bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cisplatin Resistance Associated with PARP Hyperactivation
Authors: Michels Judith , Vitale Ilio , Galluzzi Lorenzo , Adam Julien , Olaussen Ken André , Kepp Oliver , Senovilla Laura , Talhaoui Ibtissam , Guegan Justine , Enot David Pierre , Talbot Monique , Robin Angélique , Girard Philippe , Oréar Cédric , Lissa Delphine , Sukkurwala Abdul Qader , Garcia Pauline , Behnam-Motlagh Parviz , Kohno Kimitoshi , Wu Gen Sheng , Brenner Catherine , Dessen Philippe , Saparbaev Murat , Soria Jean-Charles , Castedo Maria , Kroemer Guido 
Published: April 2013

Abstract
Non–small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor–induced apoptosis. Cancer Res; 73(7); 2271–80. ©2013 AACR.
The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress
Authors: Sahm Felix , Oezen Iris , Opitz Christiane A. , Radlwimmer Bernhard , von Deimling Andreas , Ahrendt Tilman , Adams Seray , Bode Helge B. , Guillemin Gilles J. , Wick Wolfgang , Platten Michael 
Published: April 2013

Abstract
Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD+, an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression. Here, we show that quinolinic acid accumulated in human gliomas and was associated with a malignant phenotype. Quinolinic acid was produced by microglial cells, as expression of the quinolinic acid-producing enzyme 3-hydroxyanthranilate oxygenase (3-HAO) was confined to microglia in glioma tissue. Human malignant glioma cells, but not nonneoplastic astrocytes, expressed quinolinic acid phosphoribosyltransferase (QPRT) to use quinolinic acid for NAD+ synthesis and prevent apoptosis when de novo NAD+ synthesis was blocked. Oxidative stress, temozolomide, and irradiation induced QPRT in glioma cells. QPRT expression increased with malignancy. In recurrent glioblastomas after radiochemotherapy, QPRT expression was associated with a poor prognosis in two independent datasets. Our data indicate that neoplastic transformation in astrocytes is associated with a QPRT-mediated switch in NAD+ metabolism by exploiting microglia-derived quinolinic acid as an alternative source of replenishing intracellular NAD+ pools. The elevated levels of QPRT expression increase resistance to oxidative stress induced by radiochemotherapy, conferring a poorer prognosis. These findings have implications for therapeutic approaches inducing intracellular NAD+ depletion, such as alkylating agents or direct NAD+ synthesis inhibitors, and identify QPRT as a potential therapeutic target in malignant gliomas. Cancer Res; 73(11); 3225–34. ©2013 AACR.
ATR Inhibition Broadly Sensitizes Ovarian Cancer Cells to Chemotherapy Independent of BRCA Status
Authors: Huntoon Catherine J. , Flatten Karen S. , Wahner Hendrickson Andrea E. , Huehls Amelia M. , Sutor Shari L. , Kaufmann Scott H. , Karnitz Larry M. 
Published: April 2013

Abstract
Replication stress and DNA damage activate the ATR-Chk1 checkpoint signaling pathway that licenses repair and cell survival processes. In this study, we examined the respective roles of the ATR and Chk1 kinases in ovarian cancer cells using genetic and pharmacologic inhibitors in combination with cisplatin, topotecan, gemcitabine, and the PARP inhibitor veliparib (ABT-888), four agents with clinical activity in ovarian cancer. RNA interference (RNAi)–mediated depletion or inhibition of ATR sensitized ovarian cancer cells to all four agents. In contrast, while cisplatin, topotecan, and gemcitabine each activated Chk1, RNAi-mediated depletion or inhibition of this kinase in cells sensitized them only to gemcitabine. Unexpectedly, we found that neither the ATR kinase inhibitor VE-821 nor the Chk1 inhibitor MK-8776 blocked ATR-mediated Chk1 phosphorylation or autophosphorylation, two commonly used readouts for inhibition of the ATR-Chk1 pathway. Instead, their ability to sensitize cells correlated with enhanced CDC25A levels. In addition, we also found that VE-821 could further sensitize BRCA1-depleted cells to cisplatin, topotecan, and veliparib beyond the potent sensitization already caused by their deficiency in homologous recombination. Taken together, our results established that ATR and Chk1 inhibitors differentially sensitize ovarian cancer cells to commonly used chemotherapy agents and that Chk1 phosphorylation status may not offer a reliable marker for inhibition of the ATR-Chk1 pathway. A key implication of our work is the clinical rationale it provides to evaluate ATR inhibitors in combination with PARP inhibitors in BRCA1/2-deficient cells. Cancer Res; 73(12); 3683–91. ©2013 AACR.
Dual Targeting of the Type 1 Insulin-like Growth Factor Receptor and Its Ligands as an Effective Antiangiogenic Strategy
Authors: Bid Hemant K. , London Cheryl A. , Gao Jin , Zhong Haihong , Hollingsworth Robert E. , Fernandez Soledad , Mo Xiaokui , Houghton Peter J. 
Published: April 2013

Abstract
Background: In pediatric tumor xenograft models, tumor-derived insulin growth factor (IGF-2) results in intrinsic resistance to IGF-IR–targeted antibodies, maintaining continued tumor angiogenesis. We evaluated the antiangiogenic activity of a ligand-binding antibody (MEDI-573) alone or in combination with IGF-I receptor binding antibodies (MAB391, CP01-B02).
Methods: IGF-stimulated signaling was monitored by increased Akt phosphorylation in sarcoma and human umbilical cord vascular endothelial cells (HUVEC). Angiogenesis was determined in vitro using capillary tube formation in HUVECs and in vivo using a VEGF-stimulated Matrigel assay. Tumor growth delay was examined in 4 sarcoma xenograft models.
Results: The IGF ligand-binding antibody MEDI-573 suppressed Akt phosphorylation induced by exogenous IGF-I and IGF-2 in sarcoma cells. Receptor-binding antibodies suppressed IGF-I stimulation of Akt phosphorylation, but IGF-2 circumvented this effect and maintained HUVEC tube formation. MEDI-573 inhibited HUVEC proliferation and tube formation in vitro, but did not inhibit angiogenesis in vivo, probably because MEDI-573 binds murine IGF-I with low affinity. However, in vitro antiangiogenic activity of MEDI-573 was also circumvented by human recombinant IGF-I. The combination of receptor- and ligand-binding antibodies completely suppressed VEGF-stimulated proliferation of HUVECs in the presence of IGF-I and IGF-2, prevented ligand-induced phosphorylation of IGF-IR/IR receptors, and suppressed VEGF/IGF-2–driven angiogenesis in vivo. The combination of CP1-BO2 plus MEDI-573 was significantly superior to therapy with either antibody alone against IGF-I and IGF-2 secreting pediatric sarcoma xenograft models.
Conclusions: These results suggest that combination of antibodies targeting IGF receptor and ligands may be an effective therapeutic strategy to block angiogenesis for IGF-driven tumors. Clin Cancer Res; 19(11); 2984–94. ©2013 AACR.
Concomitant BRAF and PI3K/mTOR Blockade Is Required for Effective Treatment of BRAFV600E Colorectal Cancer
Authors: Coffee Erin M. , Faber Anthony C. , Roper Jatin , Sinnamon Mark J. , Goel Gautam , Keung Lily , Wang Wei Vivian , Vecchione Loredana , de Vriendt Veerle , Weinstein Barbara J. , Bronson Roderick T. , Tejpar Sabine , Xavier Ramnik J. , Engelman Jeffrey A. , Martin Eric S. , Hung Kenneth E. 
Published: April 2013

Abstract
Purpose: BRAFV600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAFV600E CRC.
Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAFV600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAFV600E CRC.
Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAFV600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.
Conclusions: We have established a novel GEMM to interrogate BRAFV600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials. Clin Cancer Res; 19(10); 2688–98. ©2013 AACR.
Identification of Prognosis-Relevant Subgroups in Patients with Chemoresistant Triple-Negative Breast Cancer
Authors: Yu Ke-Da , Zhu Rui , Zhan Ming , Rodriguez Angel A. , Yang Wei , Wong Stephen , Makris Andreas , Lehmann Brian D. , Chen Xi , Mayer Ingrid , Pietenpol Jennifer A. , Shao Zhi-Ming , Symmans W. Fraser , Chang Jenny C. 
Published: April 2013

Abstract
Purpose: Patients with triple-negative breast cancer (TNBC) and residual disease after neoadjuvant chemotherapy generally have worse outcome; however, some patients with residual tumor after neoadjuvant chemotherapy do not relapse. We hypothesize that there are subgroups of patients with chemoresistant TNBC with different prognosis.
Experimental Design: Forty-nine chemoresistant cases from 111 patients with TNBC treated with neoadjuvant chemotherapy (M.D. Anderson Cancer Center, Houston, TX) constituted the discovery cohort, and 25 chemoresistant samples from 47 neoadjuvant chemotherapy-treated TNBC (The Methodist Hospital, Houston, TX) were chosen for validation. Extended validation was carried out in 269 operable TNBC predicted to be chemoresistant by expression pattern from published datasets.
Results: We established a seven-gene prognostic signature using dChip and gene set enrichment analyses. In the independent validation cohort, the classifier predicted correctly with positive predictive value of 75.0% and negative predictive value (i.e., relapse-free survival; RFS) of 76.9% at 3 years. Those predicted to relapse had a HR of 4.67 [95% confidence interval (CI): 1.27–17.15] for relapse in 3 years. In extended validation, patients predicted not to relapse exhibited 3-year RFS of 78.9%, whereas the 3-year RFS was 48.5% for patients predicted to relapse, with HR of 2.61 (95% CI: 1.52–4.49). The TNBC subgroup that predicted to have relatively favorable prognosis was characterized by high expression of “luminal-like” genes [androgen-receptor (AR) and GATA3], whereas the subgroup with worse prognosis was characterized by expression of cancer stem-cell markers.
Conclusion: We developed a clinically relevant signature for patients with chemoresistant TNBC. For these women, new therapeutic strategies like targeting AR activation or cancer stem cells may need to be developed. Clin Cancer Res; 19(10); 2723–33. ©2013 AACR.
Prespecified Candidate Biomarkers Identify Follicular Lymphoma Patients Who Achieved Longer Progression-Free Survival with Bortezomib–Rituximab Versus Rituximab
Authors: Coiffier Bertrand , Li Weimin , Henitz Erin D. , Karkera Jayaprakash D. , Favis Reyna , Gaffney Dana , Shapiro Alice , Theocharous Panteli , Elsayed Yusri A. , van de Velde Helgi , Schaffer Michael E. , Osmanov Evgenii A. , Hong Xiaonan , Scheliga Adriana , Mayer Jiri , Offner Fritz , Rule Simon , Teixeira Adriana , Romejko-Jarosinska Joanna , de Vos Sven , Crump Michael , Shpilberg Ofer , Zinzani Pier Luigi , Cakana Andrew , Esseltine Dixie-Lee , Mulligan George , Ricci Deborah 
Published: April 2013

AbstractPurpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study.Experimental Design: A total of 676 patients were randomized to five 5-week cycles of bortezomib–rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.Results: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib–rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib–rituximab versus 9.1 months with rituximab (HR 0.47, P &lt; 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib–rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. ©2013 AACR.
Oncolytic Virotherapy Needs Trials, Not Access Programs
Authors: Harrington Kevin J. 
Published: April 2013

Abstract
Oncolytic virotherapy is a novel treatment for cancer that exerts direct lytic and indirect immune-mediated antitumor effects. A Finnish research team has reported on an advanced therapy access program for oncolytic adenovirus. The strengths and weaknesses of this approach are highlighted with a view to informing future study conduct. Clin Cancer Res; 19(10); 2595–7. ©2013 AACR.
Synergistic Anticancer Activity of Arsenic Trioxide with Erlotinib Is Based on Inhibition of EGFR-Mediated DNA Double-Strand Break Repair
Authors: Kryeziu Kushtrim , Jungwirth Ute , Hoda Mir Alireza , Ferk Franziska , Knasmüller Siegfried , Karnthaler-Benbakka Claudia , Kowol Christian R. , Berger Walter , Heffeter Petra 
Published: April 2013

Abstract
Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as an anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against nonhematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated EGF receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G2–M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT and mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibitors, suggesting an essential role of the EGFR-mediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double-strand breaks (DSB) well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA DSB repair proteins such as Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both monotreatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR. Mol Cancer Ther; 12(6); 1073–84. ©2013 AACR.
Abstract A12: Identification of microRNA-based therapeutic candidates using a unique lentiviral microRNA overexpression library
Authors: van Noort Paula I. , Babae Negar , Verhaegh Gerald W. , Gommans Willemijn M. , Cerisoli Francesco , Verheul Mark , Schiffelers Raymond M. , Griffioen Arjan W. , Schalken Jack A. , Berezikov Eugene , Cuppen Edwin , Schaapveld Roel Q. J. , Poell Jos B. , Prevost Gregoire P. , Bourajjaj Meriem , Vidic Suzanna , van Beijnum Judy R. , van Haastert Rick J. , Schultz Iman , de Gunt Thijs , van Hooij Onno 
Published: April 2013

Abstract
microRNA (miRNA) genes transcribed by RNA polymerase II generate small noncoding miRNAs of 18 to 24 nucleotides after maturation process. The mature miRNAs and their associated isomirs specifically bind to different mRNA transcripts, resulting in down regulation of multiple genes within the cell in a highly multiplexed way. miRNA expression profiles differ between human cell types suggesting cell-specific impacts of each miRNA on the regulation of different biological processes. Comparison of miRNA profiles of tumor samples and adjacent normal tissues showed that some miRNAs are up- or down- regulated and suggested their implication during tumor progression. However, such a miRNA profiling approach is not sufficient to identify the respective role of each miRNA gene during the tumorigenesis.
Here, to assess the individual role of each miRNA gene and its different isomirs in a specific cell environment, we have constructed a lentiviral miRNA expression library containing more than 1100 human known and novel miRNA precursors. The arrayed layout of our library allowed high-throughput screens with a large spectrum of functional read-outs using either normal or tumor cells. To exemplify this approach, the results of three different screens will be presented; i.e. identification of miRNAs that inhibit the BRAF pathway, miRNAs that inhibit tumor angiogenesis and miRNAs that stimulate the mesenchymal to epithelial transition. In addition, beyond this hit identification step, we will present detailed characterization of the role of the identified miRNAs in tumor progression by means of molecular and cellular functional assays.
Combining our unique miRNA expression library with a functional screening platform has allowed the identification and the further characterization of several miRNAs able to significantly impact on tumor behavior supporting the therapeutic interest of some candidates.
Citation Format: Paula I. van Noort, Negar Babae, Gerald W. Verhaegh, Willemijn M. Gommans, Francesco Cerisoli, Mark Verheul, Raymond M. Schiffelers, Arjan W. Griffioen, Jack A. Schalken, Eugene Berezikov, Edwin Cuppen, Roel Q. J. Schaapveld, Jos B. Poell, Gregoire P. Prevost, Meriem Bourajjaj, Suzanna Vidic, Judy R. van Beijnum, Rick J. van Haastert, Iman Schultz, Thijs de Gunt, Onno van Hooij. Identification of microRNA-based therapeutic candidates using a unique lentiviral microRNA overexpression library [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A12.
Abstract A13: The microRNA-200 family overcomes cisplatin resistance by targeting ceramide glycosylation
Authors: Cai Chunxiao , Ashktorab Hassan , Pang Xiaowu , Zhao Yuan , Sha Wei , Liu Yulan , Gu Xinbin 
Published: April 2013

Abstract
Background: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. Methodology/Principal Findings: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116miR-211) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116miR-211 cells was upregulated by 16-fold compared to vector control cells (HCT-116vector). Exogenous miR-211 directly binds to the 3′ untranslated region (3′ UTR) of CHD5 mRNA, resulting in a 50% decrease in CHD5 protein level in HCT-116miR-211 cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116miR-211 cells were significantly higher than HCT-116vector cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, tumor xenografts, and scratch assay, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. Conclusion/Significance: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression of miR-211 promotes tumor cell growth at least in part by downregulating the expression level of the CHD5 tumor suppressor. Our results provide a better understanding of the association of between miR-211-regulated CHD5 expression and CHD5 function in colorectal tumorigenesis.
Citation Format: Chunxiao Cai, Hassan Ashktorab, Xiaowu Pang, Yuan Zhao, Wei Sha, Yulan Liu, Xinbin Gu. The microRNA-200 family overcomes cisplatin resistance by targeting ceramide glycosylation [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A13.