المؤلفون: David Shih, Luca Massimi, Sidney Croul, William A. Weiss, Boleslaw Lach, Abhijit Guha, Vijay Ramaswamy, Nada Jabado, Mark Barszczyk, Stefan M. Pfister, Nadia Hill, Kory Zayne, Wiesława Grajkowska, Xin Wang, Andrey Korshunov, Cynthia Hawkins, Hendrik Witt, James T. Rutka, Michael D. Taylor, Kelsey C. Bertrand, Marc Remke, Melike Pekmezci, Joanna Philips, Tarik Tihan, Gelareh Zadeh, Sameer Agnihotri, Marina Ryzhova, Nalin Gupta, Stephen C. Mack, Yuan Yao Thompson

المصدر: Mack, SC; Agnihotri, S; Bertrand, KC; Wang, X; Shih, DJ; Witt, H; et al.(2015). Spinal myxopapillary ependymomas demonstrate a warburg phenotype. Clinical Cancer Research, 21(16), 3750-3758. doi: 10.1158/1078-0432.CCR-14-2650. UCSF: Retrieved from: http://www.escholarship.org/uc/item/3280q17rTest

مصطلحات موضوعية: Adult, Male, Ependymoma, Cancer Research, Pathology, medicine.medical_specialty, DNA Copy Number Variations, Protein Serine-Threonine Kinases, PKM2, Biology, Article, Western blot, Hexokinase, medicine, Humans, Neoplasm Metastasis, Gene, Aged, Regulation of gene expression, Spinal Neoplasms, medicine.diagnostic_test, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Middle Aged, Hypoxia-Inducible Factor 1, alpha Subunit, medicine.disease, Spinal cord, Phenotype, Gene Expression Regulation, Neoplastic, Gene expression profiling, medicine.anatomical_structure, Spinal Cord, Oncology, Cancer research, Female, Transcriptome

الوصف: Purpose: Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy. Experimental Design: Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production. Results: At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production. Conclusions: Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE. Clin Cancer Res; 21(16); 3750–8. ©2015 AACR.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e808b5009b6f13eedcaf3441edf6676fTest
https://doi.org/10.1158/1078-0432.ccr-14-2650Test

المؤلفون: Chang-Qi Zhu, Melania Pintilie, Desmond She, Frances A. Shepherd, Shingo Sakashita, David W. Cescon, Ming-Sound Tsao

المصدر: Clinical Cancer Research. 21:2499-2505

مصطلحات موضوعية: Adult, Male, Cancer Research, NF-E2-Related Factor 2, Biology, Bioinformatics, medicine.disease_cause, Vinorelbine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Gene expression, Carcinoma, medicine, Humans, Aged, Aged, 80 and over, Cisplatin, Regulation of gene expression, Mutation, Kelch-Like ECH-Associated Protein 1, Intracellular Signaling Peptides and Proteins, Middle Aged, Prognosis, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Oncology, Chemotherapy, Adjuvant, Significance analysis of microarrays, Cancer research, Immunohistochemistry, Female, Signal Transduction, medicine.drug

الوصف: Purpose: Genomic profiling of lung squamous cell carcinomas (SCC) has identified NRF2 pathway alterations, which activate oxidative response pathways, in one third of tumors. Preclinical data suggest these tumors may be resistant to platinum-based chemotherapy. We evaluated the clinical relevance of these findings and assessed whether NRF2 activation predicts benefit from adjuvant chemotherapy in SCC. Experimental Design: Logistic regression (LR) and significance analysis of microarrays (SAM) were applied to all 104 TCGA (The Cancer Genome Atlas) SCC cases that had microarray gene expression and mutation data to identify genes associated with somatic NRF2 pathway alterations. The resulting signature (NRF2ACT) was tested in 3 independent SCC datasets to evaluate its prognostic and predictive effects. IHC and sequencing for NRF2 and KEAP1 were evaluated in one cohort (n = 43) to assess the relationship between gene expression, mutational status, and protein expression. Results: Twenty-eight genes were identified by overlap between LR (291 genes) and SAM (30 genes), and these consistently separated SCC into 2 groups in all datasets, corresponding to putatively NRF pathway–activated and wild-type (WT) tumors. NRF2ACT was not prognostic. However, improved survival with adjuvant chemotherapy in the JBR.10-randomized trial appears limited to patients with the WT signature (HR 0.32, P = 0.16; NRF2ACT HR 2.28, P = 0.48; interaction P = 0.15). NRF2ACT was highly correlated with mutations in NRF2 and KEAP1, and with high NRF2 protein expression. Conclusions: A gene expression signature of NRF2 pathway activation is associated with benefit from adjuvant cisplatin/vinorelbine in SCC. Patients with NRF2 pathway–activating somatic alterations may have reduced benefit from this therapy. Clin Cancer Res; 21(11); 2499–505. ©2015 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::135de72cf152ecfb74c7aec58d5fafd2Test
https://doi.org/10.1158/1078-0432.ccr-14-2206Test

المؤلفون: Maria Simonsson, Ann H. Rosendahl, Christian Ingvar, Li Zeng, Claire M Perks, Jeffrey M P Holly, Andrea Markkula, Carsten Rose, Helena Jernström

المصدر: Clinical Cancer Research. 21:1877-1887

مصطلحات موضوعية: Adult, Cancer Research, medicine.medical_specialty, Cell Survival, Population, Estrogen receptor, Breast Neoplasms, Coffea, Receptor, IGF Type 1, Young Adult, chemistry.chemical_compound, Caffeic Acids, Breast cancer, Risk Factors, Caffeine, Cell Line, Tumor, Internal medicine, Biomarkers, Tumor, Caffeic acid, medicine, Humans, Neoplasm Metastasis, education, Aged, Cell Proliferation, Aged, 80 and over, education.field_of_study, business.industry, Cell Cycle, Cancer, Middle Aged, medicine.disease, Tumor Burden, Endocrinology, Receptors, Estrogen, Oncology, chemistry, Hormone receptor, Female, Neoplasm Grading, Neoplasm Recurrence, Local, business, Tamoxifen, medicine.drug

الوصف: Purpose: Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how coffee may affect breast cancer growth in relation to estrogen receptor-α (ER) status. Experimental Design: The influence of coffee consumption on patient and tumor characteristics and disease-free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER+ (MCF-7) and ER− (MDA-MB-231) breast cancer cells. Results: Moderate (2–4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (Ptrend = 0.013) and lower proportion of ER+ tumors (Ptrend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER+ tumors (adjusted HR, 0.51; 95% confidence interval, 0.26–0.97). Caffeine and caffeic acid suppressed the growth of ER+ (P ≤ 0.01) and ER− (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER+ cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER+ and ER− cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death. Conclusions: The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER+ and ER− breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth. Clin Cancer Res; 21(8); 1877–87. ©2015 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cbf8c09abf9f33988899ad55eee957c8Test
https://doi.org/10.1158/1078-0432.ccr-14-1748Test

المؤلفون: Anton C.M. Martens, Willy A. Noort, Joost M. Bakker, Tuna Mutis, Paul W. H. I. Parren, Berris van Kessel, Inger S. Nijhof, Jeroen J. Lammerts van Bueren, Richard W.J. Groen, Regina de Jong-Korlaar, Niels W.C.J. van de Donk, Henk M. Lokhorst

المساهمون: Hematology laboratory, Hematology, CCA - Innovative therapy

المصدر: Clinical Cancer Research, 21(12), 2802-2810. American Association for Cancer Research Inc.
Nijhof, I S, Groen, R W J, Noort, W A, van Kessel, B, de Jong-Korlaar, R, Bakker, J, van Bueren, J J L, Parren, P W H I, Lokhorst, H M, van de Donk, N W C J, Martens, A C M & Mutis, T 2015, ' Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib ', Clinical Cancer Research, vol. 21, no. 12, pp. 2802-2810 . https://doi.org/10.1158/1078-0432.CCR-14-1813Test
Nijhof, I S, Groen, R W J, Noort, W A, van Kessel, B, de Jong-Korlaar, R, Bakker, J, van Bueren, J J L, Parren, P W H I, Lokhorst, H M, van de Donk, N, Martens, A C M & Mutis, T 2015, ' Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib ', Clinical Cancer Research, vol. 21, no. 12, pp. 2802-2810 . https://doi.org/10.1158/1078-0432.CCR-14-1813Test

مصطلحات موضوعية: Male, Cancer Research, medicine.medical_treatment, Drug Evaluation, Preclinical, Antibody-Dependent Cell Cytotoxicity/immunology, Pharmacology, Lymphocyte Activation, Bortezomib, Mice, immune system diseases, hemic and lymphatic diseases, ADP-ribosyl Cyclase 1/antagonists & inhibitors, Molecular Targeted Therapy, Lenalidomide, Multiple myeloma, Killer Cells, Natural/drug effects, Isatuximab, Drug Synergism, Middle Aged, Lymphocyte Activation/drug effects, Thalidomide, Killer Cells, Natural, medicine.anatomical_structure, Oncology, Female, Immunotherapy, Multiple Myeloma, medicine.drug, Adult, Cell Line, Tumor, medicine, Animals, Humans, Multiple Myeloma/diagnosis, Aged, Thalidomide/administration & dosage, business.industry, Antibody-Dependent Cell Cytotoxicity, Daratumumab, NATURAL-KILLER-CELLS APOPTOSIS-INDUCING LIGAND PROTEASOME INHIBITION ANTIBODY DARATUMUMAB CYTOTOXICITY COMBINATION ELOTUZUMAB MULTICENTER THALIDOMIDE EXPRESSION, medicine.disease, ADP-ribosyl Cyclase 1, Xenograft Model Antitumor Assays, Disease Models, Animal, Cancer research, Bortezomib/administration & dosage, Bone marrow, business, Ex vivo

الوصف: Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. Experimental Design: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Results: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. Conclusions: Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients. Clin Cancer Res; 21(12); 2802–10. ©2014 AACR. See related commentary by Laubach and Richardson, p. 2660

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ebc002482a8f6d680034431f465f4cc8Test
https://doi.org/10.1158/1078-0432.ccr-14-1813Test

المؤلفون: Takeshi Uchiumi, Kentaro Kuroiwa, Yasuhiro Tada, Akira Yokomizo, Yoshinao Oda, Hiroshi Uchino, Keijiro Kiyoshima, YooHyun Song, Katsunori Tatsugami, Junichi Inokuchi, Masaki Shiota, Seiji Naito

المصدر: Clinical Cancer Research. 16(23):5654-5663

مصطلحات موضوعية: Adult, Male, Cancer Research, Down-Regulation, Motility, Biology, Transfection, Metastasis, Gene expression, Biomarkers, Tumor, Tumor Cells, Cultured, medicine, Humans, Neoplasm Invasiveness, Molecular Targeted Therapy, Transcription factor, Aged, Aged, 80 and over, Gene knockdown, Cadherin, Carcinoma, Forkhead Box Protein O3, Twist-Related Protein 1, Nuclear Proteins, Cancer, Forkhead Transcription Factors, Middle Aged, Y box binding protein 1, Cadherins, medicine.disease, Molecular biology, Gene Expression Regulation, Neoplastic, Urinary Bladder Neoplasms, Oncology, Female, Y-Box-Binding Protein 1, Urothelium

الوصف: Purpose: Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion. Experimental Design: Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells. Results: Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box–binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCCsup cells that expressed Twist1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility. Conclusion: The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics. Clin Cancer Res; 16(23); 5654–63. ©2010 AACR.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e166368f06fedbc4dd2d5dd346129515Test
http://hdl.handle.net/2324/26053Test

المؤلفون: Judith E. Karp, Harry P. Erba, Brian Parkin, Moshe Talpaz, Sajid Shakhan, Paula L. Bockenstedt, Cheng Li, Sami N. Malek, Ammar Al-Zoubi, Diane Roulston, Yang Liu, Kerby Shedden, Yin Wang, Lisa Kujawski, Yan Liu, Amanda Dressel, Whitney Wright, Anjali A. Purkayastha, Peter Ouillette

المصدر: Clinical Cancer Research. 16:4135-4147

مصطلحات موضوعية: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Myeloid, Blotting, Western, Gene Dosage, CD34, Cell Separation, Polymorphism, Single Nucleotide, Frameshift mutation, Young Adult, hemic and lymphatic diseases, Genes, Neurofibromatosis 1, medicine, Humans, Gene silencing, Gene Silencing, Frameshift Mutation, neoplasms, In Situ Hybridization, Fluorescence, Aged, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, biology, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Middle Aged, Flow Cytometry, medicine.disease, Neurofibromin 1, nervous system diseases, Gene expression profiling, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Oncology, Immunology, ras Proteins, biology.protein, Cancer research, Female, Bone marrow, Signal Transduction

الوصف: Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). Experimental Design: We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix single nucleotide polymorphism 6.0 array–based genomic profiling. Results: Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of ∼0.9-Mb length that harbors 11 known genes; this region includes Neurofibromin 1 (NF1). Sequence analysis of all NF1 coding exons in the 11 AML cases with NF1 copy number changes identified acquired truncating frameshift mutations in two patients. These NF1 mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and short hairpin RNA–mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitated colony formation in methylcellulose. Primary AML blasts without functional NF1, unlike blasts with functional NF1, displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mammalian target of rapamycin (mTOR) signaling for survival. Finally, colony formation in methylcellulose ex vivo of NF1 null CD34+/CD38− cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin. Conclusions: NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin–directed therapeutics. Clin Cancer Res; 16(16); 4135–47. ©2010 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dbe0cb331781288fd94d8b8a6e95148eTest
https://doi.org/10.1158/1078-0432.ccr-09-2639Test

المؤلفون: Noelle V. Frey, F. Brad Johnson, David L. Porter, Gregory L. Beatty, Robert H. Vonderheide, Theresa A. Colligon, Barbara A. Vance, Ran Reshef, Jasmine S. Smith, Kunal P. Patel

المصدر: Clinical Cancer Research. 15:4944-4953

مصطلحات موضوعية: Adult, Cancer Research, Myeloid, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Graft vs Leukemia Effect, Hematopoietic stem cell transplantation, CD8-Positive T-Lymphocytes, Biology, Article, Interferon-gamma, Young Adult, Myelogenous, Antigens, CD, Lysosomal-Associated Membrane Protein 1, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Humans, Cytotoxic T cell, Cellular Senescence, Aged, Myeloid leukemia, Middle Aged, Telomere, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, surgical procedures, operative, medicine.anatomical_structure, Oncology, Immunology, Cancer research, Female, Apoptosis Regulatory Proteins, CD8, Stem Cell Transplantation, Chronic myelogenous leukemia

الوصف: Purpose: The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8+ T-cell responses to MHC class I–restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood.Experimental Design: We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8+ T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library.Results: Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8+ T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8+ T cells from patients were predominantly CD28− CD57+ and had relatively short telomeres, consistent with cellular senescence.Conclusions: Circulating leukemia-specific CD8+ T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02d7fa4278ad8c57e3d778b89a5f0ddeTest
https://doi.org/10.1158/1078-0432.ccr-08-3332Test

المؤلفون: Ignacio I. Wistuba, Razelle Kurzrock, David S. Hong, Jean Pierre J. Issa, David J. Stewart, Maria I. Nunez, Yasuhiro Oki, Zhong Guo, Jaroslav Jelinek, Sanjay Gupta

المصدر: Clinical Cancer Research. 15:3881-3888

مصطلحات موضوعية: Adult, DNA (Cytosine-5-)-Methyltransferase 1, Male, Antimetabolites, Antineoplastic, Cancer Research, medicine.medical_specialty, Thymoma, Lymphoma, Azacitidine, Decitabine, Apoptosis, Blood Pressure, Biology, DNA methyltransferase, Peripheral blood mononuclear cell, Young Adult, Sex Factors, Neoplasms, Internal medicine, In Situ Nick-End Labeling, medicine, Humans, Neoplasm, DNA (Cytosine-5-)-Methyltransferases, Cation Transport Proteins, DNA Modification Methylases, Aged, Copper Transporter 1, Dose-Response Relationship, Drug, Methylation, DNA Methylation, Hydrogen-Ion Concentration, Middle Aged, medicine.disease, Ki-67 Antigen, Treatment Outcome, Endocrinology, Oncology, Drug Resistance, Neoplasm, DNA methylation, Leukocytes, Mononuclear, Cancer research, Female, medicine.drug

الوصف: Purpose: By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1.Experimental Design: Thirty-one patients with refractory malignancies received decitabine 2.5 to 10 mg/m2 on days 1 to 5, and 8 to 12 or 15 to 20 mg/m2 on days 1 to 5. Tumor was assessed for DNA methylation (by LINE assays), apoptosis, necrosis, mitoses, Ki67, DNA methyltransferase (DNMT1), CTR1, and p16.Results: Febrile neutropenia was dose limiting. One thymoma patient responded. Decitabine decreased tumor DNA methylation (from median 51.2% predecitabine to 43.7% postdecitabine; P = 0.01, with effects at all doses) and in peripheral blood mononuclear cells (from 65.3-56.0%). There was no correlation between tumor and peripheral blood mononuclear cells. Patients starting decitabine ≤3 versus >3 months after last prior cytotoxic or targeted therapy had lower predecitabine tumor CTR1 scores (P = 0.02), higher p16 (P = 0.04), and trends (P = 0.07) toward higher tumor methylation and apoptosis. Decitabine decreased tumor DNMT1 for scores initially >0 (P = 0.04). Decitabine increased tumor apoptosis (P < 0.05), mitoses (if initially low, P = 0.02), and CTR1 (if initially low, P = 0.025, or if ≤3 months from last prior therapy, P = 0.04). Tumor CTR1 scores correlated inversely with methylation (r = −0.41, P = 0.005), but CTR1 promoter was not hypermethylated. Only three patients had tumor p16 promoter hypermethylation. P16 scores did not increase. Higher blood pressure correlated with lower tumor necrosis (P = 0.03) and a trend toward greater DNA demethylation (P = 0.10).Conclusions: Exposure to various cytotoxic and targeted agents might generate broad pleiotropic resistance by reducing CTR1 and other transporters. Decitabine decreases DNA methylation and augments CTR1 expression through methylation-independent mechanisms.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af49e93ad5bd6e830762f1d024cc00ccTest
https://doi.org/10.1158/1078-0432.ccr-08-2196Test

المؤلفون: Jan C. Buckner, Shaji Kumar, Evanthia Galanis, Caterina Giannini, Kurt A. Jaeckle, Patrick J. Flynn, Jacqueline M. Lafky, Joon H. Uhm, Donald W. Northfelt, S. Keith Anderson, Teresa K. Kimlinger, Timothy J. Kaufmann

المصدر: Clinical Cancer Research. 19:4816-4823

مصطلحات موضوعية: Adult, Male, Niacinamide, Vascular Endothelial Growth Factor A, Sorafenib, Oncology, Cancer Research, medicine.medical_specialty, Bevacizumab, Angiogenesis, Phases of clinical research, Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Disease-Free Survival, Article, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Aged, Proportional Hazards Models, Biologic marker, Brain Neoplasms, business.industry, Phenylurea Compounds, Therapeutic effect, Cancer, Middle Aged, Hypoxia-Inducible Factor 1, alpha Subunit, Neoplastic Cells, Circulating, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Surgery, Toxicity, Female, Neoplasm Recurrence, Local, Glioblastoma, business, medicine.drug

الوصف: Purpose: We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity. Experimental Design: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1–5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B). Results: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5–24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7–8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P < 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell–derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome. Conclusions: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation. Clin Cancer Res; 19(17); 4816–23. ©2013 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::77bcc6b23403f955f82ac59e0e9630ecTest
https://doi.org/10.1158/1078-0432.ccr-13-0708Test

المؤلفون: Marc H.G.P. Raaijmakers, Joop H. Jansen, Theo de Witte, Bert A. van der Reijden, Reinier Raymakers, Elke P.L.M. de Grouw

المصدر: Clinical Cancer Research, 12, 11 Pt 1, pp. 3452-8
Clinical Cancer Research, 12, 3452-8

مصطلحات موضوعية: Adult, Male, Cancer Research, ATP Binding Cassette Transporter, Subfamily B, Myeloid, Adolescent, Oncogene Proteins, Fusion, CD34, Antigens, CD34, Bone Marrow Cells, Cyclosporins, Biology, CD38, Immune Regulation [NCMLS 2], Translational research [ONCOL 3], hemic and lymphatic diseases, medicine, Humans, Iron metabolism [IGMD 7], ATP Binding Cassette Transporter, Subfamily B, Member 1, Progenitor cell, Aged, Molecular diagnosis, prognosis and monitoring [UMCN 1.2], Mitoxantrone, Reverse Transcriptase Polymerase Chain Reaction, Biological Transport, Middle Aged, Flow Cytometry, Hematopoietic Stem Cells, medicine.disease, ADP-ribosyl Cyclase 1, Antigens, Differentiation, Drug Resistance, Multiple, Pathogenesis and modulation of inflammation [N4i 1], Leukemia, Myeloid, Acute, Haematopoiesis, Leukemia, medicine.anatomical_structure, Verapamil, Oncology, Immunology, Cancer research, Female, Microbial pathogenesis and host defense [UMCN 4.1], Stem cell, Immunity, infection and tissue repair [NCMLS 1], medicine.drug

الوصف: Purpose: Acute myelogenous leukemia (AML) is a disease originating from normal hematopoietic CD34+CD38− progenitor cells. Modulation of the multidrug ATP-binding cassette transporter ABCB1 has not resulted in improved outcome in AML, raising the question whether leukemic CD34+CD38− cells are targeted by this strategy. Experimental Design: ABCB1-mediated transport in leukemic CD34+CD38− cells compared with their normal counterparts was assessed by quantitating the effect of specific ABCB1 modulators (verapamil and PSC-833) on mitoxantrone retention [defined as efflux index (EI), intracellular mitoxantrone fluorescence intensity in the presence/absence of inhibitor]. Results: ABCB1 was the major drug transporter in CD34+CD38− cells in normal bone marrow (n = 16), as shown by the abrogation of mitoxantrone extrusion by ABCB1 modulators (EI, 1.99 ± 0.08). Surprisingly, ABCB1-mediated drug extrusion was invariably reduced in CD34+CD38− cells in AML (n = 15; EI, 1.21 ± 0.05; P < 0.001), which resulted in increased intracellular mitoxantrone retention in these cells (mitoxantrone fluorescence intensity, 4.54 ± 0.46 versus 3.08 ± 0.23; P = 0.004). Active drug extrusion from these cells occurred in the presence of ABCB1 modulators in the majority of samples, pointing in the direction of redundant drug extrusion mechanisms. Residual normal CD34+CD38− cells could be identified by their conserved ABCB1-mediated extrusion capacity. Conclusion: ABCB1-mediated drug extrusion is reduced in leukemic CD34+CD38− progenitor cells compared with their residual normal counterparts. Redundant drug transport mechanisms confer mitoxantrone transport from leukemic progenitors. These data argue that ABCB1 modulation is not an effective strategy to circumvent drug extrusion from primitive leukemic progenitor cells and may preferentially target residual normal progenitors in AML.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7dd56d62990d210e89957df974edf845Test
https://doi.org/10.1158/1078-0432.ccr-05-1945Test