Cancer Discovery

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Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes
Cancer Discovery - Tập 2 Số 3 - Trang 248-259 - 2012
Gui-Rong Xue, David F. Restuccia, Qiang Lan, Debby Hynx, Stephan Dirnhofer, Daniel Heß, Curzio Rüegg, Brian A. Hemmings
Abstract Metastatic breast tumor cells display an epithelial–mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invas... hiện toàn bộ
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma
Cancer Discovery - Tập 8 Số 7 - Trang 822-835 - 2018
Ferdinandos Skoulidis, Michael E. Goldberg, Danielle Greenawalt, Matthew D. Hellmann, Mark M. Awad, Justin F. Gainor, Alexa B. Schrock, Ryan J. Hartmaier, Sally E. Trabucco, Laurie M. Gay, Siraj M. Ali, Julia A. Elvin, Gaurav Singal, Jeffrey S. Ross, David Fabrizio, Péter M. Szabó, Chang Han, Ariella Sasson, Sujaya Srinivasan, Stefan Kirov, Joseph D. Szustakowski, Patrik Vitazka, Robin Edwards, José A. Bufill, Neelesh Sharma, Sai‐Hong Ignatius Ou, Nir Peled, David R. Spigel, Hira Rizvi, Elizabeth Jiménez Aguilar, Brett W. Carter, Jeremy J. Erasmus, Darragh Halpenny, Andrew J. Plodkowski, Niamh M. Long, Mizuki Nishino, Warren L. Denning, Ana Galán‐Cobo, Haïfa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez‐Canales, Pamela Villalobos, Edwin R. Parra, Neda Kalhor, Lynette M. Sholl, Jennifer L. Sauter, Achim A. Jungbluth, Mari Mino‐Kenudson, Roxana Azimi, Yasir Y. Elamin, Jianjun Zhang, Giulia C. Leonardi, Fei Jiang, Kwok‐Kin Wong, John Lee, Vassiliki A. Papadimitrakopoulou, Ignacio I. Wistuba, Vincent A. Miller, Garrett M. Frampton, Jedd D. Wolchok, Alice T. Shaw, Pasi A. Jänne, Philip J. Stephens, Charles M. Rudin, William J. Geese, Lee A. Albacker, John V. Heymach
Abstract KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.0... hiện toàn bộ
Co-occurring Genomic Alterations Define Major Subsets of KRAS-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities
Cancer Discovery - Tập 5 Số 8 - Trang 860-877 - 2015
Ferdinandos Skoulidis, Lauren A. Byers, Lixia Diao, Vassiliki A. Papadimitrakopoulou, Pan Tong, Julie Izzo, Carmen Behrens, Humam Kadara, Edwin R. Parra, Jaime Rodriguez Canales, Jianjun Zhang, Uma Giri, Jayanthi Gudikote, María Angélica Cortez, Chao Yang, You Hong Fan, Michael Peyton, Luc Girard, Kevin R. Coombes, Carlo Toniatti, Timothy P. Heffernan, Murim Choi, Garrett M. Frampton, Vincent A. Miller, John N. Weinstein, Roy S. Herbst, Kwok‐Kin Wong, Jianhua Zhang, Padmanee Sharma, Gordon B. Mills, Waun Ki Hong, John D. Minna, James P. Allison, P. Andrew Futreal, Jing Wang, Ignacio I. Wistuba, John V. Heymach
Abstract The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in ST... hiện toàn bộ
Elucidating Distinct Roles for NF1 in Melanomagenesis
Cancer Discovery - Tập 3 Số 3 - Trang 338-349 - 2013
Ophélia Maertens, Bryan W. Johnson, Pablo E. Hollstein, Dennie T. Frederick, Zachary A. Cooper, Ludwine Messiaen, Roderick T. Bronson, Martin McMahon, Scott R. Granter, Keith T. Flaherty, Jennifer A. Wargo, Richard Marais, Karen Cichowski
Abstract BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced s... hiện toàn bộ
Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage–Derived VEGFA
Cancer Discovery - Tập 5 Số 9 - Trang 932-943 - 2015
Allison S. Harney, Esther N. Arwert, David Entenberg, Yarong Wang, Peng Guo, Bin-Zhi Qian, Maja H. Oktay, Jeffrey W. Pollard, Joan G. Jones, John S. Condeelis
Abstract Dissemination of tumor cells is an essential step in metastasis. Direct contact between a macrophage, mammalian-enabled (MENA)–overexpressing tumor cell, and endothelial cell [Tumor MicroEnvironment of Metastasis (TMEM)] correlates with metastasis in breast cancer patients. Here we show, using intravital high-resolution two-photon microscopy, that transient vascular permeability and tumor... hiện toàn bộ
Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth
Cancer Discovery - Tập 2 Số 10 - Trang 948-959 - 2012
Fred Harbinski, Vanessa J. Craig, Sneha Sanghavi, Douglas A. Jeffery, Lijuan Liu, Kelly-Ann Sheppard, Sabrina Wagner, Christelle Stamm, Andreas Buneß, Christian Chatenay‐Rivauday, Yao Yao, Feng He, Chris X. Lu, Vito Guagnano, Thomas Metz, Peter M. Finan, Francesco Hofmann, William R. Sellers, Jeffrey A. Porter, Vic E. Myer, Diana Graus-Porta, Christopher J. Wilson, Alan Buckler, Ralph Tiedt
Abstract The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells o... hiện toàn bộ
nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer
Cancer Discovery - Tập 2 Số 3 - Trang 260-269 - 2012
Natalie Cook, Albrecht Neeße, Tashinga E. Bapiro, Martijn P. Lolkema, Duncan I. Jodrell, David A. Tuveson
Abstract Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechani... hiện toàn bộ
ARID1A Mutations in Cancer: Another Epigenetic Tumor Suppressor?
Cancer Discovery - Tập 3 Số 1 - Trang 35-43 - 2013
Jennifer N. Wu, Charles W.M. Roberts
Abstract Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: frequent mutation of epigenetic regulators. Among these, the ARID1A/BAF250A subunit ... hiện toàn bộ
In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma
Cancer Discovery - Tập 8 Số 10 - Trang 1258-1269 - 2018
Matthew J. Frank, Patrick M. Reagan, Nancy L. Bartlett, Leo I. Gordon, Jonathan W. Friedberg, Debra K. Czerwinski, Steven Long, Richard T. Hoppe, Robert Janssen, Albert F. Candia, Robert L. Coffman, Ronald Levy
Abstract This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor r... hiện toàn bộ
Targeting the Tumor Microenvironment in Cancer: Why Hyaluronidase Deserves a Second Look
Cancer Discovery - Tập 1 Số 4 - Trang 291-296 - 2011
Clifford J. Whatcott, Haiyong Han, Richard G. Posner, Galen Hostetter, Daniel D. Von Hoff
AbstractIncreased extracellular matrix (ECM) deposition is a characteristic observed in many solid tumors. Increased levels of one ECM component—namely, hyaluronan (HA)—leads to reduced elasticity of tumor tissue and increased interstitial fluid pressure. Multiple initial reports showed that the addition of hyaluronidase (HYAL) to chemotherapeutic regimens could greatly improve efficacy. Unfortuna... hiện toàn bộ
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