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Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

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https://www.readbyqxmd.com/read/29348296/cart-targeting-of-solid-tumors-more-pieces-to-the-puzzle
#1
Michael Kalos
CART-based targeting of solid tumors remains a considerable and worthwhile challenge in the field of immunotherapy. The role of chemotherapy to target stroma and enhance CAR cell anti-tumor function, expansion and persistence is still unresolved.
January 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29343557/dicer1-and-associated-conditions-%C3%A2-identification-of-at-risk-individuals-and-recommended-surveillance-strategies
#2
Kris Ann P Schultz, Gretchen M Williams, Junne Kamihara, Douglas R Stewart, Anne K Harris, Andrew J Bauer, Joyce Turner, Rachana Shah, Katherine Schneider, Kami Wolfe Schneider, Ann Garrity Carr, Laura A Harney, Shari Baldinger, A Lindsay Frazier, Daniel Orbach, Dominik T Schneider, David Malkin, Louis P Dehner, Yoav H Messinger, Ashley Hill
Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations. In addition to conferring increased cancer risks for pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors, particularly Sertoli-Leydig cell tumor, individuals with pathogenic germline DICER1 variants may also develop lung cysts, cystic nephroma, renal sarcoma and Wilms tumor, nodular hyperplasia of the thyroid, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, genitourinary embryonal rhabdomyosarcoma and brain tumors including pineoblastoma and pituitary blastoma...
January 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29343556/rasa1-nf1-mutant-lung-cancer-racing-to-the-clinic
#3
Shunsuke Kitajima, David A Barbie
Although mutation of NF1 has been described in non-small cell lung cancer (NSCLC), co-mutation with RASA1, another Ras-GTPase activating protein (RasGAP), defines a novel genetically defined subclass of NSCLC. RASA1/NF1 mutant cell lines are highly sensitive to MEK inhibitors, warranting clinical evaluation of MAPK inhibition in this subclass of patients.
January 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339440/repurposing-tin-mesoporphyrin-as-an-immune-checkpoint-inhibitor-shows-therapeutic-efficacy-in-preclinical-models-of-cancer
#4
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339439/idh1-2-mutations-sensitize-acute-myeloid-leukemia-to-parp-inhibition-and-this-is-reversed-by-idh1-2-mutant-inhibitors
#5
Remco J Molenaar, Tomas Radivoyevitch, Yasunobu Nagata, Mohammed Khurshed, Bartlomiej Przychodzen, Hideki Makishima, Mingjiang Xu, Fonnet E Bleeker, Johanna W Wilmink, Hetty Carraway, Sudipto Mukherjee, Mikkael A Sekeres, Cornelis J F Van Noorden, Jaroslaw P Maciejewski
PURPOSE: Somatic mutations in IDH1/2 occur in ~20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increases in DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known. EXPERIMENTAL DESIGN: Well-characterized primary IDH1MUT, IDH2MUT and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation and PARP inhibitors...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330207/early-assessment-of-lung-cancer-immunotherapy-response-via-circulating-tumor-dna
#6
Sarah B Goldberg, Azeet Narayan, Adam J Kole, Roy H Decker, Jimmitti Teysir, Nicholas J Carriero, Angela Lee, Roxanne Nemati, Sameer K Nath, Shrikant M Mane, Yanhong Deng, Nitin Sukumar, Daniel Zelterman, Daniel J Boffa, Katerina Politi, Scott Gettinger, Lynn D Wilson, Roy S Herbst, Abhijit A Patel
PURPOSE: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging.  However, immunotherapy responses are uniquely challenging to interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation.  We hypothesized that monitoring tumor cell death in real-time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330206/evolution-of-cytogenetically-normal-acute-myeloid-leukemia-during-therapy-and-relapse-an-exome-sequencing-study-of-50-patients
#7
Philipp A Greif, Luise Hartmann, Sebastian Vosberg, Sophie Stief, Raphael Mattes, Ines Hellmann, Klaus H Metzeler, Tobias Herold, Stefanos Bamopoulos, Paul Kerbs, Vindi Jurinovic, Daniela Schumacher, Friederike Pastore, Kathrin Bräundl, Evelyn Zellmeier, Bianka Ksienzyk, Nikola Konstandin, Stephanie Schneider, Alexander Graf, Stefan Krebs, Helmut Blum, Martin Neumann, Claudia Baldus, Stefan K Bohlander, Stephan Wolf, Dennis Goerlich, Wolfgang E Berdel, Bernhard J Woermann, Wolfgang Hiddemann, Karsten Spiekermann
PURPOSE: To study mechanisms of therapy-resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations. EXPERIMENTAL DESIGN: We performed exome-sequencing of matched diagnosis, remission and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters. RESULTS: Evolutionary patterns correlated with clinical outcome...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330205/clinical-utility-of-a-stat3-regulated-microrna-200-family-signature-with-prognostic-potential-in-early-gastric-cancer
#8
Liang Yu, Di Wu, Hugh Gao, Jesse Balic, Anna Tsykin, Tae-Su Han, You Dong Liu, Catherine Lydia Kennedy, Ji-Kun Li, Jie-Qi Mao, Patrick Tan, Masanobu Oshima, Gregory J Goodall, Brendan J Jenkins
PURPOSE: The majority of gastric cancer (GC) patients are diagnosed with late stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early stage GC (EGC) because the molecular events promoting GC initiation remain ill-defined. EXPERIMENTAL DESIGN: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330204/pazopanib-exposure-relationship-with-clinical-efficacy-and-safety-in-the-adjuvant-treatment-of-advanced-renal-cell-carcinoma
#9
Cora Sternberg, Frede Donskov, Naomi B Haas, Christian Doehn, Paul Russo, Mohamed A Elmeliegy, Guillaume Baneyx, Hiya Banerjee, Paola Aimone, Robert J Motzer
PURPOSE: PROTECT, a phase III randomized placebo-controlled study, evaluated pazopanib efficacy and safety in the adjuvant RCC setting. The relationship between pazopanib exposure (Ctrough) and efficacy and safety was evaluated. EXPERIMENTAL DESIGN: Evaluable steady-state blood trough concentrations were collected from 311 patients at week 3 or 5 (early Ctrough), and 250 patients at week 16 or 20 (late Ctrough). Pazopanib pharmacokinetic (PK) data was analyzed via a population model approach...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330203/personalized-rna-medicine-for-pancreatic-cancer
#10
Maud-Emmanuelle Gilles, Liangliang Hao, Ling Huang, Rajesha Rupaimoole, Pedro P Lopez-Casas, Emilia Pulver, Jong Cheol Jeong, Senthil K Muthuswamy, Manuel Hidalgo, Sangeeta N Bhatia, Frank J Slack
PURPOSE: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.  Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29330202/high-risk-tp53-mutations-are-associated-with-extra-nodal-extension-ene-in-oral-cavity-squamous-cell-carcinoma-oscc
#11
Vlad C Sandulache, Chieko Michikawa, Pranav Kataria, Frederico O Gleber-Netto, Diana Bell, Sanchit Trivedi, Xiayu Rao, Jing Wang, Mei Zhao, Samar A Jasser, Jeffrey N Myers, Curtis R Pickering
PURPOSE:   Development of extra-nodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. EXPERIMENTAL DESIGN: An institutional cohort (University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue...
January 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29326282/rnf126-as-a-biomarker-of-a-poor-prognosis-in-invasive-breast-cancer-and-chk1-inhibitor-efficacy-in-breast-cancer-cells
#12
Xiaosong Yang, You Pan, Zhaojun Qiu, Zhanwen Du, Yao Zhang, Pengyan Fa, Shashank Gorityala, Shanhuai Ma, Shunqiang Li, Ceshi Chen, Hongbing Wang, Yan Xu, Chunhong Yan, Ruth A Keri, Zhefu Ma, Junran Zhang
PURPOSE: 1) To investigate expression of the E3 ligase, RNF126, in human invasive breast cancer (BC) and its links with BC outcomes. 2) To test the hypothesis that RNF126 determines the efficacy of inhibitors targeting the cell cycle checkpoint kinase, CHK1. EXPERIMENTAL DESIGN: A retrospective analysis by immunohistochemistry (IHC) compared RNF126 staining in 110 invasive BC and 78 paired adjacent normal tissues with clinicopathologic data. Whether RNF126 controls CHK1 expression was determined by chromatin immunoprecipitation and a CHK1 promoter driven luciferase reporter...
January 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29326281/evaluation-of-overall-response-rate-and-progression-free-survival-as-potential-surrogate-endpoints-for-overall-survival-in-immunotherapy-trials
#13
Sirisha L Mushti, Flora Mulkey, Rajeshwari Sridhara
PURPOSE: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials...
January 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29311118/therapeutic-challenge-with-a-cdk-4-6-inhibitor-induces-an-rb-dependent-smac-mediated-apoptotic-response-in-non-small-cell-lung-cancer
#14
Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Christopher McNair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M Salvino, Adam P Dicker, Karen E Knudsen, Robert B Den
The retinoblastoma tumor suppressor (RB), a key regulator of cell cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC).  RB function is exquisitely controlled by a series of proteins including the CyclinD-CDK4/6 complex. In the current study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.   Experimental Design and Results: We employed multiple isogenic RB proficient and deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo  We demonstrate that while short term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth...
January 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29311117/expanded-genomic-profiling-of-circulating-tumor-cells-in-metastatic-breast-cancer-patients-to-assess-biomarker-status-and-biology-over-time
#15
Mark Jesus M Magbanua, Hope S Rugo, Denise M Wolfe, Louai Hauranieh, Ritu Roy, Praveen Pendyala, Eduardo Sosa, Janet H Scott, Jin Sun Lee, Brandelyn N Pitcher, Terry M Hyslop, William T Barry, Steven J Isakoff, Maura N Dickler, Laura J Van't Veer, John W Park
Purpose: We profiled circulating tumor cells (CTCs) patients to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 MBC patients using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACs), 28 of whom had serial CTC analysis (74 samples, 2-5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n=151) and genome-wide copy number analysis by array comparative genomic hybridization (n=49)...
January 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301833/establishing-a-preclinical-multidisciplinary-board-for-brain-tumors
#16
Birgit Nimmervoll, Nidal Boulos, Brandon M Bianski, Jason Dapper, Michael DeCuypere, Anang A Shelat, Sabrina Terranova, Hope Elizabeth Terhune, Amar Gajjar, Yogesh T Patel, Burgess B Freeman, Arzu Onar-Thomas, Clinton F Stewart, Martine F Roussel, R Kiplin Guy, Thomas E Merchant, Christopher Calabrese, Karen D Wright, Richard J Gilbertson
PURPOSE: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies.  It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors.  Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.  Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC)...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301832/pharmacological-inhibition-of-nos-activates-ask1-jnk-pathway-augmenting-docetaxel-mediated-apoptosis-in-triple-negative-breast-cancer
#17
Daniel Dávila-González, Dong Soon Choi, Roberto R Rosato, Sergio Granados-Principal, John G Kuhn, Wen-Feng Li, Wei Qian, Wen Chen, Anthony J Kozielski, Helen H Wong, Bhuvanesh Dave, Jenny C Chang
PURPOSE: Chemoresistance in triple negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacological NOS-inhibition on TNBC. EXPERIMENTAL DESIGN: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS-inibitor (L-NMMA) for 24, 48 and 72 hours...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301831/efficacy-safety-and-pharmacokinetics-of-axitinib-in-nasopharyngeal-carcinoma-a-preclinical-and-phase-2-correlative-study
#18
Edwin P Hui, Brigette B Y Ma, Herbert Loong, Frankie Mo, Leung Li, Ann D King, Ki Wang, Anil T Ahuja, Charles Ml Chan, Connie Wc Hui, Chi-Hang Wong, Anthony Tc Chan
PURPOSE: We hypothesized that axitinib is active with improved safety profile in nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: We evaluated axitinib in preclinical models of NPC, and studied its efficacy in a phase 2 clinical trial in recurrent or metastatic NPC patients who progressed after at least one line of prior platinum-based chemotherapy. We excluded patients with local recurrence or vascular invasion. Axitinib was started at 5 mg twice-daily in continuous 4-weeks cycles...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301830/activation-of-4-1bb-on-liver-myeloid-cells-triggers-hepatitis-via-an-interleukin-27-dependent-pathway
#19
Todd Bartkowiak, Ashvin R Jaiswal, Casey R Ager, Renee Chin, Chao-Hsien Chen, Pratha Budhani, Midan Ai, Matthew J Reilley, Manu M Sebastian, David S Hong, Michael A Curran
PURPOSE: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. EXPERIMENTAL DESIGN: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29301829/identification-of-a-novel-ebv-based-antibody-risk-stratification-signature-for-early-detection-of-nasopharyngeal-carcinoma-in-taiwan
#20
Anna E Coghill, Ruth M Pfeiffer, Carla Proietti, Wan-Lun Hsu, Yin-Chu Chien, Lea Lekieffre, Lutz Krause, Andy Teng, Jozelyn Pablo, Kelly J Yu, Pei-Jen Lou, Cheng-Ping Wang, Zhiwei Liu, Chien-Jen Chen, Jaap M Middeldorp, Jason P Mulvenna, Jeffrey Bethony, Allan Hildesheim, Denise L Doolan
BACKGROUND: Epstein-Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, ~90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective. METHODS: We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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