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Cancer Cell

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https://www.readbyqxmd.com/read/28262554/target-expression-generation-preclinical-activity-and-pharmacokinetics-of-the-bcma-t-cell-bispecific-antibody-em801-for-multiple-myeloma-treatment
#1
Anja Seckinger, Jose Antonio Delgado, Samuel Moser, Laura Moreno, Brigitte Neuber, Anna Grab, Susanne Lipp, Juana Merino, Felipe Prosper, Martina Emde, Camille Delon, Melanie Latzko, Reto Gianotti, Remo Lüoend, Ramona Murr, Ralf J Hosse, Lydia Jasmin Harnisch, Marina Bacac, Tanja Fauti, Christian Klein, Aintzane Zabaleta, Jens Hillengass, Elisabetta Ada Cavalcanti-Adam, Anthony D Ho, Michael Hundemer, Jesus F San Miguel, Klaus Strein, Pablo Umaña, Dirk Hose, Bruno Paiva, Minh Diem Vu
We identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. We constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3(+) T cell/myeloma cell crosslinking, followed by CD4(+)/CD8(+) T cell activation, and secretion of interferon-γ, granzyme B, and perforin. This effect is CD4 and CD8 T cell mediated. EM801 induced, at nanomolar concentrations, myeloma cell death by autologous T cells in 34 of 43 bone marrow aspirates, including those from high-risk patients and patients after multiple lines of treatment, tumor regression in six of nine mice in a myeloma xenograft model, and depletion of BCMA(+) cells in cynomolgus monkeys...
February 27, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28262555/membrane-proximal-epitope-facilitates-efficient-t-cell-synapse-formation-by-anti-fcrh5-cd3-and-is-a-requirement-for-myeloma-cell-killing
#2
Ji Li, Nicola J Stagg, Jennifer Johnston, Michael J Harris, Sam A Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R James, Teemu T Junttila
The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys...
February 20, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28238683/endothelial-notch1-activity-facilitates-metastasis
#3
Elfriede Wieland, Juan Rodriguez-Vita, Sven S Liebler, Carolin Mogler, Iris Moll, Stefanie E Herberich, Elisa Espinet, Esther Herpel, Amitai Menuchin, Jenny Chang-Claude, Michael Hoffmeister, Christoffer Gebhardt, Hermann Brenner, Andreas Trumpp, Christian W Siebel, Markus Hecker, Jochen Utikal, David Sprinzak, Andreas Fischer
Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis...
February 12, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28089890/single-chromosome-gains-commonly-function-as-tumor-suppressors
#4
Jason M Sheltzer, Julie H Ko, John M Replogle, Nicole C Habibe Burgos, Erica S Chung, Colleen M Meehl, Nicole M Sayles, Verena Passerini, Zuzana Storchova, Angelika Amon
Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness...
December 29, 2016: Cancer Cell
https://www.readbyqxmd.com/read/28292443/paradox-breaking-raf-inhibitors-that-also-target-src-are-effective-in-drug-resistant-braf-mutant-melanoma
#5
Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M J M Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer
No abstract text is available yet for this article.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292442/eto2-glis2-hijacks-transcriptional-complexes-to-drive-cellular-identity-and-self-renewal-in-pediatric-acute-megakaryoblastic-leukemia
#6
Cécile Thirant, Cathy Ignacimouttou, Cécile K Lopez, M'Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L Carmichael, Benjamin T Kile, Eric Soler, John D Crispino, Christian Wichmann, Françoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A Bernard, Sébastien Malinge, Thomas Mercher
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292441/spop-mutation-drives-prostate-tumorigenesis-in%C3%A2-vivo-through-coordinate-regulation-of-pi3k-mtor-and-ar-signaling
#7
Mirjam Blattner, Deli Liu, Brian D Robinson, Dennis Huang, Anton Poliakov, Dong Gao, Srilakshmi Nataraj, Lesa D Deonarine, Michael A Augello, Verena Sailer, Lalit Ponnala, Michael Ittmann, Arul M Chinnaiyan, Andrea Sboner, Yu Chen, Mark A Rubin, Christopher E Barbieri
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292440/a-kinase-inhibitor-targeted-to-mtorc1-drives-regression-in-glioblastoma
#8
QiWen Fan, Ozlem Aksoy, Robyn A Wong, Shirin Ilkhanizadeh, Chris J Novotny, William C Gustafson, Albert Yi-Que Truong, Geraldine Cayanan, Erin F Simonds, Daphne Haas-Kogan, Joanna J Phillips, Theodore Nicolaides, Masanori Okaniwa, Kevan M Shokat, William A Weiss
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292439/integrated-molecular-characterization-of-uterine-carcinosarcoma
#9
Andrew D Cherniack, Hui Shen, Vonn Walter, Chip Stewart, Bradley A Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A Soslow, Russell R Broaddus, Rosemary E Zuna, Gordon Robertson, Peter W Laird, Raju Kucherlapati, Gordon B Mills, John N Weinstein, Jiashan Zhang, Rehan Akbani, Douglas A Levine
We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292438/maoa-dependent-activation-of-shh-il6-rankl-signaling-network-promotes-prostate-cancer-metastasis-by-engaging-tumor-stromal-cell-interactions
#10
Jason Boyang Wu, Lijuan Yin, Changhong Shi, Qinlong Li, Peng Duan, Jen-Ming Huang, Chunyan Liu, Fubo Wang, Michael Lewis, Yang Wang, Tzu-Ping Lin, Chin-Chen Pan, Edwin M Posadas, Haiyen E Zhau, Leland W K Chung
Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292437/nerve-dependence-from-regeneration-to-cancer
#11
REVIEW
Benoni Boilly, Sam Faulkner, Phillip Jobling, Hubert Hondermarck
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292436/the-microenvironmental-landscape-of-brain-tumors
#12
REVIEW
Daniela F Quail, Johanna A Joyce
The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here, we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292435/obstacles-posed-by-the-tumor-microenvironment-to-t%C3%A2-cell-activity-a-case-for-synergistic-therapies
#13
REVIEW
Kristin G Anderson, Ingunn M Stromnes, Philip D Greenberg
T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles...
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292434/pancreatic-cancer-genomics-2-0-profiling-metastases
#14
Eric A Collisson, Anirban Maitra
Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292433/eto2-glis2-a-chimeric-transcription-factor-drives-leukemogenesis-through-a-neomorphic-transcription-network
#15
Justin C Wheat, Ulrich Steidl
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease with a relatively poorly understood pathogenesis. In this issue of Cancer Cell, Thirant and colleagues systematically examine unique transcriptional and functional effects of ETO2-GLIS2, an oncogenic fusion protein frequently encountered in AMKL, and elucidate a therapeutic vulnerability in this poor-prognosis leukemia.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292432/antibodies-create-killer-bonds-in-myeloma
#16
Marta Chesi, Rafael Fonseca
In this issue of Cancer Cell, Li et al. and Seckinger et al. describe promising results of two T-cell-dependent bi-specific antibodies for the treatment of multiple myeloma: one targets FcRH5 expressed on B cells, whereas the other targets the B cell maturation antigen expressed on plasma cells.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292431/anti-depressant-therapy-brightens-the-outlook-for-prostate-cancer-bone-metastases
#17
Michael D Nyquist, Peter S Nelson
In this issue of Cancer Cell, Wu et al. identify MAOA as a key mediator of osteolytic bone responses that involve complex paracrine interactions between tumor cells, osteoblasts, and osteoclasts. Pharmacological inhibition of MAOA enzymatic activity effectively interrupted osteolysis and metastatic progression in preclinical models, suggesting a new treatment opportunity.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28292430/dangerous-liaisons-deviant-endothelium-notches-toward-tumor-metastasis
#18
Peipei Guo, Shahin Rafii
In this issue of Cancer Cell, Wieland et al. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis.
March 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196596/chemosensitive-relapse-in-small-cell-lung-cancer-proceeds-through-an-ezh2-slfn11-axis
#19
Eric E Gardner, Benjamin H Lok, Valentina E Schneeberger, Patrice Desmeules, Linde A Miles, Paige K Arnold, Andy Ni, Inna Khodos, Elisa de Stanchina, Thuyen Nguyen, Julien Sage, John E Campbell, Scott Ribich, Natasha Rekhtman, Afshin Dowlati, Pierre P Massion, Charles M Rudin, John T Poirier
Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing...
February 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28196595/characterization-of-human-cancer-cell-lines-by-reverse-phase-protein-arrays
#20
Jun Li, Wei Zhao, Rehan Akbani, Wenbin Liu, Zhenlin Ju, Shiyun Ling, Christopher P Vellano, Paul Roebuck, Qinghua Yu, A Karina Eterovic, Lauren A Byers, Michael A Davies, Wanleng Deng, Y N Vashisht Gopal, Guo Chen, Erika M von Euw, Dennis Slamon, Dylan Conklin, John V Heymach, Adi F Gazdar, John D Minna, Jeffrey N Myers, Yiling Lu, Gordon B Mills, Han Liang
Cancer cell lines are major model systems for mechanistic investigation and drug development. However, protein expression data linked to high-quality DNA, RNA, and drug-screening data have not been available across a large number of cancer cell lines. Using reverse-phase protein arrays, we measured expression levels of ∼230 key cancer-related proteins in >650 independent cell lines, many of which have publically available genomic, transcriptomic, and drug-screening data. Our dataset recapitulates the effects of mutated pathways on protein expression observed in patient samples, and demonstrates that proteins and particularly phosphoproteins provide information for predicting drug sensitivity that is not available from the corresponding mRNAs...
February 13, 2017: Cancer Cell
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