bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer
Authors: Jimeno Antonio , Tan Aik Choon , Coffa Jordy , Rajeshkumar N.V. , Kulesza Peter , Rubio-Viqueira Belen , Wheelhouse Jenna , Diosdado Begoña , Messersmith Wells A. , Iacobuzio-Donahue Christine , Maitra Anirban , Varella-Garcia Marileila , Hirsch Fred R. , Meijer Gerrit A. , Hidalgo Manuel 
Published: April 2008

Abstract
The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease. We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy. Pancreatic cancer tumors directly xenografted at surgery were treated with the EGFR inhibitors erlotinib and cetuximab and analyzed for biological features. Two of 10 tumors were sensitive, and by global gene expression profiling with gene set enrichment analysis, the EGFR pathway was highly expressed in sensitive compared with resistant tumors. The core gene components driving EGFR pathway overexpression were pathway ligands and positive effectors. In a prospective validation, the EGFR pathway-based signature correctly predicted anti-EGFR treatment response in eight additional tumors and was not predictive of response to gemcitabine and CI1040 (a MEK inhibitor). Analysis of EGFR, KRAS, and PIK3CA mutations and gene amplification by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification showed that none of these genetic abnormalities were neither predictive nor responsible for the EGFR pathway activation. Coordinated overexpression of the EGFR pathway predicts susceptibility to EGFR inhibitors in pancreatic cancer. These results suggest a phenomenon of pathway addiction and support the value of unbiased system biology approaches in drug development. [Cancer Res 2008;68(8):2841–9]
Redirecting Specificity of T-Cell Populations For CD19 Using the Sleeping Beauty System
Authors: Singh Harjeet , Manuri Pallavi R. , Olivares Simon , Dara Navid , Dawson Margaret J. , Huls Helen , Hackett Perry B. , Kohn Donald B. , Shpall Elizabeth J. , Champlin Richard E. , Cooper Laurence J.N. 
Published: April 2008

Abstract
Genetic modification of clinical-grade T cells is undertaken to augment function, including redirecting specificity for desired antigen. We and others have introduced a chimeric antigen receptor (CAR) to enable T cells to recognize lineage-specific tumor antigen, such as CD19, and early-phase human trials are currently assessing safety and feasibility. However, a significant barrier to next-generation clinical studies is developing a suitable CAR expression vector capable of genetically modifying a broad population of T cells. Transduction of T cells is relatively efficient but it requires specialized manufacture of expensive clinical grade recombinant virus. Electrotransfer of naked DNA plasmid offers a cost-effective alternative approach, but the inefficiency of transgene integration mandates ex vivo selection under cytocidal concentrations of drug to enforce expression of selection genes to achieve clinically meaningful numbers of CAR+ T cells. We report a new approach to efficiently generating T cells with redirected specificity, introducing DNA plasmids from the Sleeping Beauty transposon/transposase system to directly express a CD19-specific CAR in memory and effector T cells without drug selection. When coupled with numerical expansion on CD19+ artificial antigen-presenting cells, this gene transfer method results in rapid outgrowth of CD4+ and CD8+ T cells expressing CAR to redirect specificity for CD19+ tumor cells. [Cancer Res 2008;68(8):2961–71]
Synthetic CD4+ T Cell–Targeted Antigen-Presenting Cells Elicit Protective Antitumor Responses
Authors: Caserta Stefano , Alessi Patrizia , Guarnerio Jlenia , Basso Veronica , Mondino Anna 
Published: April 2008

AbstractCD4+ helper T cells are critical for protective immune responses and yet suboptimally primed in response to tumors. Cell-based vaccination strategies are under evaluation in clinical trials but limited by the need to derive antigen-presenting cells (APC) from patients or compatible healthy donors. To overcome these limitations, we developed CD4+ T cell–targeted synthetic microbead-based artificial APC (aAPC) and used them to activate CD4+ T lymphocytes specific for a tumor-associated model antigen (Ag) directly from the naive repertoire. In vitro, aAPC specifically primed Ag-specific CD4+ T cells that were activated to express high levels of CD44, produced mainly interleukin 2, and could differentiate into Th1-ike or Th2-like cells in combination with polarizing cytokines. I.v. administration of aAPC led to Ag-specific CD4+ T-cell activation and proliferation in secondary lymphoid organs, conferred partial protection against subcutaneous tumors, and prevented the establishment of lung metastasis. Taken together, our data support the use of cell-free, synthetic aAPC as a specific and versatile alternative to expand peptide-specific CD4+ T cells in adoptive and active immunotherapy. [Cancer Res 2008;68(8):3010–8]
Role of the Aggresome Pathway in Cancer: Targeting Histone Deacetylase 6–Dependent Protein Degradation
Authors: Rodriguez-Gonzalez Agustin , Lin Tara , Ikeda Alan K. , Simms-Waldrip Tiffany , Fu Cecilia , Sakamoto Kathleen M. 
Published: April 2008

Abstract
Misfolded or aggregated proteins have two fates: they are either refolded with the help of chaperones or degraded by the proteasome. Cells also have an alternative pathway that involves intracellular “storage bins” for misfolded intracellular proteins known as aggresomes. Aggresomes recruit motor proteins that transport misfolded or aggregated proteins to chaperones and proteasomes for subsequent destruction. There is emerging evidence that inhibiting the aggresome pathway leads to accumulation of misfolded proteins and apoptosis in tumor cells through autophagy. We discuss the role of aggresomes in cancer and the potential to target this pathway for therapy. [Cancer Res 2008;68(8):2557–60]
Targeted Deletion of Prkar1a Reveals a Role for Protein Kinase A in Mesenchymal-to-Epithelial Transition
Authors: Nadella Kiran S. , Jones Georgette N. , Trimboli Anthony , Stratakis Constantine A. , Leone Gustavo , Kirschner Lawrence S. 
Published: April 2008

Abstract
Dysregulation of protein kinase A (PKA) activity, caused by loss of function mutations in PRKAR1A, is known to induce tumor formation in the inherited tumor syndrome Carney complex (CNC) and is also associated with sporadic tumors of the thyroid and adrenal. We have previously shown that Prkar1a+/− mice develop schwannomas reminiscent of those seen in CNC and that similar tumors are observed in tissue-specific knockouts (KO) of Prkar1a targeted to the neural crest. Within these tumors, we have previously described the presence of epithelial islands, although the nature of these structures was unclear. In this article, we report that these epithelial structures are derived from KO cells originating in the neural crest. Analysis of the mesenchymal marker vimentin revealed that this protein was markedly down-regulated not only from the epithelial islands, but also from the tumor as a whole, consistent with mesenchymal-to-epithelial transition (MET). In vitro, Prkar1a null primary mouse embryonic fibroblasts, which display constitutive PKA signaling, also showed evidence for MET, with a loss of vimentin and up-regulation of the epithelial marker E-cadherin. Reduction of vimentin protein occurred at the posttranslational level and was rescued by proteasomal inhibition. Finally, this down-regulation of vimentin was recapitulated in the adrenal nodules of CNC patients, confirming an unexpected and previously unrecognized role for PKA in MET. [Cancer Res 2008;68(8):2671–7]
Interleukin 21 Enhances Antibody-Mediated Tumor Rejection
Authors: Smyth Mark J. , Teng Michele W.L. , Sharkey Janelle , Westwood Jennifer A. , Haynes Nicole M. , Yagita Hideo , Takeda Kazuyoshi , Sivakumar Pallavur V. , Kershaw Michael H. 
Published: April 2008

AbstractInterleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15 that has antitumor activity alone in mouse experimental tumor models and a tolerable safety profile in phase I trials in patients with metastatic melanoma and renal cell carcinoma. Several monoclonal antibodies (mAb) targeted at tumor-associated antigens also have improved antitumor activities in mice when used in combination with IL-21. Recently, we described a rational three antibody-based approach (triple mAb, TrimAb) to eradicating established mouse tumors that required the generation of tumor-reactive CD8+ T cells and IFN-γ. Herein, we show that sequentially combining TrimAb with recombinant IL-21 can significantly improve the antitumor activity of this combination against very advanced disease. These data further support the use of IL-21 in adjuvant settings where strong T cell–mediated immune responses to tumors can be generated. [Cancer Res 2008;68(8):3019–25]
Negative Regulation of YAP by LATS1 Underscores Evolutionary Conservation of the Drosophila Hippo Pathway
Authors: Zhang Jianmin , Smolen Gromoslaw A. , Haber Daniel A. 
Published: April 2008

Abstract
The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here, we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Because this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition, suggesting that this is a key feature of YAP signaling in mammalian cells. [Cancer Res 2008;68(8):2789–94]
Tumor Escape Mechanism Governed by Myeloid-Derived Suppressor Cells
Authors: Nagaraj Srinivas , Gabrilovich Dmitry I. 
Published: April 2008

Abstract
T-cell nonresponsiveness is a critical factor in immune escape and myeloid-derived suppressor cells play a major role in organizing this phenomenon. Recent findings indicate that myeloid-derived suppressor cells can induce antigen-specific CD8+ T-cell tolerance through a posttranslation mechanism which involves modification (nitration) of CD8 and the T-cell receptor itself on the T-cell surface. Elucidation of this mechanism of T-cell tolerance offers new opportunities for therapeutic corrections of immune escape in cancer. [Cancer Res 2008;68(8):2561–63]
Soft Tissue Sarcoma Cells Are Highly Sensitive to AKT Blockade: A Role for p53-Independent Up-regulation of GADD45α
Authors: Zhu Quan-Sheng , Ren Wenhong , Korchin Borys , Lahat Guy , Dicker Adam , Lu Yiling , Mills Gordon , Pollock Raphael E. , Lev Dina 
Published: April 2008

AbstractThe AKT signaling pathway is activated in soft tissue sarcoma (STS). However, AKT blockade has not yet been studied as a potential targeted therapeutic approach. Here, we examined the in vitro and in vivo effects of AKT inhibition in STS cells. Western blot analysis was used to evaluate the expression of AKT pathway components and the effect of AKT stimulation and inhibition on their phosphorylation. Cell culture assays were used to assess the effect of AKT blockade (using a phosphatidylinositol 3-kinase inhibitor and a specific AKT inhibitor) on STS cell growth, cell cycle, and apoptosis. Oligoarrays were used to determine gene expression changes in response to AKT inhibition. Reverse transcription–PCR was used for array validation. Specific small inhibitory RNA was used to knockdown GADD45α. Human STS xenografts in nude mice were used for in vivo studies, and immunohistochemistry was used to assess the effect of treatment on GADD45α expression, proliferation, and apoptosis. Multiple STS cell lines expressed activated AKT. AKT inhibition decreased STS downstream target phosphorylation and growth in vitro; G2 cell cycle arrest and apoptosis were also observed. AKT inhibition induced GADD45α mRNA and protein expression in all STS cells treated independent of p53 mutational status. GADD45α knockdown attenuated the G2 arrest induced by AKT inhibition. In vivo, AKT inhibition led to decreased STS xenograft growth. AKT plays a critical role in survival and proliferation of STS cells. Modulation of AKT kinase activity may provide a novel molecularly based strategy for STS-targeted therapies. [Cancer Res 2008;68(8):2895–903]
Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal Cancer
Authors: Zhang Wei , Glöckner Sabine C. , Guo Mingzhou , Machida Emi Ota , Wang David H. , Easwaran Hariharan , Van Neste Leander , Herman James G. , Schuebel Kornel E. , Watkins D. Neil , Ahuja Nita , Baylin Stephen B. 
Published: April 2008

Abstract
SRY-box containing gene 17 (Sox17) is a member of the high mobility group (HMG) transcription factor superfamily, which plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of Wnt pathway activity. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. Our recent global analysis of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that SOX17 gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. Here, we report that CpG island methylation-dependent silencing of SOX17 occurs in 100% of CRC cell lines, 86% of colorectal adenomas, 100% of stage I and II CRC, 89% of stage III CRC, 89% of primary esophageal cancer, and 50% of non–small cell lung cancer. Overexpression of SOX17 in HCT116 CRC cells inhibits colony growth and β-catenin/T-cell factor–dependent transcription. Structure-based deletion analysis further shows the presence of a Wnt signaling repression domain in the SOX17 HMG box. Together, our studies suggest that SOX17 is a negative modulator of canonical Wnt signaling, and that SOX17 silencing due to promoter hypermethylation is an early event during tumorigenesis and may contribute to aberrant activation of Wnt signaling in CRC. [Cancer Res 2008;68(8):2764–72]
Novel and Highly Recurrent Chromosomal Alterations in Sézary Syndrome
Authors: Vermeer Maarten H. , van Doorn Remco , Dijkman Remco , Mao Xin , Whittaker Sean , van Voorst Vader Pieter C. , Gerritsen Marie-Jeanne P. , Geerts Marie-Louise , Gellrich Sylke , Söderberg Ola , Leuchowius Karl-Johan , Landegren Ulf , Out-Luiting Jacoba J. , Knijnenburg Jeroen , IJszenga Marije , Szuhai Karoly , Willemze Rein , Tensen Cornelis P. 
Published: April 2008

Abstract
This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components. [Cancer Res 2008;68(8):2689–98]
A Requirement for DICER to Maintain Full Promoter CpG Island Hypermethylation in Human Cancer Cells
Authors: Ting Angela H. , Suzuki Hiromu , Cope Leslie , Schuebel Kornel E. , Lee Byron H. , Toyota Minoru , Imai Kohzoh , Shinomura Yasuhisa , Tokino Takashi , Baylin Stephen B. 
Published: April 2008

Abstract
Promoter hypermethylation is a prevalent phenomenon, found in virtually all cancer types studied thus far, and accounts for tumor suppressor gene silencing in the absence of genetic mutations. The mechanism behind the establishment and maintenance of such aberrant hypermethylation has been under intense study. Here, we have uncovered a link between aberrant gene silencing associated with promoter CpG island DNA methylation and the siRNA/miRNA processing enzyme, DICER, in human cancer cells. By comparing demethylated HCT116 colon cancer cells with HCT116 cells genetically rendered hypomorphic for DICER, we identified a group of epigenetically silenced genes that became reactivated in the absence of functional DICER. This reactivation is associated with a dramatic loss of localized promoter DNA hypermethylation. Thus, intact DICER is required to maintain full promoter DNA hypermethylation of select epigenetically silenced loci in human cancer cells. [Cancer Res 2008;68(8):2570–5]
New Derivatives of Vitamin B12 Show Preferential Targeting of Tumors
Authors: Waibel Robert , Treichler Hansjörg , Schaefer Niklaus G. , van Staveren Dave R. , Mundwiler Stefan , Kunze Susanne , Küenzi Martin , Alberto Roger , Nüesch Jakob , Knuth Alexander , Moch Holger , Schibli Roger , Schubiger Pius August 
Published: April 2008

Abstract
Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled (57Co and 111In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue. By abolishing the interaction of a tailored vitamin B12 derivative to its transport protein transcobalamin II and therefore interrupting transcobalamin II receptor and megalin mediated uptake in normal tissue, preferential accumulation of a radiolabeled vitamin in cancer tissue could be accomplished. We identified transcobalamin I on tumors as a possible new receptor for this preferential accumulation of vitamin-mediated targeting. The low systemic distribution of radioactivity and the high tumor to blood ratio opens the possibility of a more successful clinical application of vitamin B12 for imaging or therapy. [Cancer Res 2008;68(8):2904–11]
Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients
Authors: Speetjens Frank M. , Kuppen Peter J.K. , Sandel Maro H. , Menon Anand G. , Burg Danny , van de Velde Cornelis J.H. , Tollenaar Rob A.E.M. , de Bont Hans J.G.M. , Nagelkerke J. Fred 
Published: April 2008

AbstractPurpose: We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5. The purpose of this study was to determine the effect of CXCL5 expression on colorectal tumor growth and metastasis.Experimental Design: CC531 clones were generated with either knockdown or restored expression of CXCL5. These clones were inoculated in the liver of rats. In addition, in two independent cohorts of colorectal cancer patients, the level of CXCL5 expression was determined and associated to clinical variables.Results: Knockdown of CXCL5 expression in CC531S resulted in rapid tumor growth and increased number of metastasis, whereas restored expression of CXCL5 in CC531M resulted in a return of the “mild” tumor growth pattern of the parental cell line CC531S. In vitro, no difference was found in proliferation rate between clones with either high or low expression of CXCL5, suggesting that environmental interactions directed by CXCL5 determine tumor outgrowth. Finally, the importance of our findings was established for patients with colorectal cancer. We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients. CXCL5 showed a trend (P = 0.05) for a positive correlation with intratumoral CD8+ T-cell infiltration, suggesting a possible explanation for the observed poorer prognosis.Conclusions: Our results show that CXCL5 is important in growth and development of colorectal cancer, implicating a future role in both cancer therapy and diagnosis.
Sunitinib for Treatment of Advanced Renal Cell Cancer: Primary Tumor Response
Authors: van der Veldt Astrid A.M. , Meijerink Martijn R. , van den Eertwegh Alfons J.M. , Bex Axel , de Gast Gijsbert , Haanen John B.A.G. , Boven Epie 
Published: April 2008

Abstract
Purpose: Nephrectomy before immunotherapy in patients with metastatic renal cell cancer (RCC) will improve patient outcome. In addition, the primary tumor is known to be refractory to cytokines. Sunitinib is now approved for treatment of advanced RCC, but its effect on the primary tumor has yet to be reported.
Experimental Design: All patients treated with sunitinib for advanced RCC without prior nephrectomy were reviewed and sequential computed tomography scans were evaluated for response in the primary tumor as well as metastases according to Response Evaluation Criteria in Solid Tumors. Volumes of primary tumors and central necrotic areas were measured with the perimeter method.
Results: Computed tomography scans were available for evaluation of response in 17 of 22 patients with a primary tumor in situ (1 patient with two primaries). According to Response Evaluation Criteria in Solid Tumors, 4 patients had a partial response, 12 had stable disease, and 1 had progressive disease. The one-dimensional longest diameter of the primary tumor correlated with the volumetric measurements both at baseline and at the time of evaluation of response. Excluding the patient with progressive disease, the median volume reduction was 31% associated with a median increase in the volume of necrosis of 39%. Three patients underwent nephrectomy and tumors showed extensive necrotic areas next to small fields of vital tumor cells.
Conclusions: Sunitinib can induce a significant reduction in volume of primary renal cell tumors. Further trials need to address the role of nephrectomy in advanced RCC patients on sunitinib treatment.