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Cancer Discovery

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https://www.readbyqxmd.com/read/29907590/autologous-t-cells-targeting-four-neoantigens-induce-tumor-regression
#1
(no author information available yet)
Autologous T-cell transfer achieves a durable regression in a patient with metastatic breast cancer.
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29907589/il1-blockade-may-ameliorate-cytokine-release-syndrome
#2
(no author information available yet)
Targeting IL1 attenuates cytokine release syndrome (CRS) without affecting CAR T-cell antitumor activity.
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29907588/bai1-stabilizes-p53-to-suppress-medulloblastoma-tumorigenesis
#3
(no author information available yet)
Epigenetic silencing of BAI1 results in p53 degradation and accelerated medulloblastoma tumorigenesis.
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29907587/precision-prevention-and-early-detection-of-cancer-fundamental-principles
#4
Timothy R Rebbeck, Karen Burns-White, Andrew T Chan, Karen Emmons, Matthew Freedman, David J Hunter, Peter Kraft, Francine Laden, Lorelei Mucci, Giovanni Parmigiani, Deborah Schrag, Sapna Syngal, Rulla M Tamimi, Kasisomayajula Viswanath, Matthew B Yurgelun, Judy E Garber
Prevention and early detection is critical for reducing the population cancer burden. Two approaches have been used: Population approaches change social norms (e.g., smoking bans) or impose incentives (e.g., cigarette taxes); high-risk strategies intervene upon individuals with elevated cancer risk (e.g., smoking cessation). Knowledge about carcinogenesis mechanisms, extreme exposures, and inherited susceptibility provides opportunities to develop precision prevention and early-detection (PPED) strategies. PPED aims to understand the basis of risk, identify groups that optimally benefit from interventions, characterize heterogeneity in intervention responses, optimize intervention timing, and minimize toxicities...
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29907586/yap-is-essential-for-treg-mediated-suppression-of-anti-tumor-immunity
#5
Xuhao Ni, Jinhui Tao, Joseph Barbi, Qian Chen, Benjamin V Park, Zhiguang Li, Nailing Zhang, Andriana Lebid, Anjali Ramaswamy, Ping Wei, Ying Zheng, Xuehong Zhang, Xingmei Wu, Paolo D A Vignali, Cuiping Yang, Huabin Li, Drew Pardoll, Ling Lu, Duojia Pan, Fan Pan
Regulatory T cells (Tregs) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective anti-tumor immune responses. Foxp3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing Foxp3 expression and Treg function are not completely understood. Herein, we report that Yes-associated protein (YAP), a co-activator of the Hippo pathway, is highly expressed in Tregs and bolsters Foxp3 expression and Treg function in vitro and in vivo...
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29907585/antibiotics-protect-against-liver-tumors-in-mice
#6
(no author information available yet)
Researchers have discovered how the gut microbiome affects tumor development in the mouse liver. By treating mice with antibiotics, they showed that depleting gut commensal bacteria enhances certain primary bile acids in the liver. This causes natural killer T cells to accumulate there, where they protect against tumors. A trial to determine whether this mechanism also operates in humans is being planned.
June 15, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29903880/real-time-genomic-characterization-of-advanced-pancreatic-cancer-to-enable-precision-medicine
#7
Andrew J Aguirre, Jonathan A Nowak, Nicholas D Camarda, Richard A Moffitt, Arezou A Ghazani, Mehlika Hazar-Rethinam, Srivatsan Raghavan, Jaegil Kim, Lauren K Brais, Dorisanne Ragon, Marisa W Welch, Emma Reilly, Devin McCabe, Lori Marini, Kristin Anderka, Karla Helvie, Nelly Oliver, Ana Babic, Annacarolina Da Silva, Brandon Nadres, Emily E Van Seventer, Heather A Shahzade, Joseph P St Pierre, Kelly P Burke, Thomas E Clancy, James M Cleary, Leona A Doyle, Kunal Jajoo, Nadine J McCleary, Jeffrey A Meyerhardt, Janet E Murphy, Kimmie Ng, Anuj K Patel, Kimberly Perez, Michael H Rosenthal, Douglas A Rubinson, Marvin Ryou, Geoffrey I Shapiro, Ewa Sicinska, Stuart G Silverman, Rebecca J Nagy, Richard B Lanman, Deborah Knoerzer, Dean J Welsch, Matthew B Yurgelun, Charles S Fuchs, Levi A Garraway, Gad Getz, Jason L Hornick, Bruce E Johnson, Matthew H Kulke, Robert J Mayer, Jeffrey W Miller, Paul B Shyn, David A Tuveson, Nikhil Wagle, Jen Jen Yeh, William C Hahn, Ryan B Corcoran, Scott L Carter, Brian M Wolpin
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole exome sequencing and RNA-sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data...
June 14, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29903879/adipocyte-derived-lipids-mediate-melanoma-progression-via-fatp-proteins
#8
Maomao Zhang, Julie S Di Martino, Robert L Bowman, Nathaniel R Campbell, Sanjeethan C Baksh, Theresa Simon-Vermot, Isabella S Kim, Pearce Haldeman, Chandrani Mondal, Vladimir Yong-Gonzalez, Mohsen Abu-Akeel, Taha Merghoub, Drew R Jones, Xiphias Ge Zhu, Arshi Arora, Charlotte E Ariyan, Kivanc Birsoy, Jedd D Wolchok, Katherine S Panageas, Travis J Hollmann, Jose Javier Bravo-Cordero, Richard M White
Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface...
June 14, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29899063/cdk6-antagonizes-p53-induced-responses-during-tumorigenesis
#9
Florian Bellutti, Anca-Sarmiza Tigan, Sofie Nebenfuehr, Marlies Dolezal, Markus Zojer, Reinhard Grausenburger, Svenja Hartenberger, Sebastian Kollmann, Eszter Doma, Michaela Prchal-Murphy, Iris Z Uras, Alexander Höllein, Donna S Neuberg, Benjamin L Ebert, Anna Ringler, Andre C Mueller, Joanna I Loizou, Philip W Hinds, Claus Vogl, Gerwin Heller, Stefan Kubicek, Johannes Zuber, Marcos Malumbres, Matthias Farlik, Andreas Villunger, Karoline Kollmann, Veronika Sexl
Tumor formation is a multi-step process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages CDK6 kinase induces a complex transcriptional program to block p53 in hematopoietic cells. Cells lacking CDK6 kinase function are required to mutate p53 to achieve a fully transformed immortalized state. CDK6 binds to the promoters of genes including the p53-antagonists PRMT5, PPM1D and MDM4...
June 13, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29899062/immunotherapy-resistance-by-inflammation-induced-dedifferentiation
#10
Arnav Mehta, Yeon Joo Kim, Lidia Robert, Jennifer Tsoi, Begoña Comin-Anduix, Beata Berent-Maoz, Alistair J Cochran, James Economou, Paul C Tumeh, Cristina Puig-Saus, Antoni Ribas
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T cell transfer therapy (ACT) to the MART-1 antigen, a phenomenon that had only been observed in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) and expressing an inflammation-induced neural crest marker (NGFR)...
June 13, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29891538/antitumor-activity-associated-with-prolonged-persistence-of-adoptively-transferred-ny-eso-1c259t-cells-in-synovial-sarcoma
#11
Sandra P D'Angelo, Luca Melchiori, Melinda S Merchant, Donna B Bernstein, John Glod, Rosandra N Kaplan, Stephan A Grupp, William D Tap, Karen Chagin, Gwendolyn K Binder, Samik Basu, Daniel E Lowther, Ruoxi Wang, Natalie Bath, Alex Tipping, Gareth Betts, Indu Ramachandran, Jean-Marc Navenot, Hua Zhang, Daniel K Wells, Erin Van Winkle, Gabor Kari, Trupti Trivedi, Tom Holdich, Lini N Pandite, Rafael Amado, Crystal L Mackall
We evaluated safety and activity of autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE-1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1c259T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present post-infusion in all patients and persisted for at least 6 months in all responders...
June 11, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884731/squamous-nsclc-improves-with-atezolizumab-plus-chemo
#12
(no author information available yet)
A combination of chemotherapy and the PD-L1 inhibitor atezolizumab may be an effective initial therapy for patients with advanced squamous non-small cell lung cancer. In a clinical trial, patients who received the combination had longer progression-free survival, a higher objective response rate, and a longer duration of response than patients who received chemotherapy alone, regardless of PD-L1 expression level.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884730/ss18-ssx-retargets-the-baf-complex-to-drive-synovial-sarcoma
#13
(no author information available yet)
SS18-SSX targets BAF complexes away from enhancers to broad domains where they activate bivalent genes.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884729/the-lncrna-arlnc1-promotes-prostate-tumorigenesis
#14
(no author information available yet)
ARLNC1 is expressed in prostate cancer and stabilizes the AR transcript to promote AR signaling.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884728/an-empirical-approach-leveraging-tumorgrafts-to-dissect-the-tumor-microenvironment-in-renal-cell-carcinoma-identifies-missing-link-to-prognostic-inflammatory-factors
#15
Tao Wang, Rong Lu, Payal Kapur, Bijay S Jaiswal, Raquibul Hannan, Ze Zhang, Ivan Pedrosa, Jason J Luke, He Zhang, Leonard D Goldstein, Qurratulain Yousuf, Yi-Feng Gu, Tiffani McKenzie, Allison Joyce, Min S Kim, Xinlei Wang, Danni Luo, Oreoluwa Onabolu, Christina Stevens, Zhiqun Xie, Mingyi Chen, Alexander Filatenkov, Jose Torrealba, Xin Luo, Wenbin Guo, Jingxuan He, Eric Stawiski, Zora Modrusan, Steffen Durinck, Somasekar Seshagiri, James Brugarolas
By leveraging tumorgraft (PDX) RNA-Seq data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in Renal Cell Carcinoma (RCC), and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for Tregs, NK cells, Th1 cells, neutrophils, macrophages, B cells, and CD8+ T cells...
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884727/erasing-cd33-in-normal-myeloid-cells-averts-car-t-cell-driven-toxicity
#16
(no author information available yet)
Inactivation of CD33 in HSPCs permits CD33-directed CAR T-cell treatment of AML.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884726/an-immunosuppressive-role-for-eya3-in-tnbc
#17
(no author information available yet)
A recent study indicates that the protein Eya3 influences the adaptive immune response to promote tumor growth, not only decreasing the number of tumor-infiltrating CD8+ T cells, but also driving their exhaustion through PD-L1 upregulation. These findings could spur new strategies to treat triple-negative breast cancer, which currently lacks targeted therapies.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29884725/-tet2-disruption-enhances-the-efficacy-of-cd19-car-t-cell-therapy
#18
(no author information available yet)
Expansion of a single CAR T-cell clone triggers a complete remission in a patient with CLL.
June 8, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29880586/enhancing-the-potency-and-specificity-of-engineered-t-cells-for-cancer-treatment
#19
Sujita Sukumaran, Norihiro Watanabe, Pradip Bajgain, Kanchana Raja, Somala Mohammed, William E Fisher, Malcolm K Brenner, Ann M Leen, Juan F Vera
The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in "on-target, off-tumor" toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize PSCA, TGFβ, and IL4, and whose endodomains recapitulate physiologic T cell signaling by providing signals for activation, co-stimulation and cytokine support, produce potent anti-tumor effects selectively at the tumor site...
June 7, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29880585/macrod2-haploinsufficiency-impairs-catalytic-activity-of-parp1-and-promotes-chromosome-instability-and-growth-of-intestinal-tumors
#20
Anuratha Sakthianandeswaren, Marie Parsons, Dmitri Mouradov, Ruth N MacKinnon, Bruno Catimel, Sheng Liu, Michelle Palmieri, Christopher G Love, Robert N Jorissen, Shan Li, Lachlan Whitehead, Tracy L Putoczki, Adele Preaudet, Cary Tsui, Cameron J Nowell, Robyn L Ward, Nicholas J Hawkins, Jayesh Desai, Peter Gibbs, Matthias Ernst, Ian Street, Michael Buchert, Oliver M Sieber
ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here we show that frequent deletions (~30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer (CRC) cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage, and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human CRC xenografts...
June 7, 2018: Cancer Discovery
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