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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/28341752/the-promise-of-targeting-macrophages-in-cancer-therapy
#1
J Martin Brown, Lawrence Recht, Samuel Strober
Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this Review we outline the importance of tumor associated macrophages (TAMs), a major component of the TME, in the response of tumors to cancer therapy...
March 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28341751/low-recombination-proficiency-score-rps-predicts-heightened-sensitivity-to-dna-damaging-chemotherapy-in-breast-cancer
#2
Sean Pitroda, Riyue Bao, Jorge Andrade, Ralph R Weichselbaum, Philip P Connell
PURPOSE: Molecular-based cancer tests have been developed to augment the standard clinical and pathologic features used to tailor treatments to individual breast cancer patients. Homologous recombination (HR) repairs double-stranded DNA breaks and promotes tolerance to lesions that disrupt DNA replication. Recombination Proficiency Score (RPS) quantifies HR efficiency based on the expression of four genes involved in DNA damage repair. We hypothesized low RPS values can identify HR-deficient breast cancers most sensitive to DNA-damaging chemotherapy...
March 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28336564/identification-of-a-novel-syk-c-myc-malat1-signaling-pathway-and-its-potential-therapeutic-value-in-ewing-sarcoma
#3
Haibo Sun, De-Chen Lin, Qi Cao, Brendan Pang, David D Gae, Victor Km Lee, Huey Jin Lim, Ngan Doan, Jonathan W Said, Sigal Gery, Marilynn Chow, Anand Mayakonda, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
PURPOSE: Ewing Sarcoma (EWS) is a devastating soft tissue sarcoma affecting predominantly young individuals. Tyrosine kinases (TKs) and associated pathways are continuously activated in many malignancies including EWS; these enzymes provide candidate therapeutic targets. EXPERIMENTAL DESIGN: Two high-throughput screens (a siRNA library and a small-molecule inhibitor library) were performed in EWS cells to establish candidate targets. Spleen tyrosine kinase (SYK) phosphorylation was assessed in EWS patients and cell lines...
March 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28331050/first-in-human-clinical-trial-of-oral-onc201-in-patients-with-refractory-solid-tumors
#4
Mark N Stein, Joseph R Bertino, Howard L Kaufman, Tina Mayer, Rebecca Moss, Ann Silk, Nancy Chan, Jyoti Malhotra, Lorna Rodriguez-Rodriguez, Joseph Aisner, Robert D Aiken, Bruce G Haffty, Robert S DiPaola, Tracie Saunders, Andrew Zloza, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Siobhan Dickerson, Ling Zheng, Wafik S El-Deiry, Joshua Allen, Martin Stogniew, Wolfgang Oster, Janice M Mehnert
Purpose ONC201 is a small molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design This open-label study treated 10 patients during dose escalation with histologically-confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design...
March 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28331049/achieving-precision-death-with-cell-cycle-inhibitors-that-target-dna-replication-and-repair
#5
Aimee Bence Lin, Samuel C McNeely, Richard P Beckmann
All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts the efficacy of these classes of drugs can be impressive but, because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest...
March 22, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28325750/molecular-pathways-evaluating-the-potential-for-b7-h4-as-an-immunoregulatory-target
#6
Heather L MacGregor, Pamela S Ohashi
With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment anti-tumor responses by targeting other inhibitory molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies...
March 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28320758/tumor-cell-free-dna-copy-number-instability-predicts-therapeutic-response-to-immunotherapy
#7
Glen J Weiss, Julia Beck, Donald P Braun, Kristen Bornemann-Kolatzki, Heather Barilla, Rhiannon Cubello, Walter Quan, Ashish Sangal, Vivek Khemka, Jordan Waypa, William M Mitchell, Howard Urnovitz, Ekkehard Schütz
PURPOSE: Chromosomal instability is a fundamental property of cancer, which can be quantified by Next Generation Sequencing (NGS) from plasma/serum derived cell-free DNA (cfDNA). We hypothesized that cfDNA could be used as a real time surrogate for imaging analysis of disease status as a function of response to immunotherapy and as a more reliable tool than tumor biomarkers. EXPERIMENTAL DESIGN: Plasma cfDNA sequences from 56 patients with diverse advanced cancers, were prospectively collected and analyzed in a single-blinded study for copy number variations, expressed as a quantitative chromosomal number instability (CNI) score versus 126 non-cancer controls in a training set of 23 and a blinded validation set of 33...
March 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314790/selinexor-kpt-330-induces-tumor-suppression-through-nuclear-sequestration-of-ikappab-and-down-regulation-of-survivin
#8
Jayasree S Nair, Elgilda Musi, Gary K Schwartz
PURPOSE: Selinexor, a small molecule that inhibits nuclear export protein XPO1 has demonstrated efficacy in solid tumors and hematologic malignancies with the evidence of clinical activity in sarcoma as a single agent. Treatment options available are very few and hence the need to identify novel targets and strategic therapies is of utmost importance. EXPERIMENTAL DESIGN: The mechanistic effects of selinexor in sarcomas as a monotherapy and in combination with proteasome inhibitor, carfilzomib, across a panel of cell lines in vitro and few in xenograft mouse models were investigated...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314789/non-invasive-imaging-of-cycling-hypoxia-in-head-neck-cancer-using-intrinsic-susceptibility-mri
#9
Rafal Panek, Liam Welsh, Lauren Cj Baker, Maria A Schmidt, Kee H Wong, Angela Riddell, Dow-Mu Koh, Alex Dunlop, Dualta Mcquaid, James A d'Arcy, Shreerang Bhide, Kevin J Harrington, Christopher M Nutting, Georgina Hopkinson, Cheryl Richardson, Carol Box, Suzanne A Eccles, Martin O Leach, Simon P Robinson, Katie L Newbold
PURPOSE: To evaluate intrinsic susceptibility (IS) MRI for the identification of cycling hypoxia, and the assessment of its extent and spatial distribution, in head and neck squamous cell carcinoma (HNSCC) xenografts and patients. EXPERIMENTAL DESIGN: Quantitation of the transverse relaxation rate R2*, which is sensitive to paramagnetic deoxyhemoglobin, using serial IS-MRI acquisitions, was used to monitor temporal oscillations in levels of paramagnetic deoxyhemoglobin in human CAL(R) xenografts and patients with HNSCC at 3T...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28314788/the-parp-inhibitor-veliparib-can-be-safely-added-to-bendamustine-and-rituximab-and-has-preliminary-evidence-of-activity-in-b-cell-lymphoma
#10
Jacob D Soumerai, Andrew D Zelenetz, Craig Moskowitz, M Lia Palomba, Paul A Hamlin, Ariela Noy, David J Straus, Alison J Moskowitz, Anas Younes, Matthew J Matasar, Steven Horwitz, Carol Portlock, Jason Konner, Mrinal M Gounder, David M Hyman, Martin H Voss, Matthew G Fury, Devika Gajria, Richard D Carvajal, Alan L Ho, Jan H Beumer, Brian Kiesel, Zhigang Zhang, Alice Chen, Richard F Little, Christine Jarjies, Thu O Dang, Fallon France, Nishant Mishra, John F Gerecitano
PURPOSE: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase 1 study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. EXPERIMENTAL DESIGN: This dose-escalation study evaluated safety, pharmacokinetics and preliminary efficacy of veliparib (20-400 mg BID, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 IV, days 1 and 2)...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28302866/genomic-profiling-of-patient-derived-xenografts-for-lung-cancer-identifies-b2m-inactivation-impairing-immunorecognition
#11
Carolina Pereira, Pol Gimenez-Xavier, Eva Pros, Maria J Pajares, Massimo Moro, Antonio Gomez, Alejandro Navarro, Enric Condom, Sebastian Moran, Gonzalo Gomez-Lopez, Osvaldo Graña, Miriam Rubio-Camarillo, Alex Martinez-Martí, Jun Yokota, Julian Carretero, Jose M Galbis, Ernest Nadal, David Pisano, Gabriella Sozzi, Enriqueta Felip, Luis M Montuenga, Luca Roz, Alberto Villanueva, Montse Sanchez-Cespedes
Purpose: We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs).Experimental Design: We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of β2-microglobulin (B2M), a component of the HLA class-I complex.Results: We identified alterations in genes involved in various functions, such as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to about 230 lung cancers...
March 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28298546/64cu-mm-302-positron-emission-tomography-quantifies-variability-of-enhanced-permeability-and-retention-of-nanoparticles-in-relation-to-treatment-response-in-patients-with-metastatic-breast-cancer
#12
Helen Lee, Anthony F Shields, Barry A Siegel, Kathy D Miller, Ian Krop, Cynthia X Ma, Patricia M LoRusso, Pamela N Munster, Karen Campbell, Daniel F Gaddy, Shannon C Leonard, Elena Geretti, Stephanie J Blocker, Dmitri B Kirpotin, Victor Moyo, Thomas J Wickham, Bart S Hendriks
PURPOSE: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. EXPERIMENTAL DESIGN: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by Positron Emission Tomography/Computed Tomography (PET/CT)...
March 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28298545/homeobox-b9-mediates-resistance-to-anti-vegf-therapy-in-colorectal-cancer-patients
#13
Carmine Carbone, Geny Piro, Francesca Simionato, Francesca Ligorio, Chiara Cremolini, Fotios Loupakis, Greta Alì, Daniele Rossini, Valeria Merz, Raffaela Santoro, Camilla Zecchetto, Marco Zanotto, Federica Di Nicolantonio, Alberto Bardelli, Gabriella Fontanini, Giampaolo Tortora, Davide Melisi
PURPOSE: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. EXPERIMENTAL DESIGN: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoietin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, interleukin(IL)8, and Transforming Growth Factor (TGF)β1 in tumor-bearing mice were measured by multiplex xMAP technology...
March 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28298544/can-consideration-of-the-microbiome-improve-antimicrobial-utilization-and-treatment-outcomes-in-the-oncology-patient
#14
Jessica R Galloway-Pena, Robert R Jenq, Samuel A Shelburne
The need to provide effective and timely antimicrobial treatment to cancer patients with infections is well-recognized, but tempered by preliminary, but accumulating, evidence that antibiotic-induced microbiome dysbiosis affects cancer therapy response, non-infectious toxicities, and infectious complications. Given only a minority of empirically treated cancer patients are proven to have a true bacterial infection, it is important to consider the potential negative consequences of extensive broad-spectrum antimicrobial use on the commensal microbiota...
March 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28289089/molecular-pathways-oncologic-pathways-and-their-role-in-t-cell-exclusion-and-immune-evasion-a-new-role-for-the-axl-receptor-tyrosine-kinase
#15
Todd A Aguilera, Amato J Giaccia
With the clinical impact of CTLA-4 and PD-1/PD-L1 immune checkpoint therapies, widespread interest in cancer immunotherapy has been ignited. However, the rate and extent of clinical responses to approved therapies are limited and often non-existent in many solid tumors. This is partially because immune checkpoint therapies are most effective against T-cell inflamed tumors, and non-T-cell inflamed or T-cell excluded tumors remain a significant barrier. New strategies are needed to overcome immune resistance mechanisms that arise during tumor development which result in T-cell exclusion...
March 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28280092/a-phase-i-ib-study-of-enzalutamide-alone-and-in-combination-with-endocrine-therapies-in-women-with-advanced-breast-cancer
#16
Lee S Schwartzberg, Denise Yardley, Anthony Elias, Manish Patel, Patricia M LoRusso, Howard A Burris, Ayca Gucalp, Amy Peterson, Martha Blaney, Joyce Steinberg, Jacqueline Gibbons, Tiffany A Traina
PURPOSE: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ETs). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28280091/dual-inhibition-of-egfr-and-c-src-by-cetuximab-and-dasatinib-combined-with-folfox-chemotherapy-in-patients-with-metastatic-colorectal-cancer
#17
Christine Parseghian, Nila U Parikh, Ji Yuan Wu, Zhi-Qin Jiang, Laura D Henderson, Feng Tian, Brice Pastor, Marc Ychou, Kanwal Raghav, Arvind Dasari, David Fogelman, Anastasia Katsiampoura, David G Menter, Robert A Wolff, Cathy Eng, Michael J Overman, Alain R Thierry, Gary E Gallick, Scott Kopetz
BACKGROUND: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab. METHODS: We performed a phase IB/II study of 77 patients with previously-treated mCRC. Primary objectives were to determine the MTD, dose-limiting-toxicities, pharmacodynamics, and efficacy...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28280090/pooled-clustering-of-high-grade-serous-ovarian-cancer-gene-expression-leads-to-novel-consensus-subtypes-associated-with-survival-and-surgical-outcomes
#18
Chen Wang, Sebastian M Armasu, Kimberly R Kalli, Matthew J Maurer, Ethan P Heinzen, Gary Keeney, William A Cliby, Ann L Oberg, Scott H Kaufmann, Ellen L Goode
PURPOSE: Here we assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC). EXPERIMENTAL DESIGN: Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define molecular subtypes of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28280089/successful-transfer-of-umbilical-cord-blood-cd34-hematopoietic-stem-and-progenitor-derived-nk-cells-in-older-acute-myeloid-leukemia-patients
#19
Harry Dolstra, Mieke W H Roeven, Jan Spanholtz, Basav N Hangalapura, Marleen Tordoir, Frans Maas, Marij Leenders, Fenna Bohme, Nina Kok, Carel Trilsbeek, Jos Paardekooper, Anniek B van der Waart, Peter E Westerweel, Tjeerd J F Snijders, Jan J Cornelissen, Gerard M J Bos, Hans F M Pruijt, Aniek O De Graaf, Bert van der Reijden, Joop H Jansen, Arnold van der Meer, Gerwin Huls, Jeannette Cany, Frank Preijers, Nicole M A Blijlevens, Nicolaas M Schaap
PURPOSE: Older acute myeloid leukemia (AML) patients have a poor prognosis, therefore novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting an unique scalable NK cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPCs) from partially HLA-matched umbilical cord blood units. EXPERIMENTAL DESIGN: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30x10^6/kg body weight) after lymphodepleting chemotherapy without cytokine boosting...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28280088/radiomics-features-of-multiparametric-mri-as-novel-prognostic-factors-in-advanced-nasopharyngeal-carcinoma
#20
Shuixing Zhang, Bin Zhang, Jie Tian, Di Dong, Dong Sheng Gu, Yu Hao Dong, Lu Zhang, Zhou Yang Lian, Jing Liu, Xiao Ning Luo, Shu Fang Pei, Xiao Kai Mo, Wen Hui Huang, Fu Sheng Ouyang, Bao Liang Guo, Long Liang, Wenbo Chen, Chang H Liang
PURPOSE: To identify MRI-based radiomics as prognostic factors in patients with advanced nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: One-hundred and eighteen patients (training cohort: n = 88; validation cohort: n = 30) with advanced NPC were enrolled. A total of 970 radiomics features were extracted from T2-weighted (T2-w) and contrast-enhanced T1-weighted (CET1-w) MRI. Least absolute shrinkage and selection operator (LASSO) regression was applied to select features for progression-free survival (PFS) nomograms...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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