bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-101: The expression of death receptor 4 is positively regulated by MEK/ERK signaling and suppressed upon MEK inhibition
Authors: Oh You-Take , Yao Weilong , Deng Jiusheng , Yue Ping , Sun Shi-Yong 
Published: July 2016

Abstract
Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well-known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism.We found that several MEK inhibitors, including MEK162, AZD6244 and PD0325901, effectively decreased the levels of DR4 protein including cell surface DR4 in different cancer cell lines while suppressing ERK1/2 phosphorylation. Accordingly, pre-treatment of TRAIL-sensitive cancer cell lines with a MEK inhibitor attenuated TRAIL-induced apoptosis. These results indicate that MEK inhibition negatively regulates DR4 expression and cell response to TRAIL-induced apoptosis. MEK inhibitors did not alter DR4 protein stability, rather decreased its mRNA levels, suggesting a transcriptional regulation of DR4 expression. In contrast, enforced activation of MEK/ERK signaling by expressing ectopic B-Raf (V600E) or constitutively activated MEK1 (MEK1-CA) or MEK2 (MEK2-CA) activated ERK1/2 and increased DR4 expression; these effects were inhibited when a MEK inhibitor was present. Moreover, enforced expression of MEK1-CA enhanced DR4promoter activity; this effect could be abolished by the presence of a MEK inhibitor. Hence it is clear that activation of the MEK/ERK kinase cascade positively regulates DR4 transcription, resulting in increased DR4 expression. Detailed promoter analysis through deletion and mutation identified the AP-1 binding site as an essential response element for MEK enhancement of DR4 transactivation. In addition, inhibition of AP-1 by knocking down c-Jun abrogated the ability of MEK1-CA to increase DR4 promoter activity and DR4 expression. These results suggest an essential role of AP-1 in mediating MEK/ERK activation-induced DR4 expression. Our findings together highlight a previously undiscovered mechanism that positively regulates DR4 expression through activation of the MEK/ERK/AP-1 signaling pathway. (WY and YTO contribute equally to this work. This study was supported by Emory Winship Cancer Institute Robbins Scholar awards to YTO and to JD and Halpern Research Scholar award to SYS. SYS is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar)
Citation Format: You-Take Oh, Weilong Yao, Jiusheng Deng, Ping Yue, Shi-Yong Sun. The expression of death receptor 4 is positively regulated by MEK/ERK signaling and suppressed upon MEK inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-101.
Abstract LB-109: Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma
Authors: Wei Huafeng , Chen Yang 
Published: July 2016

Abstract
As the most common type of renal cancer, clear cell renal cell carcinoma (ccRCC) with advanced stages constitutes a continued major challenge for uro-oncologists where identification of novel driver mutations and development of novel targeted therapies against them remain an unmet need. Aberrations of the anaplastic lymphoma kinase (ALK) gene have been implicated in the pathogenesis of multiple human cancers where ALK represents a rational therapeutic target as demonstrated in lung cancer with ALK rearrangement. In this study, we performed the screening of ALK expression in 87 pathologically defined ccRCC by immunohistochemistry (IHC) using a newly developed rabbit anti-human ALK monoclonal antibody (clones D5F3). Four patients were positive for ALK expression as determined by IHC among which 2 cases were further confirmed by fluorescence in situ hybridization (FISH) assay using the Vysis LSI ALK dual color break-apart probe; furthermore, we detected the presence of EML4-ALK (E13:A20, variant 1) fusion gene in tumors from these two patients by using RACE-coupled PCR sequencing and RT-PCR. Notably, we first showed that enforced EML4-ALK expression significantly promoted the in vitro proliferation, clonogenic colony formation and apoptosis resistance in immortalized normal renal tubal epithelial cell HK2 and their in vivo outgrowth when injected into immunocompromised nude mice, and importantly, this pro-tumorigenic effect could be completely abolished by ALK-specific inhibitor Crizotinib, indicating the potential effectiveness of ALK-specific inhibitors in treating ALK-positive ccRCC patients. Our data show that ALK fusions exist in adult ccRCC, which provides the rationale for ALK inhibitor therapy in selected patients of ccRCC.
Citation Format: Huafeng Wei, Yang Chen. Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-109.
Abstract LB-123: STAT3 mediates APC-driven chemoresistance in breast cancer
Authors: VanKlompenberg Monica K. , Leyden Emily A. , Zhang Jian-Ting , Prosperi Jenifer R. 
Published: July 2016

Abstract
Breast tumors frequently develop resistance to treatment with a variety of standard (i.e. cisplatin or doxorubicin) or targeted chemotherapeutic agents, resulting in tumor recurrence and increased patient mortality. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost by hypermethylation or mutation in up to 70% of sporadic breast cancers; however, the downstream effects of APC loss have not been well explored in breast cancer. Heterozygous Apc mutation using the ApcMin/+ mouse model enhanced tumorigenesis in the mouse mammary tumor virus - Polyoma Middle T transgenic model (MMTV-PyMT). Cells isolated from MMTV-PyMT;ApcMin/+ mice are resistant to chemotherapy, express higher levels of multidrug resistance protein 1 (MDR1), and have a greater population of tumor initiating cells (TICs) compared to controls. Here we demonstrate that APC loss-of-function cells have increased activation of signal transducer and activator of transcription 3 (STAT3) and the anti-apoptotic protein Mcl-1. STAT3 over-expression is common in breast cancer, leads to poor prognosis, and up-regulates MDR1 expression leading to chemotherapeutic resistance. To explore the functional role of STAT3 in mediating therapeutic resistance in APC loss-of-function models, we examined the impact of STAT3 inhibition on MDR1 and the TIC population to cause therapeutic resistance in the MMTV-PyMT;ApcMin/+ vs MMTV-PyMT;Apc+/+ murine breast cancer cells. We have made the novel observation that chemotherapy treatment has a time-dependent effect on the activation of STAT3 and expression of Mcl-1 specific to Apc-mutant cells. Finally, we have assessed the use of STAT3 inhibitors in combination with standard chemotherapy to alleviate APC-mediated resistance. Combined these data suggest that loss of APC activates STAT3-driven pathways resulting in the development of chemotherapeutic resistance.
Citation Format: Monica K. VanKlompenberg, Emily A. Leyden, Jian-Ting Zhang, Jenifer R. Prosperi. STAT3 mediates APC-driven chemoresistance in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-123.
Abstract LB-151: Positively selected enhancer elements endow tumor cells with metastatic competence
Authors: Morrow James J. , Miller Tyler E. , Saiakhova Alina , Lizardo Michael M. , Bartels Cynthia F. , Bayles Ian , Hung Stevephen , Mendoza Arnulfo , Myers Jay T. , Allen Frederick , DiFeo Analisa , Rubin Brian P. , Huang Alex Y. , Meltzer Paul S. , Helman Lee J. , Khanna Chand , Scacheri Peter C. 
Published: July 2016

Abstract
Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in signature enhancer-histone marks between near-isogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets is positively selected. Osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors whose motifs are enriched in Met-VELs, and by knockdown of individual genes activated by Met-VELs. These observations have implications for the discovery and development of targeted anti-metastatic therapies.
Citation Format: James J. Morrow, Tyler E. Miller, Alina Saiakhova, Michael M. Lizardo, Cynthia F. Bartels, Ian Bayles, Stevephen Hung, Arnulfo Mendoza, Jay T. Myers, Frederick Allen, Analisa DiFeo, Brian P. Rubin, Alex Y. Huang, Paul S. Meltzer, Lee J. Helman, Chand Khanna, Peter C. Scacheri. Positively selected enhancer elements endow tumor cells with metastatic competence. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-151.
Abstract LB-154: Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A
Authors: Vanden Berghe Wim , Szarc vel Szic Katarzyna , Declerck Ken , Crans René A.J. , Diddens Jolien , Gerhäuser Clarissa 
Published: July 2016

Abstract
Background: Triple negative breast cancer (TNBC) is characterized by poor prognosis and a DNA hypomethylation profile. We found that the steroidal lactone Withaferin A (WA), isolated from the plant Withania somnifera, triggers active chromatin remodeling and elicits promising chemosensitizing effects in triple negative breast cancer (BC) cells. Here, we have further characterized potential involvement of epigenetic reprogramming by Withaferin A in TNBC treatment.
Materials and methods: By Infinium HumanMethylation450 arrays, Epityper Mass array and CpG pyrosequencing, we determined genome-wide DNA methylation changes in weakly-metastatic and aggressive, metastatic BC cell lines treated with a pharmacologically relevant concentration of 700 nM WA. In parallel, we performed ChIP analysis of histone mark H3K4Me3 to evaluate histone demethylation by JARID1B/KDM5B. Furthermore, epigenetic changes in response to WA were crosscompared with genomewide methylation changes and clinical breast cancer patient characteristics in The Cancer Genome Atlas database.
Results: In contrast to the DNA hypomethylating agent 5-aza-2’-deoxycytidine (DAC), WA treatment of TNBC cells silences an epigenetic cancer network through gene-specific hypermethylation of tumor promoting genes including ADAM metallopeptidase domain 8 (ADAM8), urokinase-type plasminogen activator (PLAU), tumor necrosis factor (ligand) superfamily, member 12 (TNFSF12), and genes related to detoxification (glutathione S-transferase mu 1, GSTM1), or mitochondrial metabolism (malic enzyme 3, ME3). Remarkably, DNA hypermethylation of corresponding CpG sites in these genes correlates with receptor tyrosine-protein kinase erbB-2 amplification (HER2)/estrogen receptor (ER)/progesterone receptor (PR) positive status in primary BC tumors. Increased expression levels of JARID1B, promoter-specific loss of active H3K4me3 chromatin marks and gain of DNA methylation suggest that WA-specific gene silencing involves epigenetic reprogramming of HER2/ER/PR-dependent gene expression programs to suppress aggressive TNBC characteristics in favor of luminal BC hallmarks with an improved therapeutic sensitivity.
Conclusions: WA may represent a novel and attractive phytopharmaceutical to overcome therapy resistance in TNBC.
Citation Format: Wim Vanden Berghe, Katarzyna Szarc vel Szic, Ken Declerck, René A.J. Crans, Jolien Diddens, Clarissa Gerhäuser. Epigenetic silencing of triple-negative breast cancer hallmarks by Withaferin A. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-154.
Abstract LB-158: Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma
Authors: Greenall Sameer , Johns Terrance G. 
Published: July 2016

Abstract
High Grade Glioma (HGG), an incurable aggressive neoplasm of the brain, is characterised by a diverse array of genetic aberrations including those associated with receptor tyrosine kinase (RTK) signalling and cell cycle regulation pathways. Furthermore, HGG possess a highly heterogeneous intratumoral transcriptional profile, both at the global and subclonal levels, that allows for rapid resistance to a wide spectrum of therapeutics. Cyclin dependent kinase 7 (CDK7) presents an opportunity to target proliferation and global transcription simultaneously as it is the CDK activating kinase that controls multiple checkpoint progressions through the cell cycle as well as stabilising the RNA polymerase II-based transcriptional apparatus. Using a new irreversible inhibitor of CDK7, THZ1, we demonstrate that a panel of 10 patient-derived primary HGG cells lines, representing a diverse array of genotypes and phenotypes, were all exquisitely sensitive to THZ1 treatment at low nanomolar doses. THZ1 induced global transcription downregulation as measured by microarray analysis and resulted in potent caspase 3/7 activation, DNA damage and apoptosis. Cell cycle in all lines was arrested at the G2/M phase regardless of p53, CDKN2A/B or RB status, with substantial aneuploidy observed. Additionally, THZ1 treatment results in the dramatic loss of several RTKs critical in driving HGG including EGFR, EGFRvIII, PDGFR-α, PDGFR-β, MET, FGFR-3 and AXL, resulting in reduced PI3K/AKT, MAPK/ERK and STAT3 activation. Efficacy in ex vivo tumor slices and in vivo orthotopic experiments will be presented as well as insights into possible mechanisms of resistance. Our work suggest that irreversible inhibition of CDK7 represents a novel and effective treatment for HGG.
Citation Format: Sameer Greenall, Terrance G. Johns. Simultaneous targeting of the cell cycle and transcription through irreversible inhibition of CDK7: a novel, new therapeutic approach for high-grade glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-158.
Abstract LB-176: The human androgen receptor regulates DNA damage response (DDR) in prostate cancer
Authors: Asim Mohammad , Zecchini Heather , Tarish Firas , Massie Charlie , Baridi Ajoeb , Warren Anne , Zhao Wanfeng , McDuffus Leigh-Anne , Mascalchi Patrice , Shaw Greg , Dev Harveer , Wadhwa Karan , Wijnhoven Paul , Forment Josep , Lyons Scott , Lynch Andy , O’Neill Cormac , Zecchini Vincent , Rennie Paul , Baniahmad Aria , Tavare Simon , Mills Ian , Schulz Niklas , Galanty Yaron , Helleday Thomas , Neal David 
Published: July 2016

Abstract
Clinical studies have shown the improved benefit of combining androgen deprivation therapy (ADT) with radiotherapy, indicating a potential interaction between the androgen signalling and DNA damage response (DDR) pathways in PCa. We have explored the underlying basis of this interaction by interrogating the mechanism of androgen regulation of the DDR in men with PCa, both untreated and treated with an androgen inhibitor. We show that androgen receptor (AR) signalling regulates the DDR and promotes DDR foci formation leading to ATM activation in PCa. Our data showing that AR regulates DDR provides an explanation for the improved outcome of combined ADT and radiotherapy. Thus, our work identifies the rationale for targeting both the AR and DDR pathways simultaneously to improve therapy outcome in advanced or high risk prostate cancer.
Citation Format: Mohammad Asim, Heather Zecchini, Firas Tarish, Charlie Massie, Ajoeb Baridi, Anne Warren, Wanfeng Zhao, Leigh-Anne McDuffus, Patrice Mascalchi, Greg Shaw, Harveer Dev, Karan Wadhwa, Paul Wijnhoven, Josep Forment, Scott Lyons, Andy Lynch, Cormac O’Neill, Vincent Zecchini, Paul Rennie, Aria Baniahmad, Simon Tavare, Ian Mills, Niklas Schulz, Yaron Galanty, Thomas Helleday, David Neal. The human androgen receptor regulates DNA damage response (DDR) in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-176.
Abstract LB-183: The impact of protein concentration on the distribution of 111In-antibody conjugate for imaging of programmed death-ligand 1 (PD-L1)
Authors: Nedrow Jessie , Josefsson Anders , Park Sunju , Ranka Sagar , Sgouros George 
Published: July 2016

Abstract
Background: Programmed cell Death Ligand 1 (PD-L1) is part of an immune checkpoint system that is essential for preventing autoimmunity. Tumor cells have developed the ability to co-opt these immune checkpoints to suppress anti-tumor immunity. Recent approaches in immunotherapy targeting immune checkpoints have shown great promise in a variety of cancers. PD-L1 overexpression is associated with a poorer prognosis in a variety of cancers, but typically have a stronger response to anti-PD-L1 therapy. PD-L1 is a dynamic biomarker and the ability to image its dynamic nature could provide key information in identifying patients who will best respond to anti-PD-L1 treatment with limited adverse effects. Here we evaluated an 111In-antibody conjugate targeted to PD-L1 for SPECT imaging in an aggressive mouse melanoma model. In addition, we investigated the relationship between the spleen, which we have found to be a sink for anti-PD-L1 antibodies, and specific activity (activity/protein concentration) of the 111In-antibody conjugate.
Methods: An anti-PD-L1 antibody was conjugated to DTPA for 111In-labeling. The biodistribution of the resulting conjugate, 111In-DTPA-anti-PD-L1, was performed over a range of specific activities in B16F10 tumor bearing mice. SPECT imaging was also performed with the 111In tracer.
Results: 111In-DTPA-anti-PD-L1 (Kd = 0.6±0.1 nM) having a specific activity (SA) of 0.57 Ci/μmol demonstrated uptake in the B16F10 tumor (6.1±2.8%ID/g) at 24 hours, as well as high uptake in the spleen (32.8±5.1%ID/g). Decreasing the SA to 0.01 Ci/μmol blocked PD-L1-postive cells in the spleen (13.4±4.8%ID/g) forcing more of the tracer to remain in circulation, allowing for increase accumulation in the B16F10 tumor (16.8±6.2%ID/g) at 24 hours. The lower SA also demonstrated a reduction in tumor to blood ratios compared to the higher SA (2.2 vs. 4.1), but an increase was shown in the tumor to muscle ratio (27 vs. 4.6).
Conclusion: 111In-DTPA-anti-PD-L1 is capable of identifying tumors that overexpresses PD-L1, and has the potential to help select patients that will best respond to anti-PD-L1 therapy. In addition, the further understanding of the spleen/tumor relationship could be utilized to tailor individual doses for anti-PD-L1 therapy and minimize adverse effects.
Citation Format: Jessie Nedrow, Anders Josefsson, Sunju Park, Sagar Ranka, George Sgouros. The impact of protein concentration on the distribution of 111In-antibody conjugate for imaging of programmed death-ligand 1 (PD-L1). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-183.
Abstract LB-213: NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer
Authors: Picco Gabriele , Sassi Francesco , Isella Claudio , Di Nicolantonio Federica , Sapino Anna , Bardelli Alberto , Trusolino Livio , Bertotti Andrea , Medico Enzo 
Published: July 2016

Abstract
The NEDD8 conjugation pathway modulates the ubiquitination, stability and activity of a wide range of intracellular proteins, and its blockade by pevonedistat is emerging as a promising therapeutic approach in various cancer settings. However, systematic characterization of pevonedistat efficacy in specific tumor types and definition of molecular predictors of response are still missing. We investigated the in vitro sensitivity to pevonedistat in a large panel of molecularly and functionally annotated colorectal cancer (CRC) cell lines, and exploited global gene expression profiles to define a transcriptional predictor. Out of 122 tested cell lines, 16 (13%) displayed a marked response to pevonedistat, featuring DNA re-replication, proliferative block and apoptosis. Pevonedistat sensitivity did not significantly correlate with microsatellite instability or mutations in KRAS or BRAF, but was functionally associated with resistance to EGFR pathway blockade. A 184-gene transcriptional predictor generated in cell lines was applied to 87 metastatic CRC clinical samples for which patient-derived xenografts (PDX) were available. For in vivo tests, pevonedistat was provided by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Ltd. In vivo administration of pevonedistat did not affect the growth of any predicted resistant PDX; whereas, it significantly impaired growth of five out of six predicted sensitive models. In human CRC gene expression datasets, transcriptional prediction of pevonedistat sensitivity was associated with poor prognosis after surgery and early progression under cetuximab treatment. Histological and immunohistochemical analyses revealed that pevonedistat sensitivity signature captures transcriptional traits of poor differentiation and high-grade mucinous adenocarcinoma. These results highlight NEDD8-pathway inhibition by pevonedistat as a potentially effective strategy to treat poorly differentiated, clinically aggressive CRC and identify transcriptional and histological response predictors with possible clinical applicability.
Citation Format: Gabriele Picco, Francesco Sassi, Claudio Isella, Federica Di Nicolantonio, Anna Sapino, Alberto Bardelli, Livio Trusolino, Andrea Bertotti, Enzo Medico. NEDD8 pathway inhibition is effective in preclinical models of poorly differentiated, clinically aggressive colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-213.