bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Four Biomarkers to Evaluate the Risk of Breast Cancer Subtypes in the Women's Contraceptive and Reproductive Experiences Study
Authors: Ma Huiyan , Wang Yaping , Sullivan-Halley Jane , Weiss Linda , Marchbanks Polly A. , Spirtas Robert , Ursin Giske , Burkman Ronald T. , Simon Michael S. , Malone Kathleen E. , Strom Brian L. , McDonald Jill A. , Press Michael F. , Bernstein Leslie 
Published: January 2010

Abstract
Epidemiologic studies suggest that some hormone-related risk factors in breast cancer differentially influence risk for disease subtypes classified by the status of the estrogen and progesterone receptors (ER/PR). However, it remains unclear whether human epidermal growth factor receptor 2 (HER2) or p53 expression status further differentiates these exposure-risk group associations. We evaluated the associations of oral contraceptive (OC) use and reproductive factors with incident invasive breast cancer subtypes among 1,197 population-based cases and 2,015 controls from the Los Angeles County or Detroit components of the Women's Contraceptive and Reproductive Experiences Study. Case-control comparisons by ER/PR/HER2/p53 status were conducted by multivariable polychotomous unconditional logistic regression methods. We found that OC use was not associated with any breast cancer subtype as defined by ER/PR/HER2/p53 status, except for a 2.9-fold increased risk of so-called triple-negative tumors (ER−/PR−/HER2−) among women of 45 to 64 years of age who started OC use before age 18. Parity was associated with a decreased risk of luminal A (ER+ or PR+, HER2−), luminal B (ER+ or PR+/HER2+), and ER−/PR−/HER2+ tumors. Age at first full-term pregnancy was positively associated with luminal A tumors among older women. Neither of these reproductive factors was associated with triple-negative tumors. Long duration of breast-feeding lowered the risk of triple-negative and luminal A tumors. p53 status did not define further differential risk patterns. Our findings offer evidence of differences in the hormone-related risk factors between triple-negative cancers and other ER/PR/HER2-defined subtypes of breast cancer. Cancer Res; 70(2); 575–87
Integration of DNA Copy Number Alterations and Prognostic Gene Expression Signatures in Breast Cancer Patients
Authors: Horlings Hugo M. , Lai Carmen , Nuyten Dimitry S.A. , Halfwerk Hans , Kristel Petra , van Beers Erik , Joosse Simon A. , Klijn Christiaan , Nederlof Petra M. , Reinders Marcel J.T. , Wessels Lodewyk F.A. , van de Vijver Marc J. 
Published: January 2010

AbstractPurpose: Several prognostic gene expression profiles have been identified in breast cancer. In spite of this progress in prognostic classification, the underlying mechanisms that drive these gene expression patterns remain unknown. Specific genomic alterations, such as copy number alterations, are an important factor in tumor development and progression and are also associated with changes in gene expression.Experimental Design: We carried out array comparative genomic hybridization in 68 human breast carcinomas for which gene expression and clinical data were available. We used a two-class supervised algorithm, Supervised Identification of Regions of Aberration in aCGH data sets, for the identification of regions of chromosomal alterations that are associated with specific sample labeling. Using gene expression data from the same tumors, we identified genes in the altered regions for which the expression level is significantly correlated with the copy number and validated our results in public available data sets.Results: Specific chromosomal aberrations are related to clinicopathologic characteristics and prognostic gene expression signatures. The previously identified poor prognosis, 70-gene expression signature is associated with the gain of 3q26.33-27.1, 8q22.1-24.21, and 17q24.3-25.1; the 70-gene good prognosis profile is associated with the loss at 16q12.1-13 and 16q22.1-24.1; basal-like tumors are associated with the gain of 6p12.3-23, 8q24.21-22, and 10p12.33-14 and losses at 4p15.31, 5q12.3-13.1, 5q33.1, 10q23.33, 12q13.13-3, 15q15.1, and 15q21.1; HER2+ breast show amplification at 17q11.1-12 and 17q21.31-23.2 (including HER2 gene).Conclusions: There is a strong correlation between the different gene expression signatures and underlying genomic changes. These findings help to establish a link between genomic changes and gene expression signatures, enabling a better understanding of the tumor biology that causes poor prognosis. Clin Cancer Res; 16(2); 651–63
NVP-BEZ235 as a New Therapeutic Option for Sarcomas
Authors: Manara Maria C. , Nicoletti Giordano , Zambelli Diana , Ventura Selena , Guerzoni Clara , Landuzzi Lorena , Lollini Pier-Luigi , Maira Saveur-Michel , García-Echeverría Carlos , Mercuri Mario , Picci Piero , Scotlandi Katia 
Published: January 2010

Abstract
Purpose: To evaluate the in vitro and in vivo effects of NVP-BEZ235, a dual pan-phosphoinositide 3-kinase–mammalian target of rapamycin inhibitor in the three most common musculoskeletal tumors (osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma).
Experimental Design: Antiproliferative activity as well as the effects on migration and metastasis were evaluated in a panel of osteosarcoma, Ewing's sarcoma, as well as rhabdomyosarcoma cell lines. Moreover, simultaneous and sequential treatments were done in association with two of the most important conventional drugs in the treatment of sarcoma, doxorubicin and vincristine.
Results: NVPBEZ235 effectively blocked the pathway in in vitro and in vivo settings. Under the experimental conditions tested, the compound induced disease stasis, by arresting cells in G1 phase of cell cycle, without remarkable effects on apoptosis. As a consequence, to obtain the maximum exploitation of its therapeutic potential, NVP-BEZ235 has been evaluated in combination with conventional cytotoxic agents, thus showing promising efficacy with either doxorubicin and vincristine. Inhibition of the phosphoinositide 3-kinase/mammalian target of rapamycin pathway increased activation of extracellular signal-regulated kinase 1/2, likely due to the presence of autocrine circuits shifting growth factor signaling toward the mitogen-activated protein kinase pathway. This supports the combined use of NVP-BEZ235 with other small signaling inhibitors. Here, we showed synergistic effects when the compound was associated with a anti–insulin-like growth factor-I receptor tyrosine kinase inhibitor. NVP-BEZ235 also inhibited cell migration and metastasis. Combination with vincristine further potentiated the antimetastatic effects.
Conclusions: NVP-BEZ235 displays the features to be considered for sarcoma therapy to potentiate the activity of other anticancer agents. The drug is currently undergoing phase I/II clinical trials in advanced cancer patients. Clin Cancer Res; 16(2); 530–40
Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation
Authors: Bauer Joshua A. , Chakravarthy A. Bapsi , Rosenbluth Jennifer M. , Mi Deming , Seeley Erin H. , De Matos Granja-Ingram Nara , Olivares Maria G. , Kelley Mark C. , Mayer Ingrid A. , Meszoely Ingrid M. , Means-Powell Julie A. , Johnson Kimberly N. , Tsai Chiaojung Jillian , Ayers Gregory D. , Sanders Melinda E. , Schneider Robert J. , Formenti Silvia C. , Caprioli Richard M. , Pietenpol Jennifer A. 
Published: January 2010

AbstractPurpose: To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies.Experimental Design: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR).Results: Proteomic and validation immunohistochemical analyses revealed that α-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery.Conclusion: We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane–based therapy. Clin Cancer Res; 16(2); 681–90
Targeting Polo-like Kinase in Cancer Therapy
Authors: Degenhardt Yan , Lampkin Thomas 
Published: January 2010

Abstract
Polo-like kinases (Plk) function in mitosis and maintaining DNA integrity. There are four family members, of which Plk1 represents a target for anticancer therapy. Plk1 is only expressed in dividing cells with peak expression during G2/M. Plk1 functions in multiple steps of mitosis, and is overexpressed in many tumor types. Mitotic arrest and inhibition of proliferation, apoptosis, and tumor growth inhibition have been observed in preclinical studies using small interfering RNAs (siRNA) or small molecules that inhibit Plk1. Preclinical studies also show that Plk1 inhibitors may be active against tumors with RAS mutations and that tumor cells with mutations in TP53 are more sensitive to inhibition of Plk1. Several Plk inhibitors are in phase I or II clinical studies. As expected, hematologic toxicity is the primary dose-limiting toxicity. Some patients have achieved clinical response, although in some studies only at doses above the maximum tolerated dose defined in the study. Further evaluation is necessary to discern the clinical utility of Plk1 inhibitors. Clin Cancer Res; 16(2); 384–9
Tumor O6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib
Authors: Watson Amanda J. , Sabharwal Ami , Thorncroft Mary , McGown Gail , Kerr Richard , Bojanic Stana , Soonawalla Zahir , King Alexandra , Miller Andrea , Waller Sue , Leung Hing , Margison Geoffrey P. , Middleton Mark R. 
Published: January 2010

Abstract
Purpose: A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients.
Experimental Design: Lomeguatrib was administered orally as a single dose (20-160 mg) ∼12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR.
Results: Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 ± 404 fmol/mg protein (±SD) for prostate cancer, 87.4 ± 40.3 fmol/mg protein for CNS tumors, and 244 ± 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg).
Conclusions: Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies. Clin Cancer Res; 16(2); 743–9
Methylation Induced Gene Silencing of HtrA3 in Smoking-Related Lung Cancer
Authors: Beleford Daniah , Liu Zhixue , Rattan Ramandeep , Quagliuolo Lucio , Boccellino Mariarosaria , Baldi Alfonso , Maguire Jacie , Staub Julie , Molina Julian , Shridhar Viji 
Published: January 2010

Abstract
Purpose: Some 85% of lung cancers are smoking related. Here, we investigate the role of serine protease HtrA3 in smoking-related lung cancer.
Experimental Design: We assess HtrA3 methylation and its corresponding expression in the human bronchial cell line BEAS-2B following cigarette smoke carcinogen treatment, in lung cancer cell lines and in primary lung tumors from light, moderate, and heavy smokers. We also show the effects of HtrA3 downregulation on MTT reduction and clonogenic survival with etoposide and cisplatin treatment and the corresponding effects of HtrA3 re-expression during treatment.
Results: We show for the first time that HtrA3 expression is reduced or completely lost in over 50% of lung cancer cell lines and primary lung tumors from heavy smokers. Treatment of HtrA3-deficient cell lines with 5-aza-2′-deoxycytidine resulted in a dose-dependent increase in HtrA3 transcription. Further, sequence analysis of bisulfite-modified DNA from lung cancer cell lines and from primary lung tumors showed an increased frequency of methylation within the first exon of HtrA3 with a corresponding loss of HtrA3 expression, particularly in tumors from smokers. In BEAS-2B, treatment with the cigarette smoke carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone resulted in HtrA3 downregulation with a corresponding increase in methylation. Additional studies indicate resistance to etoposide and cisplatin cytotoxicity as a functional consequence of HtrA3 loss. Finally, immunohistochemical analysis of primary lung tumors revealed a strong correlation between low HtrA3 expression and heavy smoking history.
Conclusions: Collectively, these results suggest that cigarette smoke–induced methylation of HtrA3 could contribute to the etiology of chemoresistant disease in smoking-related lung cancer. Clin Cancer Res; 16(2); 398–409
Mechanisms of Ascorbate-Induced Cytotoxicity in Pancreatic Cancer
Authors: Du Juan , Martin Sean M. , Levine Mark , Wagner Brett A. , Buettner Garry R. , Wang Sih-han , Taghiyev Agshin F. , Du Changbin , Knudson Charles M. , Cullen Joseph J. 
Published: January 2010

Abstract
Purpose: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is &lt;3%.
Experimental Design: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks.
Results: There was a time- and dose-dependent increase in measured H2O2 production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H2O2. Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival.
Conclusions: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer. Clin Cancer Res; 16(2); 509–20
Interleukin 13 Mediates Signal Transduction through Interleukin 13 Receptor α2 in Pancreatic Ductal Adenocarcinoma: Role of IL-13 Pseudomonas Exotoxin in Pancreatic Cancer Therapy
Authors: Shimamura Takeshi , Fujisawa Toshio , Husain Syed R. , Joshi Bharat , Puri Raj K. 
Published: January 2010

Abstract
Purpose: Interleukin-13 receptor α2 (IL-13Rα2) is a tumor antigen that is overexpressed in certain human tumors. However, its significance and expression in pancreatic cancer is not known. It is also not known whether IL-13 can signal through IL-13Rα2 in cancer.
Experimental Design: The expression of IL-13Rα2 was assessed in pancreatic cancer samples by immunohistochemistry and in cell lines by flow cytometry and reverse transcription-PCR. The role of IL-13Rα2 was examined by IL-13–induced signaling in pancreatic cancer cell lines. IL-13Rα2–positive tumors were targeted by IL-13PE cytotoxin in vitro and in vivo in an orthotopic murine model of human pancreatic cancer.
Results: Of the pancreatic tumor samples 71% overexpressed moderate to high-density IL-13Rα2 chain compared with normal pancreatic samples. IL-13 induced transforming growth factor-β1 promoter activity in IL-13Rα2–positive tumor cells and in cells engineered to express IL-13Rα2 but not in IL-13Rα2–negative or RNA interference knockdown cells. c-Jun and c-Fos of the AP-1 family of nuclear factors were activated by IL-13 only in IL-13Rα2–positive cells. In the orthotopic mouse model, IL13-PE significantly decreased tumor growth when assessed by whole-body imaging and prolonged the mean survival time. Similar results were observed in mice xenografted with a surgically resected human pancreatic tumor sample.
Conclusions: These results indicate that IL-13Rα2 is a functional receptor as IL-13 mediates signaling in human pancreatic cancer cell lines. IL-13 causes transforming growth factor-β activation via AP-1 pathway, which may cause tumor induced immunosuppression in the host. In addition, IL13-PE cytotoxin may be an effective therapeutic agent for the treatment of pancreatic cancer. Clin Cancer Res; 16(2); 577–86
Development of Molecularly Targeted Therapies in Hepatocellular Carcinoma: Where Do We Go Now?
Authors: Finn Richard S. 
Published: January 2010

Abstract
Hepatocellular carcinoma (HCC), once considered an orphan disease in the West, has become a global health concern. It is the third leading cause of cancer death worldwide, and its incidence continues to increase. Historically, the development of new systemic agents for advanced HCC has been lacking despite no clear benefit with traditional cytotoxic therapies. Although two randomized studies with sorafenib for the treatment of HCC patients have recently been completed, survival benefits have been modest and highlight the unmet medical need among patients with HCC. Given the clear need, clinical development of novel systemic agents in HCC has begun in earnest. These clinical studies are founded on a growing body of basic and translational science that has identified several potential molecular targets in HCC. The successful development of such targeted agents in the future will be linked to our ability to appropriately select patients for treatment based on their clinical stage (including extent of liver disease and extent of tumor) and on potential predictive markers of response. Here, we review these data in the context of rational drug development in HCC in the front-line setting and in previously treated patients. Clin Cancer Res; 16(2); 390–7.
Vandetanib, Designed to Inhibit VEGFR2 and EGFR Signaling, Had No Clinical Activity as Monotherapy for Recurrent Ovarian Cancer and No Detectable Modulation of VEGFR2
Authors: Annunziata Christina M. , Walker Amanda J. , Minasian Lori , Yu Minshu , Kotz Herbert , Wood Bradford J. , Calvo Katherine , Choyke Peter , Kimm Daniel , Steinberg Seth M. , Kohn Elise C. 
Published: January 2010

Abstract
Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer.
Experimental Design: A phase II trial of orally administered vandetanib 300 mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18-gauge needle biopsies and dynamic contrast-enhanced magnetic resonance imaging were obtained before initiation of therapy and 6 weeks into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay in serially collected plasma samples.
Results: Twelve patients entered the study, and accrual was terminated in the first stage because of lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and prolonged QT interval corrected for heart rate, but not hypertension. Exploratory analyses showed that epidermal growth factor receptor (EGFR) phosphorylation was reduced in the eight paired biopsy sets obtained; vascular endothelial growth factor (VEGF) receptor-2 phosphorylation was not consistently affected nor were dynamic contrast-enhanced MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable and did not significantly change in the 11 patients assessed.
Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGF receptor-2 in ovarian tumor tissue, but only phosphorylated-EGFR was measurably inhibited by vandetanib. Clin Cancer Res; 16(2); 664–72
Immunoglobulin Heavy Chain Variable Gene Usage and (Super)-antigen Drive in Chronic Lymphocytic Leukemia
Authors: Bühler Andreas , Zenz Thorsten , Stilgenbauer Stephan 
Published: January 2010

Abstract
Increasing evidence supports the prognostic relevance of specific immunoglobulin heavy chain variable (IGHV) genes or stereotyped B-cell receptors (BCR) in chronic lymphocytic leukemia (CLL). The clonotypic BCRs differ in their specificity and affinity toward classical antigens and/or superantigens. The BCR-triggered mechanisms are distinct but could explain in part the different clinical behavior among CLL subgroups. Clin Cancer Res; 16(2); 373–5