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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/28808039/preclincial-evaluation-of-intravesical-cisplatin-nanoparticles-for-non-muscle-invasive-bladder-cancer
#1
Max Kates, Abhijit Date, Takahiro Yoshida, Umara Afzal, Pranjali Kanvinde, Taarika Babu, Nikolai A Sopko, Hotaka Matsui, Noah M Hahn, David J McConkey, Alex S Baras, Justin Hanes, Laura Ensign, Trinity J Bivalacqua
PURPOSE: Prior clinical trials evaluating cisplatin for non-muscle invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past. EXPERIMENTAL DESIGN: Cisplatin nanoparticles (CDDP NP) were developed using biocompatible poly(L-aspartic acid sodium salt) (PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG)...
August 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28808038/the-phosphatidylinositol-3-kinase-pathway-as-a-potential-therapeutic-target-in-bladder-cancer
#2
Shuxiong Zeng, Yanjun Zhu, Ai-Hong Ma, Weimin Yu, Hongyong Zhang, Tzu-Yin Lin, Wei Shi, Clifford G Tepper, Paul T Henderson, Susan Airhart, Jianming Guo, Chuanliang Xu, Ralph de Vere White, Chong-Xian Pan
PURPOSE: Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. EXPERIMENTAL DESIGN: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine...
August 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28801472/breast-cancer-immunotherapy-facts-and-hopes
#3
Leisha A Emens
Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of PD-1/PD-L1 antagonists in small numbers of metastatic breast cancer patients. Clinical activity appears more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of TILs. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple negative breast cancer (TNBC), suggesting these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert non-responders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy...
August 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790119/complementary-value-of-contralateral-parenchymal-enhancement-on-dce-mri-to-prognostic-models-and-molecular-assays-in-high-risk-er-her2-breast-cancer
#4
Bas H M van der Velden, Sjoerd G Elias, Tycho Bismeijer, Claudette E Loo, Max A Viergever, Lodewyk F A Wessels, Kenneth G A Gilhuijs
Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor. <p>Experimental Design: Patients with ER-positive/HER2-negative breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), whereupon the average of the top-10% late enhancement was calculated...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790118/anti-cd137-and-pd-1-pd-l1-antibodies-in-route-towards-clinical-synergy
#5
Elisabeth Perez-Ruiz, Iñaki Etxeberria, Maria Rodriguez-Ruis, Ignacio Melero
T-cell co-stimulation and co-inhibition can be exploited  by blocking and agonist monoclonal antibodies (mAbs) respectively. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti-PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy.
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790117/in-vivo-validation-of-papss1-3-phosphoadenosine-5-phosphosulfate-synthase-1-as-a-cisplatin-sensitizing-therapeutic-target
#6
Ada W Y Leung, Chansey J Veinotte, Nicole Melong, Min Hee Oh, Kent T J Chen, Katey Enfield, Ian Backstrom, Corinna Warburton, Donald T Yapp, Jason N Berman, Marcel B Bally, William W Lockwood
INTRODUCTION: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in pre-clinical model systems. METHODS: PAPSS1 expression and cisplatin IC50 values were assessed in 52 lung adenocarcinoma (LAC) cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790116/targeted-proteomics-identifies-proteomic-signatures-in-liquid-biopsies-of-the-endometrium-to-diagnose-endometrial-cancer-and-assist-in-the-prediction-of-the-optimal-surgical-treatment
#7
Elena Martinez, Antoine Lesur, Laura Devis, Silvia Cabrera, Xavier Matias-Guiu, Marc Hirschfeld, Jasmin Asberger, Jan van Oostrum, María de Los Ángeles Casares de Cal, Antonio Gómez-Tato, Jaume Reventos, Bruno Domon, Eva Colas, Antonio Gil-Moreno
PURPOSE: Endometrial cancer (EC) diagnosis relies on the observation of tumor cells in endometrial biopsies obtained by aspiration i.e., uterine aspirates), but it is associated with 22% undiagnosed patients and up to 50% of incorrectly assigned EC histotype and grade. We aimed to identify biomarker signatures in the fluid fraction of these biopsies to overcome these limitations. EXPERIMENTAL DESIGN: The levels of 52 proteins were measured in the fluid fraction of uterine aspirates from 116 patients by LC-PRM, the latest generation of targeted mass-spectrometry acquisition...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790115/msh2-loss-in-primary-prostate-cancer
#8
Liana Guedes, Emmanuel S Antonarakis, Michael T Schweizer, Nooshin Mirkheshti, Fawaz Almutairi, Jong Chul Park, Stephanie A Glavaris, Jessica L Hicks, Mario A Eisenberger, Angelo M De Marzo, Jonathan I Epstein, William B Isaacs, James R Eshleman, Colin C Pritchard, Tamara L Lotan
PURPOSE: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. EXPERIMENTAL DESIGN: 1133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). RESULTS: Of primary adenocarcinomas and NEPC, 1...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790114/differential-toxicity-in-patients-with-and-without-dna-repair-mutations-phase-i-study-of-carboplatin-and-talazoparib-in-advanced-solid-tumors
#9
Mallika S Dhawan, Imke H Bartelink, Rahul Aggarwal, Jim Leng, Jenna Z Zhang, Nela Pawlowska, Manuela Terranova-Barberio, Jennifer A Grabowsky, Andrew Gewitz, Amy J Chien, Mark M Moasser, Robin K Kelley, Tayeba Maktabi, Scott Thomas, Pamela N Munster
<p>Purpose: The PARP inhibitor, talazoparib, may potentiate activity of chemotherapy in cells vulnerable to DNA damage. EXPERIMENTAL DESIGN: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin. Pharmacokinetic-modeling explored associations between dosing and hematological toxicity. RESULTS: 24 patients with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790113/neurotensin-receptor-1-antagonist-sr48692-improves-response-to-carboplatin-by-enhancing-apoptosis-and-inhibiting-drug-efflux-in-ovarian-cancer
#10
Jin Liu, Mikael Agopiantz, Joel Poupon, Zherui Wu, Pierre-Alexandre Just, Bruno Borghese, Evelyne Ségal-Bendirdjian, Guillaume Gauchotte, Anne Gompel, Patricia Forgez
PURPOSE: The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), is correlated with tumor cell aggressiveness in most solid tumors. As chemo-resistance and tumor aggressiveness are often related; we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer (OC). EXPERIMENTAL DESIGN: Experimental tumors and in vitro studied were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790112/burden-and-profile-of-somatic-mutation-in-duodenal-adenomas-from-patients-with-familial-adenomatous-and-mutyh-associated-polyposis
#11
Laura Elizabeth Thomas, Joanna J Hurley, Elena Meuser, Sian Jose, Kevin E Ashelford, Matthew Mort, Shelley Idziaszczyk, Julie Maynard, Helena Leon Brito, Manon Harry, Angharad Walters, Meera Raja, Sarah Jane Walton, Sunil Dolwani, Geraint T Williams, Meleri Morgan, Morgan Moorghen, Susan K Clark, Julian R Sampson
Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.<br /><br />Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing and 47 were studied by array comparative genomic hybridization...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790111/amiloride-an-old-diuretic-drug-is-a-potential-therapeutic-agent-for-multiple-myeloma
#12
Elizabeta Rojas, Luis Corchete, Laura San Segundo, Juan F Martínez-Blanch, Francisco M Codoñer, Teresa Paíno, Noemi Puig, Ramón García-Sanz, Maria Victoria Mateos, Enrique M Ocio, Irena Misiewicz-Krzeminska, Norma C Gutiérrez
<br />The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure.<br /><br />Experimental Design:  <p>Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq, qRT-PCR, immunoblotting and immunofluorescence assays...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790110/replication-stress-leading-to-apoptosis-within-the-s-phase-contributes-to-synergism-between-vorinostat-and-azd1775-in-hnscc-harboring-high-risk-tp53-mutation
#13
Noriaki Tanaka, Ameeta A Patel, Lin Tang, Natalie L Silver, Antje Lindemann, Hideaki Takahashi, Roman Jaksik, Xiayu Rao, Nene N Kalu, Tseng-Cheng Chen, Jiping Wang, Mitchell J Frederick, Faye M Johnson, Frederico Gleber-Netto, Siqing Fu, Marek Kimmel, Jing Wang, Walter N Hittelman, Curtis R Pickering, Jeffrey N Myers, Abdullah A Osman
Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790109/prospective-validation-of-molecular-prognostic-markers-in-cutaneous-melanoma-a-correlative-analysis-of-e1690
#14
Mohammed Kashani-Sabet, Mehdi Nosrati, James Miller, Richard Sagebiel, Stanley Leong, Andrew Lesniak, Schuyler Tong, Sandra Lee, John M Kirkwood
Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose interferon alpha-2b (IFN) versus observation. <p>Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28790108/cyclophilin-a-maintains-glioma-initiating-cell-stemness-by-regulating-wnt-%C3%AE-catenin-signaling
#15
Guangzhi Wang, Jia Shen, Jiahang Sun, Zhenfeng Jiang, Jiabing Fan, Hongjun Wang, Shan Yu, Yu Long, Yi Liu, HOngbo Bao, Kelvin X Zhang, Ke Han, Min-Wei Zhu, Yongri Zheng, Zhiguo Lin, Chuanlu Jiang, Mian Guo
PURPOSE: Glioma-initiating cells (GICs) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development...
August 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28778862/targeting-rna-polymerase-i-in-both-chemosensitive-and-chemoresistant-populations-in-epithelial-ovarian-cancer
#16
Robert Cornelison, Zachary C Dobbin, Ashwini A Katre, Dae Hoon Jeong, Yinfeng Zhang, Dongquan Chen, Yuliya Petrova, Danielle C Llaneza, Adam D Steg, Laura Parsons, David Schneider, Charles N Landen
A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy.  We examined the contribution and potential targeting of ribosomal machinery in chemotherapy resistant and sensitive models of ovarian cancer.<br /><br />Experimental Design: Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient derived xenograft (PDX) models with and without chemotherapy...
August 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28774899/89zr-anti-%C3%AE-h2ax-tat-but-not-18f-fdg-allows-early-monitoring-of-response-to-chemotherapy-in-a-mouse-model-of-pancreatic-ductal-adenocarcinoma
#17
James C Knight, Michael J Mosley, Luisa Contreras Bravo, Veerle Kersemans, Philip D Allen, Somnath Mukherjee, Eric O'Neill, Bart Cornelissen
Purpose: Late-stage, unresectable pancreatic ductal adenocarcinoma (PDAC) is largely resistant to chemotherapy and consequently has a very poor 5-year survival rate of < 5%. The ability to assess the efficacy of a treatment soon after its initiation would enable rapid switching to potentially more effective therapies if the current treatment is found to be futile. We have evaluated the ability of the PET imaging agent, (89)Zr-anti-γH2AX-TAT, to monitor DNA damage in response to fluouracil (5-FU), gemcitabine, or capecitabine treatment in a mouse model of pancreatic cancer...
August 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28774898/fda-approval-summary-trabectedin-for-unresectable-or-metastatic-liposarcoma-or-leiomyosarcoma-following-an-anthracycline-containing-regimen
#18
Amy Barone, Dow-Chung Chi, Marc R Theoret, Huanyu Chen, Kun He, Dubravka Kufrin, Whitney S Helms, Sriram Subramaniam, Hong Zhao, Anuja Patel, Kirsten B Goldberg, Patricia Keegan, Richard Pazdur
On October 23, 2015, the U.S. Food and Drug Administration approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m(2) as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks to dacarbazine 1000 mg/m(2) i...
August 3, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28765329/overcoming-acquired-resistance-to-azd9291-a-third-generation-egfr-inhibitor-through-modulation-of-mek-erk-dependent-bim-and-mcl-1-degradation
#19
Puyu Shi, You-Take Oh, Liang Deng, Guojing Zhang, Guoqing Qian, Shuo Zhang, Hui Ren, Grant Wu, Benjamin Legendre, Emily Anderson, Suresh S Ramalingam, Taofeek K Owonikoko, Mingwei Chen, Shi-Yong Sun
<p>The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.</p> <br /><br />Experimental Design: <p>AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28765328/phase-1-dose-escalation-study-of-the-anti-cd70-antibody-argx-110-in-advanced-malignancies
#20
Philippe Aftimos, Christian Rolfo, Sylvie Rottey, Fritz Offner, Dominique D Bron, Marie Maerevoet, Jean-Charles Soria, Mahan Moshir, Torsten Dreier, Luc van Rompaey, Jean-Marie Michot, Karen Silence, Anna Hultberg, Domenica Gandini, Hans De Haard, Vincent Ribrag, Marc Peeters, Alain Thibault, Nicolas Leupin, Ahmad Awada
The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. <br /><br />Experimental Design: <p>Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N=26). ARGX-110 was administered intravenously every three weeks until progression or intolerable toxicity...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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