bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1779: Chronic NSAID use increases survival in PIK3CA-altered head and neck squamous cell carcinoma
Authors: Hedberg Matthew Louis , Peyser Noah , Gooding William , Li Hua , Brand Toni , Olivas Victor , Bivona Trever , Choisea Simion , Wang Lin , Johnson Jonas , Duvvuri Uma , Ferris Robert , Johnson Daniel , Ha Patrick , Bauman Julie , Grandis Jennifer 
Published: July 2017

Abstract
Background: PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). Chronic non-steroidal anti-inflammatory (NSAID) use has been shown to reduce mortality in PIK3CA-mutated colorectal cancer through an unknown mechanism. In this retrospective cohort analysis, we evaluated the impact of NSAIDs on HNSCC survival, and sought a biologically plausible explanation for the observed effect.
Methods: The PIK3CA status of tumor tissue was determined by FISH and next generation sequencing for 266 HNSCC patients treated at the University of Pittsburgh Cancer Institute. Cox joint proportional hazards models were used to generate multivariate projections of disease-specific (DSS) and overall survival (OS). Prostaglandin E2 (PGE2) secretion and NSAID sensitivity were then assessed in HNSCC cell lines with or without PIK3CA mutation.
Results: Chronic NSAID use (≥2 days/week for ≥6 months) was associated with greater disease-specific (HR 0.24; 95% CI, 0.09 - 0.62; p = 0.0032) and overall survival (HR 0.31; 95% CI, 0.14 - 0.69; p = 0.0043) in patients whose tumors harbor PIK3CA mutation and/or amplification. Survival was unchanged by chronic NSAID use in patients with wild-type, unamplified PIK3CA. Chronic NSAID users with PIK3CA-altered tumors had an increase in estimated 5-year DSS from 25% to 72% and in OS from 45% to 78%. Benefit was independent of age, stage, and human papillomavirus (HPV) status; all of which were controlled for in the model. HNSCC cells with endogenous or engineered PIK3CA mutation secreted higher levels of PGE2 and were more sensitive to growth inhibition by NSAID treatment.
Conclusions: Chronic NSAID use was associated with markedly improved survival in patients with PIK3CA-altered HNSCC, but not in those with wild-type, unamplified PIK3CA. Preclinical studies implicate the PI3K-COX-PGE2 signaling axis as a potential mediator of NSAID response. A prospective, randomized controlled trial of NSAIDs in patients with PIK3CA-altered HNSCC is warranted.
Citation Format: Matthew Louis Hedberg, Noah Peyser, William Gooding, Hua Li, Toni Brand, Victor Olivas, Trever Bivona, Simion Choisea, Lin Wang, Jonas Johnson, Uma Duvvuri, Robert Ferris, Daniel Johnson, Patrick Ha, Julie Bauman, Jennifer Grandis. Chronic NSAID use increases survival in PIK3CA-altered head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1779. doi:10.1158/1538-7445.AM2017-1779
Abstract 1781: EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas
Authors: Wu Shaofang , Gao Feng , Li Xiaolong , Ding Jie , Zheng Siyuan , Martinez-Ledesma Emmanuel , Feng Ningping , Sulman Erik , Verhaak Roel , Groot John de , Koul Dimpy , Yung W.K.Alfred 
Published: July 2017

Abstract
Poly (ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARP is a promising strategy for targeting cancers with defective DNA-damage repair. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. Glioma Stem Cells (GSCs) exhibit higher oxidative base damage, single-strand DNA breaks and genomic instability and is reliant on single-strand break repair/base excision repair to tolerate additional stress. PARP critical for maintaining genomic stability by regulating a variety of DNA damage repair mechanisms is constitutively activated in GSCs. In this study, we show that talazoparib – a unique PARP inhibitor exhibits a strong single agent activity to inhibit proliferation of GSCs in vitro and suppress tumor progression in GSCs xenografts. Talazoparib cytotoxic activity was through inhibiting PARylation and by trapping PARP-DNA complexes resulting in accumulation of DNA damage during replication and ultimately leading to apoptosis. More importantly, we found EFGR amplification, which occurs in about 45% of GBM as a biomarker of response to PARPi. Gene expression and RPPA data showed that GSCs with EGFR amplification were associated with increased ROS, basal expression of DNA repair proteins and more DNA damage following talazoparib treatment, which may partially explain the sensitivity of this group of GSCs to talazoparib. EGFR enzyme activity was important for PARPi sensitivity since kinase dead mutant of EGFR or EGFR knock down cell lines were resistant to PARPi as was also shown by decreased PARP/DNA complex formation. Talazoparib showed strong inhibition of tumor growth in subcutaneous glioma model and 20% increase in median survival in an intracranial model with a 10% blood brain penetration of talazoparib. These data provide mechanistic insights into the anti-cancer activity of PARP inhibitors with mechanistic rationale of PARP inhibition and potential EGFR amplification as biomarker in the development for precision cancer.
Citation Format: Shaofang Wu, Feng Gao, Xiaolong Li, Jie Ding, Siyuan Zheng, Emmanuel Martinez-Ledesma, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Dimpy Koul, W.K.Alfred Yung. EGFR amplification-A candidate predictive biomarker of PARP inhibitor Talazoparib sensitivity in gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1781. doi:10.1158/1538-7445.AM2017-1781
Abstract 1791: Spatially positioned tumor infiltrating lymphocytes predict survival in metastatic HER2 positive breast cancer treated with trastuzumab
Authors: Koivunen Jussi Pekka , Honkanen Tiia , Moilanen Tiina , Karihtala Peeter , Väyrynen Juha , Mäkinen Markus 
Published: July 2017

Abstract
Background: Disease outcomes of HER2+ breast cancers have dramatically changed after targeted therapies, such as trastuzumab, came to clinical practice but predictive factors for trastuzumab sensitivity and resistance are frequently unknown.
Methods: Metastatic breast cancer patients (n=48), who were treated with trastuzumab and had pre-treatment tumor samples available, were studied. The tumors were immunostained for T-cell (CD3, CD8) and NK-cell (CD56) markers and quantitative analysis of the immune cells was carried out using a computer-assisted image analysis in different tumor locations.
Results: High number of CD3 and CD8 positive T-cells was associated with significant survival benefit in the center of the tumor (CT) (p=0.007, p=0.001), but not in the invasive region. NK-cell tumor infiltration was infrequent and they could not be reliably analyzed. In a subgroup analyses, high density of CD8 CT cells was associated with significant survival benefit in non-bone only disease, in TX-3, and in ER+ tumors (p=0.006, p=0.003, p=0.001). Moreover, high CD8 CT cell density was associated with good trastuzumab responses (p=0.042).
Conclusion: High number of CD3 and CD8 positive tumor infiltrating lymphocytes in the CT area is associated with survival benefit in some patient groups with HER2+ breast cancer treated with trastuzumab. Furthermore, high number of CD8 CT cells predicts benefit from trastuzumab.
Citation Format: Jussi Pekka Koivunen, Tiia Honkanen, Tiina Moilanen, Peeter Karihtala, Juha Väyrynen, Markus Mäkinen. Spatially positioned tumor infiltrating lymphocytes predict survival in metastatic HER2 positive breast cancer treated with trastuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1791. doi:10.1158/1538-7445.AM2017-1791
Abstract 1804: Identification of novel NM23 inhibitors as potential anti-angiogenic agents
Authors: Nordmeier Senny , Evasovic Jon , Duan Suzann , Wuebbles Ryan , Burkin Dean J. , Buxton Iain L. 
Published: July 2017

Abstract
Exogenous nucleoside diphosphate kinase (eNDPK or NM23) has been shown to promote endothelial cell proliferation and migration and tumor-mediated angiogenesis. This is facilitated by its transphosphorylase activity, in which a gamma terminal phosphate group from a triphosphate nucleoside is transferred to a diphosphate nucleoside, resulting in elevated ATP levels. Increased levels of ATP in the tumor microenvironment can activate purinergic receptors (P2Y1) on adjacent endothelial cells to promote angiogenesis, independent of VEGF stimulation. Triple negative human breast cancer (MDA-MB-231) cells have been shown to elaborate exosomes that contain NM23. These exosomes have implications in targeting specific tissues/cells to promote angiogenesis and tumorigenesis. Our lab has shown that inhibition of eNDPK and the P2Y1 receptor reduces endothelial cell tubulogenesis (Rumjahn, et al., 2007) and breast cancer metastasis (Yokdang, et al., 2015). Therefore, targeted inhibition of eNDPK may have implications as a treatment for early tumor-mediated angiogenesis. For this study, we utilized a transphosphorylation activity assay to perform a drug screen on compounds from the Prestwick chemical library. Recombinant NDPK-B was added to FDA-approved drug compounds along with ADP and UTP substrates. Subsequent ATP generation was detected with a luciferase luciferin reaction. Decreased luminescence signal/inhibition of NDPK was compared to ellagic acid control, a known inhibitor of NDPK. From our initial screen, we identified eight potential compounds that inhibited NDPK at comparable levels to ellagic acid. These eight compounds were further examined to determine the dose response curve. We found that Chicago Sky Blue 6B inhibited NDPK at an IC50 value of 1.88µM. The results from this study demonstrate a drug screening method to discover alternative small molecule inhibitors of NDPK as a potential treatment of angiogenesis and breast cancer metastasis.
Citation Format: Senny Nordmeier, Jon Evasovic, Suzann Duan, Ryan Wuebbles, Dean J. Burkin, Iain L. Buxton. Identification of novel NM23 inhibitors as potential anti-angiogenic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2017-1804
Abstract 1807: Exosomal NM23 facilitates pro-angiogenic communication between triple-negative breast cancer cells and their vascular targets
Authors: Duan Suzann , Nordmeier Senny , Buxton Iain L. 
Published: July 2017

Abstract
Functional interactions between primary tumor cells and their vascular targets orchestrate the formation of a metastatic milieu enriched with oxygen and metabolic substrates. These interactions have been largely attributed to the activation of VEGF receptor pathways through localized tumor-mediated release of VEGF, in addition to indirect receptor phosphorylation. However, pro-angiogenic events are known to occur in the absence of VEGF and alternative pathways resulting in dual activation of neovascularization and enhanced vascular permeability are of growing interest. Our lab has previously shown that triple-negative human breast cancer (MDA-MB-231) cells elaborate exosomes carrying NM23, a nucleoside diphosphate kinase (eNDPK) that is suggested to act as an upstream mediator of vasodilation and pro-angiogenic activity through its action of elevating extracellular ADP/ATP levels. To further elucidate the role of eNDPK in breast cancer signaling and metastasis, we show that 231-exosomes induce a pro-angiogenic phenotype in both human umbilical vein and murine pulmonary endothelial cells. Treatment with an NDPK-specific inhibitor and an antagonist to the ADP/ATP-activated P2Y1 receptor results in amelioration of pro-angiogenic characteristics. Further, we report the development and application of a novel murine implant model to demonstrate increased specificity of 231 exosome targeting to pulmonary endothelial cells over unrelated cell lines. These results suggest the involvement of exosomes and eNDPK in pro-angiogenic communication between metastatic breast cancer cells and their vascular targets. Exosomes elaborated by these cells specifically target pulmonary endothelium in vivo, mirroring the organotropic nature of breast cancer metastasis. Implication of eNDPK in angiogenesis and metastasis may challenge current and invasive treatment methods in favor of developing novel small molecule inhibitors of eNDPK signaling. Lastly, eNDPK can be explored as a potential biomarker for early detection of metastatic breast cancer as it uniquely appears in the serum of patients with breast cancer and not in the serum of individuals with unrelated pathologies.
Citation Format: Suzann Duan, Senny Nordmeier, Iain L. Buxton. Exosomal NM23 facilitates pro-angiogenic communication between triple-negative breast cancer cells and their vascular targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1807. doi:10.1158/1538-7445.AM2017-1807
Abstract 1808: Vascular endothelial growth factor receptor-2 (VEGFR-2) N-glycosylation modulates angiogenic signaling
Authors: Chandler Kevin B. , Leon Deborah R. , Meyer Rosana D. , Rahimi Nader , Costello Catherine E. 
Published: July 2017

Abstract
Angiogenesis, the formation of new blood vessels from pre-existing vessels, is required for tumor growth and metastasis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is one of the most important receptor tyrosine kinases (RTKs) among the VEGF receptor subfamily, and activation of VEGFR-2 is essential for tumor angiogenesis. The extracellular domain of VEGFR-2 contains seven immunoglobulin-like (Ig) domains, each with multiple potential N-glycosylation sites. N-glycosylation is thought to play a central role in receptor stability, ligand binding and trafficking. However, to date the occupancy and glycoform distributions at each of the potential N-glycosylation sites and their putative role(s) in VEGFR-2 function remain largely unknown. The objective of this study is to investigate the functional importance of VEGFR-2 N-glycosylation in VEGFR-2 angiogenic signaling.
Porcine aortic endothelial (PAE) cells with ectopic expression of VEGFR-2 were treated with PNGase F to remove N-linked glycans or heat-denatured PNGase F as a control. Following PNGase F treatment for 4 hours, cells were treated with VEGF-A ligand for 0, 5, 10 or 30 minutes. VEGFR-2 phosphorylation (activation) was measured via Western blot with an anti-pTyr-1054-VEGFR-2 antibody. In addition, a polyclonal anti-VEGFR2 antibody was used to immunoprecipitate untreated and PNGase F-treated VEGFR-2 from PAE cell lysates. Evaluation of the N-glycosylation sites targeted by PNGase F was carried out by gel electrophoresis, followed by protease digestion and MS/MS analysis. MS/MS data were processed using Proteome Discoverer 1.4. To obtain site-specific glycosylation information we performed proteolysis of VEGFR-2, glycopeptide enrichment via hydrophilic interaction liquid chromatography (HILIC) and subsequent analysis of glycopeptides with an Agilent 6550 Quadrupole Time-of-Flight (Q-TOF) MS using collision-induced dissociation.
We detected a dramatic increase in ligand-mediated activation of VEGFR-2 after treatment with PNGase F, suggesting that certain N-linked glycans may hinder ligand access to the VEGF binding site, or that removal of N-linked glycans results in conformational changes that lead to increased activation of the receptor by VEGF-A. To explore this observation in greater detail, we have created a series of VEGFR-2 N-glycosylation site mutants, and we are now using the mutants to determine which glycosylation sites are involved in the observed modulation of VEGFR-2 signaling.
Citation Format: Kevin B. Chandler, Deborah R. Leon, Rosana D. Meyer, Nader Rahimi, Catherine E. Costello. Vascular endothelial growth factor receptor-2 (VEGFR-2) N-glycosylation modulates angiogenic signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1808. doi:10.1158/1538-7445.AM2017-1808
Abstract 1809: PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation
Authors: Azoitei Ninel , Becher Alexander , Steinestel Konrad , Rouhi Arefeh , Diepold Kristina , Bobrovich Susanne , Seufferlein Thomas 
Published: July 2017

Abstract
Initially identified as a molecule that catalyzes the phosphorylation from phosphoenolpyruvate to pyruvate in the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in the regulation of apoptosis and proliferation. In this study, we have identified PKM2 as a crucial molecule for progression of pancreatic cancer in which tumor microenvironment has been reported to be highly hypoxic. Our data show moderate to strong PKM2 expression in all examined human pancreatic adenocarcinoma samples. Depletion of PKM2 was associated with impaired proliferation and augmented tumor cell death in vitro, while the in vivo tumor xenograft experiments revealed a close association between impaired tumor growth and decreased blood vessel formation. Furthermore, abrogation of PKM2 prevented hypoxia-mediated HIF-1alpha accumulation and HIF-1alpha promoter activity, which negatively impacted VEGF secretion by pancreatic cancer cells deprived of oxygen. Interestingly, PKM2 expression arrest was also mirrored by impaired hypoxia-driven promoter activity of NF-kappaB which also drives the transcription of VEGF. Ectopic expression of p65 restored VEGF transcription after PKM2 ablation inferring that the kinase regulates VEGF via NF-kappaB/p65 subunit. Altogether, our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-kappaB/p65 and HIF-1alpha activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation.
Citation Format: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Susanne Bobrovich, Thomas Seufferlein. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2017-1809
Abstract 1814: IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer
Authors: Li Jie , Xie Kun , Mei Shenglin , Xu Yuanjian , Gu Hua , Li Dong , Chen Kaiming , Tao Fei , Eerdeng Jiya , Fang Jianmin 
Published: July 2017

Abstract
Anti-angiogenic therapy has been used for the treatment of a number of solid tumors in clinic, however, survival benefit is often limited due to development of tumor resistance to the therapy. In previous studies, we developed a mouse Lewis lung carcinoma (LLC) tumor model that is resistant to anti-VEGF therapy. In this model, we identified that Interleukin 11 (IL11) was among the most significantly upregulated genes in the resistant tumors. In current study, we demonstrated that IL11 was a pro-angiogenic factor and played a key role in the development of resistance to anti-VEGF therapy in LLC tumor. IL11 could effectively induce HUVEC proliferation, migration and capillary tube formation in vitro. It enhanced expression of MMP9 in endothelial cells. The conditioned medium from the resistant LLC cell culture could induce HUVEC migration, even VEGF was blocked, and this effect was attenuated by recombinant IL11 decoy receptor, an IL-11 inhibitor. Furthermore, combination therapy of anti-VEGF agent and IL11 blockade exhibited enhanced anti-tumor activity in lung cancer model. In addition, based on bioinformatics analysis on over 500 RNA-seq data deposited to The Cancer Genome Atlas (TCGA), we found that IL11 was highly expressed in various tumor types in patients. Data showed that high IL11 can predict a poor outcome in the lung cancer. The patients with the lower IL11 expression have significantly longer median survival time than those with higher expression. These findings support a role of IL11 signal as a compensatory angiogenic pathway that might trigger tumor resistance to anti-VEGF treatment. Therapeutically targeting IL11 could have a value in overcoming tumor resistance to anti-VEGF therapy.
Citation Format: Jie Li, Kun Xie, Shenglin Mei, Yuanjian Xu, Hua Gu, Dong Li, Kaiming Chen, Fei Tao, Jiya Eerdeng, Jianmin Fang. IL11 mediates tumor resistance to anti-VEGF therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1814. doi:10.1158/1538-7445.AM2017-1814