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Molecular myeloma

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https://www.readbyqxmd.com/read/28592764/multiple-myeloma-pathophysiology-and-progress-in-management
#1
Junya Kuroda, Yoshiaki Chinen
There have been dramatic recent advances in understanding the basic pathophysiology and treatment strategies for multiple myeloma (MM). Research has shown both a high inter-patient diversity and intra-clonal heterogeneity even in a single patient in terms of cytogenetic/molecular abnormalities, and has also identified marked diversity in the immunological factors involved in tumor surveillance among MM patients. In the presence of a variety of novel agents, including molecular-targeted agents, immunomodulatory agents, and monoclonal antibodies, the optimal translation of current knowledge on both molecular and immunologic findings into clinical use is crucial for managing MM...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28584253/prediction-of-outcome-in-newly-diagnosed-myeloma-a-meta-analysis-of-the-molecular-profiles-of-1-905-trial-patients
#2
V Shah, A L Sherborne, B A Walker, D C Johnson, E M Boyle, S Ellis, D B Begum, P Z Proszek, J R Jones, C Pawlyn, S Savola, M W Jenner, M T Drayson, R G Owen, R S Houlston, D A Cairns, W M Gregory, G Cook, F E Davies, G H Jackson, G J Morgan, M F Kaiser
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1...
June 6, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28573897/molecular-mechanisms-current-management-and-next-generation-therapy-in-myeloma-bone-disease
#3
Roy Heusschen, Joséphine Muller, Elodie Duray, Nadia Withofs, Arnold Bolomsky, Frédéric Baron, Yves Beguin, Eline Menu, Heinz Ludwig, Jo Caers
Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results...
June 2, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28550183/somatic-mutation-spectrum-in-monoclonal-gammopathy-of-undetermined-significance-indicates-a-less-complex-genomic-landscape-compared-to-multiple-myeloma
#4
Aneta Mikulasova, Christopher P Wardell, Alexander Murison, Eileen M Boyle, Graham H Jackson, Jan Smetana, Zuzana Kufova, Ludek Pour, Viera Sandecka, Martina Almasi, Pavla Vsianska, Evzen Gregora, Petr Kuglik, Roman Hajek, Faith E Davies, Gareth J Morgan, Brian A Walker
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about the molecular mechanism of malignant transformation. We have performed whole exome sequencing together with CGH+SNP array analysis in 33 flow-cytometry separated abnormal plasma cell samples from MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level...
May 26, 2017: Haematologica
https://www.readbyqxmd.com/read/28549851/identification-of-pathway-based-prognostic-gene-signatures-in-patients-with-multiple-myeloma
#5
Mohamad Zamani-Ahmadmahmudi, Shahreyar Dabiri, Nadia Nadimi
Molecular profiling is used to extract prognostic gene signatures in different cancers such as multiple myeloma (MM), which is the second most common hematological malignancy. In this study, we utilized gene expression profiles to find biological pathways that could efficiently predict survival time in patients with MM. Four data sets-namely GSE2658 (559 samples), GSE9782 (264 samples), GSE6477 (147 samples), and GSE57317 (55 samples)-were employed. GSE2658 was used as a training data set and the others as validation data sets...
May 9, 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28548370/current-state-of-a-dual-behavior-of-antimicrobial-peptides-therapeutic-agents-and-promising-delivery-vectors
#6
REVIEW
Urszula Piotrowska, Marcin Sobczak, Ewa Oledzka
Microorganism resistance is an important challenge in modern medicine due to the global uncontrolled use of antibiotics. Natural and synthetic antimicrobial peptides (AMPs) symbolize a new family of antibiotics, which have stimulated research and clinical interest as new therapeutic options for infections. They represent one of the most promising antimicrobial substances, due to their broad spectrum of biological activity, against bacteria, fungi, protozoa, viruses, yeast and even tumour cells. Besides, being antimicrobial, AMPs have been shown to bind and neutralize bacterial endotoxins, as well as possess immunomodulatory, anti-inflammatory, wound-healing, angiogenic and antitumour properties...
May 26, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28522584/cooperative-targets-of-combined-mtor-hdac-inhibition-promote-myc-degradation
#7
John K Simmons, Aleksandra M Michalowski, Benjamin J Gamache, Wendy DuBois, Jyoti Patel, Ke Zhang, Joy Gary, Shuling Zhang, Snehal Gaikwad, Daniel Connors, Nicholas Watson, Elena Leon, Jin-Qiu Chen, W Michael Kuehl, Maxwell P Lee, Adriana Zingone, Ola Landgren, Peter Ordentlich, Jing Huang, Beverly A Mock
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents.  In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28522572/the-prognostic-value-of-the-depth-of-response-in-multiple-myeloma-depends-on-the-time-of-assessment-risk-status-and-molecular-subtype
#8
Carolina Schinke, Antje Hoering, Hongwei Wang, Victoria Carlton, Sharmilan Thanendrarajan, Shayu Deshpande, Purvi Patel, Gabor Molnar, Sandra Susanibar, Meera Mohan, Pankaj Mathur, Muthukumar Radhakrishnan, Shadiqul Hoque, Jorge Jo Kamimoto, Monica Grazziutti, Frits van Rhee, Maurizio Zangari, Giovanni Insuasti-Beltran, Daisy Alapat, Ginell Post, Shmuel Yaccoby, Joshua Epstein, Leo Rasche, Sarah Johnson, Martin Moorhead, Tom Willis, Bart Barlogie, Brian Walker, Niels Weinhold, Faith E Davies, Gareth J Morgan
No abstract text is available yet for this article.
May 18, 2017: Haematologica
https://www.readbyqxmd.com/read/28504689/molecular-signaling-in-multiple-myeloma-association-of-ras-raf-mutations-and-mek-erk-pathway-activation
#9
J Xu, N Pfarr, V Endris, E K Mai, N H Md Hanafiah, N Lehners, R Penzel, W Weichert, A D Ho, P Schirmacher, H Goldschmidt, M Andrulis, M S Raab
Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM)...
May 15, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28504647/identification-of-a-nucleoside-analog-active-against-adenosine-kinase-expressing-plasma-cell-malignancies
#10
Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J Barelli, Michelle A Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H Shoemaker, J David Warren, Olivier Elemento, Kenneth M Kaye, Ethel Cesarman
Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity...
June 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28492226/circulating-tumour-dna-sequence-analysis-as-an-alternative-to-multiple-myeloma-bone-marrow-aspirates
#11
Olena Kis, Rayan Kaedbey, Signy Chow, Arnavaz Danesh, Mark Dowar, Tiantian Li, Zhihua Li, Jessica Liu, Mark Mansour, Esther Masih-Khan, Tong Zhang, Scott V Bratman, Amit M Oza, Suzanne Kamel-Reid, Suzanne Trudel, Trevor J Pugh
The requirement for bone-marrow aspirates for genomic profiling of multiple myeloma poses an obstacle to enrolment and retention of patients in clinical trials. We evaluated whether circulating cell-free DNA (cfDNA) analysis is comparable to molecular profiling of myeloma using bone-marrow tumour cells. We report here a hybrid-capture-based Liquid Biopsy Sequencing (LB-Seq) method used to sequence all protein-coding exons of KRAS, NRAS, BRAF, EGFR and PIK3CA in 64 cfDNA specimens from 53 myeloma patients to >20,000 × median coverage...
May 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28489849/utilizing-bmp-2-muteins-for-treatment-of-multiple-myeloma
#12
Axel Seher, Charlotte Lagler, Thorsten Stühmer, Urs Dietmar Achim Müller-Richter, Alexander Christian Kübler, Walter Sebald, Thomas Dieter Müller, Joachim Nickel
Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM...
2017: PloS One
https://www.readbyqxmd.com/read/28476134/overexpression-of-rkip-and-its-cross-talk-with-several-regulatory-gene-products-in-multiple-myeloma
#13
REVIEW
Anna Shvartsur, Kevin B Givechian, Hermes Garban, Benjamin Bonavida
Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets...
May 5, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28468088/-clinical-significance-of-s100a6-and-notch1-in-multiple-myeloma-patients
#14
H Y Bao, Y Wang, J N Wang, M Song, Q Q Meng, X Han
Objective: To investigate the expression levels of S100A6, Notch1 in multiple myeloma (MM) patients and its clinical significance. Mathods: The expression levels of S100A6, Notch1 in 28 MM cases and 20 healthy controls were determined by real time quantitative PCR (RQ-PCR) , and their relationships with clinical features and outcomes were analyzed. Immunohistochemical was used to analysis the levels of S100A6 and Notch1 in bone marrow biopsy samples and intramedullary metastases soft tissues. RQ-PCR and Western blot were used to test the changes of Notch1 mRNA and Notch1 protein in U266 MM cells after S100A6 silenced by siRNA...
April 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28456791/nk-cells-and-multiple-myeloma-associated-endothelial-cells-molecular-interactions-and-influence-of-il-27
#15
Alessandra Dondero, Beatrice Casu, Francesca Bellora, Angelo Vacca, Annunziata De Luisi, Maria Antonia Frassanito, Claudia Cantoni, Silvia Gaggero, Daniel Olive, Alessandro Moretta, Cristina Bottino, Roberta Castriconi
Angiogenesis represents a hallmark of tumor progression in Multiple Myeloma (MM), a still incurable malignancy. Here we analyzed the activity of cytokine-stimulated NK cells against tumor-associated endothelial cells isolated from bone marrow aspirates of MM patients with active disease (MMECs). We show that NK cells activated with optimal doses of IL-15 killed MMECs thanks to the concerted action of multiple activating receptors. In particular, according to the high expression of PVR and Nectin-2 on MMECs, DNAM-1 actively participated in target recognition...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28441582/synthesis-and-antiproteasomal-activity-of-novel-o-benzyl-salicylamide-based-inhibitors-built-from-leucine-and-phenylalanine
#16
Radek Jorda, Jan Dušek, Eva Řezníčková, Karel Pauk, Pratibha P Magar, Aleš Imramovský, Vladimír Kryštof
Inhibition of protein degradation is one of strategies for suppression of uncontrolled proliferation of cancer cells. Proteolytic degradation in cells is mainly ensured by proteasome and its inhibition by bortezomib showed benefit in clinical use for the treatment of multiple myeloma. We report here the library of antiproteasomal O-benzyl salicylamides built from leucine and phenylalanine. Prepared compounds displayed antiproliferative activity on K562, CEM and U266 cancer cell lines, ranging from high micromolar to submicromolar GI50 values...
April 15, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28439875/epigenetic-repression-of-mir-375-is-the-dominant-mechanism-for-constitutive-activation-of-the-pdpk1-rps6ka3-signalling-axis-in-multiple-myeloma
#17
Shotaro Tatekawa, Yoshiaki Chinen, Masaki Ri, Tomoko Narita, Yuji Shimura, Yayoi Matsumura-Kimoto, Taku Tsukamoto, Tsutomu Kobayashi, Eri Kawata, Nobuhiko Uoshima, Tomohiko Taki, Masafumi Taniwaki, Hiroshi Handa, Shinsuke Iida, Junya Kuroda
Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28429672/the-molecular-mechanisms-of-thalidomide-teratogenicity-and-implications-for-modern-medicine
#18
J Knobloch, D Jungck, A Koch
Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and anti-angiogenic activities are considered in many other refractory diseases...
March 31, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28428191/the-role-of-minimal-residual-disease-testing-in-myeloma-treatment-selection-and-drug-development-current-value-and-future-applications
#19
Kenneth C Anderson, Daniel Auclair, Gary J Kelloff, Caroline C Sigman, Herve Avet-Loiseau, Ann T Farrell, Nicole J Gormley, Shaji K Kumar, Ola Landgren, Nikhil C Munshi, Michele Cavo, Faith E Davies, Alessandra Di Bacco, Jennifer S Dickey, Steven I Gutman, Howard R Higley, Mohamad A Hussein, J Milburn Jessup, Ilan R Kirsch, Richard F Little, Robert D Loberg, Jens G Lohr, Lata Mukundan, James L Omel, Trevor J Pugh, Gregory H Reaman, Michael D Robbins, A Kate Sasser, Nancy Valente, Elena Zamagni
Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10(-5)‒10(-6) cells...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28427158/the-varied-distribution-and-impact-of-ras-codon-and-other-key-dna-alterations-across-the-translocation-cyclin-d-subgroups-in-multiple-myeloma
#20
Caleb K Stein, Charlotte Pawlyn, Shweta Chavan, Leo Rasche, Niels Weinhold, Adam Corken, Amy Buros, Pieter Sonneveld, Graham H Jackson, Ola Landgren, Tariq Mughal, Jie He, Bart Barlogie, P Leif Bergsagel, Faith E Davies, Brian A Walker, Gareth J Morgan
We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF...
April 25, 2017: Oncotarget
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