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Treatment of myeloma

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https://www.readbyqxmd.com/read/28938542/the-immune-checkpoint-molecule-v-set-ig-domain-containing-4-is-an-independent-prognostic-factor-for-multiple-myeloma
#1
Jin Roh, Youkyoung Jeon, A-Neum Lee, Sang Min Lee, YeonMee Kim, Chang Ohk Sung, Chan-Jeoung Park, Jung Yong Hong, Dok Hyun Yoon, Cheolwon Suh, Jooryung Huh, Inhak Choi, Chan-Sik Park
Multiple myeloma (MM) remains as an incurable disease, despite recent substantial improvements in treatment. Therefore, development of novel biomarkers for risk stratification and new therapeutic targets are imperative. One of the emerging treatments for MM is the immune checkpoint blockades. V-set Ig domain-containing 4 (VSIG4) is a lately studied B7-related immune checkpoint modulator. We assessed the VSIG4 expression in patients with MM and its prognostic impact. We analyzed 81 bone marrow and 66 extramedullary biopsy samples of MM patients using immunohistochemistry...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935772/the-european-medicines-agency-review-of-carfilzomib-for-the-treatment-of-adult-patients-with-multiple-myeloma-who-have-received-at-least-one-prior-therapy
#2
Kyriaki Tzogani, Jorge Camarero Jiménez, Isabel Garcia, Arantxa Sancho-López, Marc Martin, Alexandre Moreau, Pierre Demolis, Tomas Salmonson, Jonas Bergh, Edward Laane, Heinz Ludwig, Christian Gisselbrecht, Francesco Pignatti
On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression-free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0...
September 21, 2017: Oncologist
https://www.readbyqxmd.com/read/28933784/inhibition-of-the-deubiquitinase-usp5-leads-to-c-maf-protein-degradation-and-myeloma-cell-apoptosis
#3
Siyu Wang, Jiaxiang Juan, Zubin Zhang, Yanyun Du, Yujia Xu, Jiefei Tong, Biyin Cao, Michael F Moran, Yuanying Zeng, Xinliang Mao
The deubiquitinase USP5 stabilizes c-Maf, a key transcription factor in multiple myeloma (MM), but the mechanisms and significance are unclear. In the present study, USP5 was found to interact with c-Maf and prevented it from degradation by decreasing its polyubiquitination level. Specifically, the 308th and 347th lysine residues in c-Maf were critical for USP5-mediated deubiquitination and stability. There are five key domains in the USP5 protein and subsequent studies revealed that the cryptic ZnF domain and the C-box domain interacted with c-Maf but the UBA1/UBA2 domain partly increased its stability...
September 21, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28933264/from-a-better-understanding-of-the-mechanisms-of-action-of-histone-deacetylases-inhibitors-to-the-progress-of-the-treatment-of-malignant-lymphomas-and-plasma-cell-myeloma
#4
Romeo-Gabriel Mihăilă
BACKGROUND: Notable progress has been made in chemo- and immunotherapy of B-cell lymphomas, but less in the treatment of T-cell lymphomas. OBJECTIVE: Histone deacetylases inhibitors are a potentially useful therapeutic mean, as an epigenetic dysregulation is present in lymphomas, and especially in T-cell types. We aimed to study the progress made in this area. METHOD: A minireview was achieved using the articles published in PubMed in the last two years and the new patents made in this field...
September 19, 2017: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/28932850/amino-and-chloro-8-hydroxyquinolines-and-their-copper-complexes-as-proteasome-inhibitors-and-antiproliferative-agents
#5
Valentina Oliveri, Valeria Lanza, Danilo Milardi, Maurizio Viale, Irena Maric, Carmelo Sgarlata, Graziella Vecchio
Proliferation and programmed cell death are tightly correlated with the ubiquitin-proteasome system (UPS). Alterations in the UPS may be implicated in pathological conditions such as the proteasome over-activity in cancer cells. Mounting evidence indicates that many types of actively proliferating malignant cells are more sensitive to proteasome inhibition than normal cells, and therefore UPS inhibitors are actively pursued as anticancer agents. The approval of the proteasome inhibitor drug bortezomib for the treatment of myeloma and lymphoma further highlights the need for UPS inhibitors...
September 21, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28932638/the-anti-slamf7-antibody-elotuzumab-mediates-nk-cell-activation-through-both-cd16-dependent-and-independent-mechanisms
#6
Tatiana Pazina, Ashley M James, Alexander W MacFarlane, Natalie A Bezman, Karla A Henning, Christine Bee, Robert F Graziano, Michael D Robbins, Adam D Cohen, Kerry S Campbell
Elotuzumab is a humanized therapeutic monoclonal antibody directed to the surface glycoprotein SLAMF7 (CS1, CRACC, CD319), which is highly expressed on multiple myeloma (MM) tumor cells. Improved clinical outcomes have been observed following treatment of MM patients with elotuzumab in combination with lenalidomide or bortezomib. Previous work showed that elotuzumab stimulates NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), via Fc-domain engagement with FcγRIIIa (CD16). SLAMF7 is also expressed on NK cells, where it can transmit stimulatory signals...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28930776/a-phase1b-dose-escalation-study-of-recombinant-circularly-permuted-trail-in-patients-with-relapsed-or-refractory-multiple-myeloma
#7
Jian Hou, Lugui Qiu, Yaozhong Zhao, Xuejun Zhang, Yan Liu, Zhao Wang, Fang Zhou, Yun Leng, Shifang Yang, Hao Xi, Fuxu Wang, Bing Zhu, Wenming Chen, Peng Wei, Xiangjun Zheng
OBJECTIVES: Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT), or CPT, is a novel antitumor drug candidate. This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of single-agent CPT in patients with relapsed or refractory multiple myeloma (RRMM), and aimed to identify the recommended dose for the phase 2 study. MATERIALS AND METHODS: Patients received single or multiple doses (once daily for 5 consecutive days per 21-d cycle) of CPT intravenous infusion at doses of 5, 6...
September 19, 2017: American Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28928900/dihydroorotate-dehydrogenase-inhibitors-target-c-myc-and-arrest-melanoma-myeloma-and-lymphoma-cells-at-s-phase
#8
Mathura Subangari Dorasamy, Bhavesh Choudhary, Kavitha Nellore, Hosahalli Subramanya, Pooi-Fong Wong
Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. Inhibition of this enzyme impedes cancer cell proliferation but the exact mechanisms of action of these inhibitors in cancer cells are poorly understood. In this study, we showed that cancer cells, namely melanoma, myeloma and lymphoma overexpressed DHODH protein and treatment with A771726 and Brequinar sodium resulted in cell cycle arrest at S-phase. Transfection with DHODH shRNA depleted DHODH protein expression and impeded the proliferation of melanoma cells...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28928810/characteristics-of-baff-and-april-factor-expression-in-multiple-myeloma-and-clinical-significance
#9
Jing Pan, Yuanyuan Sun, Ning Zhang, Jianming Li, Fangxin Ta, Wei Wei, Shanshan Yu, Limei Ai
The characteristics of the proliferation of B-cell activating factor (BAFF) and the proliferation-inducing ligand (APRIL) mRNA expression in mononuclear cell in multiple myeloma patients were detected, and the correlation was analyzed between the BAFF and APRIL concentrations in plasma and tumor burden parameters of multiple myeloma. Bone marrow samples from 60 patients with multiple myeloma and 20 healthy persons taken as controls, were collected. Bone marrow mononuclear cells (BMMCs) were harvested, and plasma was extracted...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28928126/chimeric-antigen-receptor-t-cell-therapies-for-multiple-myeloma
#10
Lekha Mikkilineni, James N Kochenderfer
Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T-cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR T-cells against leukemia and lymphoma has encouraged development of CAR T-cell therapies for MM...
September 19, 2017: Blood
https://www.readbyqxmd.com/read/28926977/mouse-monoclonal-antibodies-generated-from-full-length-human-cereblon-detection-of-cereblon-protein-in-patients-with-multiple-myeloma
#11
Xiubao Chang, Qinqin Xu, Yuexian Hou, Cynthia Li, Ye Xu, A Keith Stewart
Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs' action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor...
September 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28923647/is-cytomegalovirus-surveillance-necessary-for-patients-with-low-reactivation-risk-in-an-autologous-hematopoietic-cell-transplantation-setting
#12
A H Kaya, E Tekgunduz, S Akpinar, H Batgi, F Bekdemir, O Kayikci, S Namdaroglu, B U Ulu, M S Dal, M K Cakar, S Korkmaz, F Altuntas
BACKGROUND: In an autologous hematopoietic cell transplantation (AHCT) setting, routine cytomegalovirus (CMV) surveillance is not indicated except in high-risk situations. On the other hand, some studies reported increased CMV reactivation in AHCT setting as a result of incorporation of novel agents into treatment algorithms, such as bortezomib and rituximab. We retrospectively analyzed CMV reactivation and infection rates in patients with no high-risk features, who were treated with AHCT...
October 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28923389/1-4-naphthoquinones-as-inhibitors-of-itch-a-hect-domain-e3-ligase-and-tumor-growth-suppressors-in-multiple-myeloma
#13
Yi-Min Liu, Wei-Chun HuangFu, Han-Li Huang, Wei-Cheng Wu, Yi-Lin Chen, Yun Yen, Hsiang-Ling Huang, Chih-Ying Nien, Mei-Jung Lai, Shiow-Lin Pan, Jing-Ping Liou
A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28920142/acupuncture-for-reduction-of-symptom-burden-in-multiple-myeloma-patients-undergoing-autologous-hematopoietic-stem-cell-transplantation-a-randomized-sham-controlled-trial
#14
Gary Deng, Sergio Giralt, David J Chung, Heather Landau, Jonathan Siman, Benjamin Search, Marci Coleton, Emily Vertosick, Nathan Shapiro, Christine Chien, Xin S Wang, Barrie Cassileth, Jun J Mao
PURPOSE: Hematopoietic stem cell transplantation (HCT) is potentially curative for a number of hematologic malignancies, but is associated with high symptom burden. We conducted a randomized sham-controlled trial (RCT) to evaluate efficacy and safety of acupuncture as an integrative treatment for managing common symptoms during HCT. METHODS: Adult patients with multiple myeloma undergoing high-dose melphalan followed by autologous HCT (AHCT) were randomized to receive either true or sham acupuncture once daily for 5 days starting the day after chemotherapy...
September 17, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28918747/omega-3-polyunsaturated-fatty-acids-eicosapentaenoic-acid-and-docosahexaenoic-acid-enhance-dexamethasone-sensitivity-in-multiple-myeloma-cells-by-the-p53-mir-34a-bcl-2-axis
#15
Xianping Dai, Mengshun Li, Feng Geng
Dexamethasone is widely used in multiple myeloma (MM) for its cytotoxic effects on lymphoid cells. However, many MM patients are resistant to dexamethasone, although some can benefit from dexamethasone treatment. In this study, we noted that ω-3 polyunsaturated fatty acids (PUFAs) enhanced the dexamethasone sensitivity of MM cells by inducing cell apoptosis. q-PCR analysis revealed that miR-34a could be significantly induced by PUFAs in U266 and primary MM cells. Transfection with miR-34a antagonist or miR-34a agomir could restore or suppress the dexamethasone sensitivity in U266 cells...
July 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28918692/the-cyclin-dependent-kinase-4-6-inhibitor-abemaciclib-exerts-dose-dependent-cytostatic-and-cytocidal-effects-and-induces-autophagy-in-multiple-myeloma-cells
#16
Noriyoshi Iriyama, Hirotsugu Hino, Shota Moriya, Masaki Hiramoto, Yoshihiro Hatta, Masami Takei, Keisuke Miyazawa
The D-type cyclin (CCND)-cyclin-dependent kinase 4/6 (CDK4/6) complex has been implicated in multiple myeloma development. We investigated the biological activity of CDK4/6 inhibitor abemaciclib on cell growth and survival in three myeloma cell lines, KMS-12-PE, RPMI 8226, and IM-9. Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all cell lines, with significant differences seen at a concentration of 320 nM. Treatment with 1 μM abemaciclib increased the fraction of cells in the G0/G1 phase and decreased the fraction in the S-G2/M phases...
September 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28916148/chemokine-receptor-directed-imaging-and-therapy
#17
REVIEW
Andreas K Buck, Antje Stolzenburg, Heribert Hänscheid, Andreas Schirbel, Katharina Lückerath, Margret Schottelius, Hans-Jürgen Wester, Constantin Lapa
The C - X - C chemokine receptor 4 (CXCR4) and its natural ligand CXCL12 are key factors in the process of cell migration, homing of hematopoietic stem cells to the bone marrow, and represent important mediators of angiogenesis and cell proliferation. The CXCR4/CXCL12 interplay can be disrupted by CXCR4 antagonists such as Plerixafor which are already in daily clinical use, i.e. for mobilization and subsequent harvesting of hematopoietic progenitor cells and stem cell transplantation. In a pathological condition, involvement in the process of metastasis and homing of cancer cells to a protective niche has been described, making CXCR4 an attractive target for imaging and treatment of malignant diseases...
September 12, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28915615/expression-of-cd38-in-myeloma-bone-niche-a-rational-basis-for-the-use-of-anti-cd38-immunotherapy-to-inhibit-osteoclast-formation
#18
Federica Costa, Denise Toscani, Antonella Chillemi, Valeria Quarona, Marina Bolzoni, Valentina Marchica, Rosanna Vescovini, Cristina Mancini, Eugenia Martella, Nicoletta Campanini, Chiara Schifano, Sabrina Bonomini, Fabrizio Accardi, Alberto L Horenstein, Franco Aversa, Fabio Malavasi, Nicola Giuliani
It is known that multiple myeloma (MM) cells express CD38 and that a recently developed human anti-CD38 monoclonal antibody Daratumumab mediates myeloma killing. However, the expression of CD38 and other functionally related ectoenzymes within the MM bone niche and the potential effects of Daratumumab on bone cells are still unknown. This study firstly defines by flow cytometry and immunohistochemistry the expression of CD38 by bone marrow cells in a cohort of patients with MM and indolent monoclonal gammopathies...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915594/identification-of-precision-treatment-strategies-for-relapsed-refractory-multiple-myeloma-by-functional-drug-sensitivity-testing
#19
Muntasir Mamun Majumder, Raija Silvennoinen, Pekka Anttila, David Tamborero, Samuli Eldfors, Bhagwan Yadav, Riikka Karjalainen, Heikki Kuusanmäki, Juha Lievonen, Alun Parsons, Minna Suvela, Esa Jantunen, Kimmo Porkka, Caroline A Heckman
Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915587/expression-and-release-of-glucose-regulated-protein-78-grp78-in-multiple-myeloma
#20
Normann Steiner, Bojana Borjan, Roman Hajek, Karin Jöhrer, Georg Göbel, Wolfgang Willenbacher, Johann Kern, Eberhard Gunsilius, Gerold Untergasser
INTRODUCTION: Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses. RESULTS: GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM...
August 22, 2017: Oncotarget
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