Younsoo Bae
AIM: Proteasome inhibitors, such as carfilzomib (CFZ), have shown potential to treat various types of cancers in preclinical models, but clinical applications are limited likely due to formulation and delivery issues. Results & methodology: Tethered polymer nanoassemblies (TNAs) were synthesized by tethering hydrophilic polymers and hydrophobic groups to charged polymer scaffolds, and then end-capping remaining amines on scaffold. Drug entrapment and drug release half-lives increased as charge was removed from scaffold...
October 2016: Therapeutic Delivery
https://www.readbyqxmd.com/read/27785949/apremilast-reversed-carfilzomib-induced-cardiotoxicity-through-inhibition-of-oxidative-stress-nf-%C3%AE%C2%BAb-and-mapk-signaling-in-rats
#14
Faisal Imam, Naif O Al-Harbi, Mohammad Matar Al-Harbi, Mushtaq Ahmad Ansari, Mashal M Almutairi, Musaad Alshammari, Talal Saad Almukhlafi, Mohd Nazam Ansari, Khaldoon Aljerian, Sheikh Fayaz Ahmad
Carfilzomib (CFZ), is a potent, selective second generation proteasome inhibitor, used for the treatment of multiple myeloma. The aim of the present study was to investigate the possible protective effect of apremilast (AP) on the CFZ -induced cardiotoxicity. Rats were randomly divided into four groups: Group 1, served as the control group, received normal saline. Group 2, served as the toxic group, received CFZ (4 mg/kg, intraperitoneally [i.p.]). Groups 3 and 4, served as treatment groups, and received CFZ with concomitant oral administration of AP in doses of 10 and 20 mg/kg/day, respectively...
October 27, 2016: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/27784673/silencing-c-myc-translation-as-a-therapeutic-strategy-through-targeting-pi3k-delta-and-ck1-epsilon-in-hematological-malignancies
#15
Changchun Deng, Mark R Lipstein, Luigi Scotto, Xavier O Jirau Serrano, Michael A Mangone, Shirong Li, Jeremie Vendome, Yun Hao, Xiaoming Xu, Shi-Xian Deng, Ronald B Realubit, Nicholas P Tatonetti, Charles Karan, Suzanne Lentzsch, David A Fruman, Barry Honig, Donald W Landry, Owen A O'Connor
Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of mRNA translation, we hypothesized that co-targeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K delta isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells...
October 26, 2016: Blood
https://www.readbyqxmd.com/read/27782060/identification%C3%A2-of%C3%A2-long%C3%A2-non-coding%C3%A2-rnas-deregulated%C3%A2-in%C3%A2-multiple%C3%A2-myeloma%C3%A2-cells%C3%A2-resistant%C3%A2-to-proteasome%C3%A2-inhibitors
#16
Ehsan Malek, Byung-Gyu Kim, James J Driscoll
While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance...
October 6, 2016: Genes
https://www.readbyqxmd.com/read/27769052/cannabinoids-synergize-with-carfilzomib-reducing-multiple-myeloma-cells-viability-and-migration
#17
Massimo Nabissi, Maria Beatrice Morelli, Massimo Offidani, Consuelo Amantini, Silvia Gentili, Alessandra Soriani, Claudio Cardinali, Pietro Leoni, Giorgio Santoni
Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Δ9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765932/cisplatin-induced-synthetic-lethality-to-arginine-starvation-therapy-by-transcriptional-suppression-of-ass1-is-regulated-by-dec1-hif-1%C3%AE-and-c-myc-transcription-network-and-is-independent-of-ass1-promoter-dna-methylation
#18
Yan Long, Wen-Bin Tsai, Jeffrey T Chang, Marcos Estecio, Medhi Wangpaichitr, Naramol Savaraj, Lynn G Feun, Helen H W Chen, Macus Tien Kuo
Many human tumors require extracellular arginine (Arg) for growth because the key enzyme for de novo biosynthesis of Arg, argininosuccinate synthetase 1 (ASS1), is silenced. These tumors are sensitive to Arg-starvation therapy using pegylated arginine deiminase (ADI-PEG20) which digests extracellular Arg. Many previous studies reported that ASS1 silencing is due to epigenetic inactivation of ASS1 expression by DNA methylation, and that the demethylation agent 5-aza-deoxycytidine (Aza-dC) can induce ASS1 expression...
September 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27765408/design-synthesis-and-biological-evaluation-of-novel-non-covalent-piperidine-containing-peptidyl-proteasome-inhibitors
#19
Jiankang Zhang, Lixin Gao, Jianjun Xi, Li Sheng, Yanmei Zhao, Lei Xu, Yidan Shao, Shourong Liu, Rangxiao Zhuang, Yubo Zhou, Jia Li
A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib...
October 6, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27764795/a-novel-3d-mesenchymal-stem-cell-model-of-the-multiple-myeloma-bone-marrow-niche-biologic-and-clinical-applications
#20
Jana Jakubikova, Danka Cholujova, Teru Hideshima, Paulina Gronesova, Andrea Soltysova, Takeshi Harada, Jungnam Joo, Sun-Young Kong, Raphael E Szalat, Paul G Richardson, Nikhil C Munshi, David M Dorfman, Kenneth C Anderson
Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system...
October 13, 2016: Oncotarget
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