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https://www.readbyqxmd.com/read/29768064/a-look-at-treatment-strategies-for-relapsed-multiple-myeloma
#1
Giusy Cetani, Mario Boccadoro, Stefania Oliva
Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials...
May 16, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29766327/characterization-of-carfilzomib-resistant-non-small-cell-lung-cancer-cell-lines
#2
Neale T Hanke, Elliot Imler, Marilyn T Marron, Bruce E Seligmann, Linda L Garland, Amanda F Baker
PURPOSE: We previously showed that carfilzomib (CFZ) has potent anti-proliferative and cytotoxic activity in a broad range of lung cancer cell lines. Here we investigate possible mechanisms of CFZ acquired resistance in lung cancer cell lines. METHODS: CFZ-resistant non-small cell lung cancer (NSCLC) cell lines were developed by exposing A549 and H520 cells to stepwise increasing concentrations of CFZ. Resistance to CFZ and cross-resistance to bortezomib and other chemotherapy drugs was measured using the MTT assay...
May 15, 2018: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/29765356/soluble-and-cell-cell-mediated-drivers-of-proteasome-inhibitor-resistance-in-multiple-myeloma
#3
REVIEW
Mariah L Farrell, Michaela R Reagan
It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29755650/preclinical-comparison-of-proteasome-and-ubiquitin-e1-enzyme-inhibitors-in-cutaneous-squamous-cell-carcinoma-the-identification-of-mechanisms-of-differential-sensitivity
#4
Angela McHugh, Kenneth Fernandes, Andrew P South, Jemima E Mellerio, Julio C Salas-Alanís, Charlotte M Proby, Irene M Leigh, Mark K Saville
Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29748955/investigational-agents-in-immunotherapy-a-new-horizon-for-the-treatment-of-multiple-myeloma
#5
REVIEW
Cindy Varga, Jacob P Laubach, Kenneth C Anderson, Paul G Richardson
The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment...
May 10, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29748013/loss-of-c-ebp-%C3%AE-lip-drives-cisplatin-resistance-in-malignant-pleural-mesothelioma
#6
Joanna Kopecka, Iris C Salaroglio, Luisella Righi, Roberta Libener, Sara Orecchia, Federica Grosso, Vladan Milosevic, Preeta Ananthanarayanan, Luisa Ricci, Enrica Capelletto, Monica Pradotto, Francesca Napoli, Massimo Di Maio, Silvia Novello, Menachem Rubinstein, Giorgio V Scagliotti, Chiara Riganti
OBJECTIVES: Cisplatin-based chemotherapy is moderately active in malignant pleural mesothelioma (MPM) due to intrinsic drug resistance and to low immunogenicity of MPM cells. CAAT/enhancer binding protein (C/EBP)-β LIP is a pro-apoptotic and chemosensitizing transcription factor activated in response to endoplasmic reticulum (ER) stress. MATERIALS AND METHODS: We investigated if LIP levels can predict the clinical response to cisplatin and survival of MPM patients receiving cisplatin-based chemotherapy...
June 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29742565/current-challenges-and-opportunities-in-the-management-of-antibody-mediated-rejection-in-lung-transplantation
#7
Amanda L Hulbert, Elizabeth N Pavlisko, Scott M Palmer
PURPOSE OF REVIEW: There is increasing recognition of the importance of antibody-mediated rejection (AMR) after lung transplantation. The development of donor-specific antibodies, a key feature of AMR, occurs in approximately 30% of lung transplant recipients and is associated with poor posttransplant outcomes. This review highlights recently developed AMR diagnostic criteria in lung transplantation, potential mechanisms that mediate the development of AMR, and discusses current and emerging treatment strategies for this significant, graft-limiting complication...
June 2018: Current Opinion in Organ Transplantation
https://www.readbyqxmd.com/read/29734808/enhanced-glioblastoma-targeting-ability-of-carfilzomib-enabled-by-d-a7r-modified-lipid-nanodisk
#8
Mingfei Zhang, Linwei Lu, Man Ying, Huitong Ruan, Xiaoyi Wang, Huan Wang, Zhilan Chai, Songli Wang, Changyou Zhan, Jun Pan, Weiyue Lu
The robust proliferation of tumors relies on rich neovasculature for nutrients supply. Therefore, a basic strategy of tumor targeting therapy should include not only killing regular cancer cells but also blocking tumor neovasculature. D-peptide DA7R, which was previously reported to specifically bind vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), could achieve the goal of multi-targets recognition. Accordingly, the main purposes of this work were to establish a carfilzomib loaded lipid nanodisk modified with multifunctional peptide DA7R (DA7R-ND/CFZ) and to evaluate its anti-glioblastoma efficacy in vitro and in vivo...
May 7, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29728700/combination-therapy-with-carfilzomib-lenalidomide-and-dexamethasone-krd-results-in-an-unprecedented-purity-of-the-stem-cell-graft-in-newly-diagnosed-patients-with-myeloma
#9
Nishant Tageja, Neha Korde, Dickran Kazandjian, Sandhya Panch, Elisabet Manasanch, Manisha Bhutani, Mary Kwok, Sham Mailankody, Constance Yuan, Maryalice Stetler-Stevenson, Susan F Leitman, Claude Sportes, Ola Landgren
Still, many physicians give 4 cycles of combination therapy to multiple myeloma patients prior to collection of stem cells for autologous bone marrow transplant. This tradition originates from older doxorubicin-containing regiments which limited the number of cycles due to cumulative cardiotoxicity. Using older regiments, most patients had residual myeloma cells in their autologous stem-cell grafts during collection. Emerging data show that newly diagnosed multiple myeloma patients treated with modern carfilzomib/lenalidomide/dexamethasone (KRd) therapy, on average, take 6 cycles until reaching minimal residual disease (MRD) negativity...
May 4, 2018: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/29707147/molecular-responses-to-therapeutic-proteasome-inhibitors-in-multiple-myeloma-patients-are-donor-cell-type-and-drug-dependent
#10
Eleni-Dimitra Papanagnou, Evangelos Terpos, Efstathios Kastritis, Issidora S Papassideri, Ourania E Tsitsilonis, Meletios A Dimopoulos, Ioannis P Trougakos
Proteasome is central to proteostasis network functionality and its over-activation represents a hallmark of advanced tumors; thus, its selective inhibition provides a strategy for the development of novel antitumor therapies. In support, proteasome inhibitors, e.g. Bortezomib or Carfilzomib have demonstrated clinical efficacy against hematological cancers. Herein, we studied proteasome regulation in peripheral blood mononuclear cells and erythrocytes isolated from healthy donors or from Multiple Myeloma patients treated with Bortezomib or Carfilzomib...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29670315/carfilzomib-for-multiple-myeloma
#11
REVIEW
(no author information available yet)
No abstract text is available yet for this article.
April 2018: Australian Prescriber
https://www.readbyqxmd.com/read/29650268/efficacy-and-toxicity-profile-of-carfilzomib-based-regimens-for-treatment-of-multiple-myeloma-a-systematic-review
#12
REVIEW
Adeela Mushtaq, Vikas Kapoor, Azka Latif, Ahmad Iftikhar, Umar Zahid, Ali McBride, Ivo Abraham, Irbaz Bin Riaz, Faiz Anwer
Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone...
May 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29616843/phase-1-trial-of-ibrutinib-and-carfilzomib-combination-therapy-for-relapsed-or-relapsed-and-refractory-multiple-myeloma
#13
Ajai Chari, Sarah Larson, Beata Holkova, Robert F Cornell, Cristina Gasparetto, Chatchada Karanes, Jeffrey V Matous, Ruben Niesvizky, Jason Valent, Matthew Lunning, Saad Z Usmani, Larry D Anderson, Lipo Chang, Yihua Lee, Yvonne Pak, Zeena Salman, Thorsten Graef, Elizabeth Bilotti, Saurabh Chhabra
This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia...
April 4, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29615082/response-and-progression-free-survival-according-to-planned-treatment-duration-in-patients-with-relapsed-multiple-myeloma-treated-with-carfilzomib-lenalidomide-and-dexamethasone-krd-versus-lenalidomide-and-dexamethasone-rd-in-the-phase-iii-aspire-study
#14
Meletios Dimopoulos, Michael Wang, Vladimir Maisnar, Jiri Minarik, William Bensinger, Maria-Victoria Mateos, Mihaela Obreja, Julie Blaedel, Philippe Moreau
BACKGROUND: In ASPIRE, carfilzomib, lenalidomide, and dexamethasone (KRd) significantly improved progression-free survival (PFS) and response rates versus lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma. Per protocol, patients received KRd for a maximum of 18 cycles followed by Rd to progression, so the benefit/risk profile of KRd to progression was not established. METHODS: This post hoc analysis evaluated the efficacy and safety of KRd versus Rd at 18 months from randomization...
April 4, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29603798/the-start-of-a-new-wave-developments-in-proteasome-inhibition-in-multiple-myeloma
#15
REVIEW
Kwee Yong, Sebastian Gonzalez-McQuire, Zsolt Szabo, Paul Schoen, Roman Hajek
Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first-line treatment for eligible patients but, historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy, and the development of resistance...
March 30, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29582365/evaluation-of-cardiovascular-toxicity-associated-with-treatments-containing-proteasome-inhibitors-in-multiple-myeloma-therapy
#16
Andrea Iannaccone, G Bruno, A Ravera, F Gay, M Salvini, S Bringhen, L Sabia, E Avenatti, F Veglio, A Milan
INTRODUCTION: Recently new treatment options have substantially increased survival for patients with relapsed and/or refractory multiple myeloma (RRMM). Among these, proteasome inhibitors (PI), such as bortezomib and carfilzomib, offer high response rate and prolonged survival. These agents are generally well tolerated but demonstrated a significant cardiovascular toxicity, mostly for regimen containing carfilzomib. AIM: To assess the cardiovascular damage in patients treated with PI for RRMM...
March 26, 2018: High Blood Pressure & Cardiovascular Prevention: the Official Journal of the Italian Society of Hypertension
https://www.readbyqxmd.com/read/29550338/mechanism-of-cardiovascular-toxicity-by-proteasome-inhibitors-new-paradigm-derived-from-clinical-and-pre-clinical-evidence
#17
REVIEW
Mara Gavazzoni, Enrico Vizzardi, Elio Gorga, Ivano Bonadei, Laura Rossi, Angelo Belotti, Giuseppe Rossi, Rossella Ribolla, Marco Metra, Riccardo Raddino
Proteasome Inhibitors (PI) have now become the cornerstone of treatment of multiple myeloma (MM). Carfilzomib has been demonstrated to cause more frequent cardiovascular side effects such as dyspnea, hypertension, and heart failure. Recent pre-clinical studies have investigated the effects of proteasome on myocardial and vascular cells, but the pathogenic mechanism underlying the effects of proteasome inhibition on these cells is poorly understood. We reviewed the evidence from clinical trials, post-hoc analysis and small observational studies currently available and summarized the data from experimental, focusing on the pathogenic mechanisms potentially implicated in the cardiovascular toxicity of proteasome inhibitor, particularly of carfilzomib that is most responsible for cardiovascular side effects...
June 5, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29508628/drug-associated-pulmonary-arterial-hypertension
#18
Michael McGee, Nicholas Whitehead, Jennifer Martin, Nicholas Collins
INTRODUCTION: While pulmonary arterial hypertension remains an uncommon diagnosis, various therapeutic agents are recognized as important associations. These agents are typically categorized into "definite", "likely", "possible", or "unlikely" to cause pulmonary arterial hypertension, based on the strength of evidence. OBJECTIVE: This review will focus on those therapeutic agents where there is sufficient literature to adequately comment on the role of the agent in the pathogenesis of pulmonary arterial hypertension...
March 6, 2018: Clinical Toxicology
https://www.readbyqxmd.com/read/29508087/cardiovascular-complications-of-multiple-myeloma-treatment-evaluation-management-and-prevention
#19
REVIEW
Dae Hyun Lee, Michael G Fradley
PURPOSE OF REVIEW: Multiple myeloma treatment regimens consist of proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and steroids. In this paper, we will review the pathophysiology and associated cardiotoxicities of the different multiple myeloma therapeutic modalities and present methods to mitigate the development of cardiovascular complications. RECENT FINDINGS: Although proteasome inhibitors and immunomodulatory drugs have led to significant improvements in oncologic outcomes, there is increasing evidence of serious cardiovascular side effects which may be exacerbated in the setting of underlying cardiovascular risk factors or disease...
March 6, 2018: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29497034/proteasome-inhibition-blocks-necroptosis-by-attenuating-death-complex-aggregation
#20
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
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