bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 339: Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC
Authors: Satyam Leena Khare , Chikkanna Dinesh , G Aswani K. , Khairnar Vinayak V. , Reddy Sreekanth , Durgaprasad Vakkapatla , Radhakrishna Kowju , Panigrahi Sunil K. , Ramanathan Anuradha , Mahasweta Kumari , Lakshminarasimhan Anirudha , K Narasimha R. , R Vinutha , Gopinath Sreevalsam , Kumar Suryakant , Shah Mubarak H. , Ramachandra Raghuveer , B Kiran A. , Pandit Chetan , Ramachandra Murali 
Published: July 2016

Abstract
KRAS is the frequently mutated isoform in RAS driven cancers. The G12C mutation is more predominantly associated with various tumor types over other changes in K-Ras. Although direct targeting of RAS is very challenging, it is possible to selectively target G12C mutant K-Ras using a covalent approach. Mutant specific covalent inhibitors with high selectivity against wild type K-Ras and other GTPases are expected to lead to efficacy with a very high degree of tolerability. Here, we report identification of lead compounds from two distinct chemical series that selectively target K-Ras G12C. Molecular modeling based on the reported crystal structures aided in the identification of these compounds. Covalent binding of the lead compounds to K-Ras G12C was demonstrated by MALDI-TOF. Lead compounds were potent in selectively inhibiting proliferation of cell lines with K-Ras G12C mutation but not with wild type K-Ras. The anti-proliferative activity of the lead compounds correlated well with their potency in a cellular mechanistic assay. Lead compounds from both series exhibited excellent drug-like properties including solubility, metabolic stability, permeability lack of CYP inhibition and desired exposure in pharmacokinetic studies. In a xenograft model of NSCLC, the lead compound demonstrated dose-dependent tumor growth inhibition with excellent tolerability upon oral dosing. In summary, we have identified a novel, potent and selective K-Ras G12C inhibitor with optimized drug-like properties including oral bioavailability and efficacy in a NSCLC derived xenograft model. Toxicity evaluation is ongoing towards progressing the lead compound to the clinic.
Citation Format: Leena Khare Satyam, Dinesh Chikkanna, Aswani K. G, Vinayak V. Khairnar, Sreekanth Reddy, Vakkapatla Durgaprasad, Kowju Radhakrishna, Sunil K. Panigrahi, Anuradha Ramanathan, Kumari Mahasweta, Anirudha Lakshminarasimhan, Narasimha R. K, Vinutha R, Sreevalsam Gopinath, Suryakant Kumar, Mubarak H. Shah, Raghuveer Ramachandra, Kiran A. B, Chetan Pandit, Murali Ramachandra. Identification of novel covalent inhibitors of K-Ras G12C that are efficacious in a xenograft model of NSCLC. [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 339.
Abstract 3396: Purinergic regulation of tumor-mediated angiogenesis: A role for exosomal NM23
Authors: Nordmeier Senny , Duan Suzann , Buxton. Iain L.O. 
Published: July 2016

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. ATP can active purinergic receptors (P2Y1) on adjacent endothelial cells to promote angiogenesis. We previously reported that eNDPK was detected in conditioned media of breast cancer cells and in the serum of breast cancer patients (Yokdang, et al., 2011; Yokdang, et al., 2015). This suggests that eNDPK may have a role in tumorigenesis, but the mechanism by which eNDPK is released into the extracellular environment remains unknown. It is known that all cell types secrete small vesicles called exosomes, 30-100 nm wide vesicles of endocytic origin. We hypothesize that exosomal eNDPK secreted by breast cancer cells targets and promotes endothelial cell tubulogenesis and direct inhibition of eNDPK and P2Y1 activity attenuates angiogenesis. Exosomes were purified from human breast cancer cells, MDA-MB-231 (231) and non-tumorigenic human mammary epithelial cells (HME1) using ExoQuick TC. Transmission electron microscopy, mass spectrometry, and flow cytometry were performed to characterize the exosomes. Purified exosomes labeled with GFP-tagged tetraspanin (CD63) were introduced to human umbilical vein endothelial cells (HUVEC) to detect and measure tubulogenesis formation. We show that 231 secreted exosomes contain eNDPK and HUVEC cells treated with NDPK in the presence of ADP and GTP form tubules. In addition, fluorescently-labeled exosomes are associated with HUVEC tubules. The role of exosomal NDPK released by cancer cells in promoting angiogenesis and tumorigenesis may be used as a potential biomarker and target for treatment in breast cancer management. For future investigations of exosomal eNDPK, this study suggests that breast cancer exosomes promote endothelial tubulogenesis in a P2Y receptor-dependent manner.
Citation Format: Senny Nordmeier, Suzann Duan, Iain L.O. Buxton. Purinergic regulation of tumor-mediated angiogenesis: A role for exosomal NM23. [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 3396.
Abstract 3399: CTGF promotes tumor angiogenesis process in osteosarcoma through induction of angiopoietin-2
Authors: Cheng Yu-che , Tsai Hsiao-Chi , Tan Tzu-Wei , Tang Chih-Hsin 
Published: July 2016

Abstract
Osteosarcoma is the most common primary malignant bone tumor. Angiogenesis is essential for the tumor growth. Angiopoietin-2 (Angpt2) plays a critical role in angiogenesis and tumor progression. Connective tissue growth factor (CTGF), a secreted protein that binds to integrins, modulates the angiogenesis of certain human cancer cells. However, the effect of CTGF on Angpt2 expression in human osteosarcoma cells is mostly unknown. In this study, we found that overexpression of CTGF in osteosarcoma promoted angiogenesis in vitro and in vivo by tube formation assay, and Matrigel plug assay. Knockdown of CTGF obviously reduced expression of Angpt2 and angiogenesis. Recently, microRNAs (miRNAs) have been demonstrated that functions as oncogenes or angiogenesis regulators in human cancer. Here, we also found that overexpression of CTGF significantly decreased miR-543 in osteosarcoma cells. Transfection of miR-543 mimic reduced Angpt2 expression and angiogenesis. Taken together, CTGF promotes angiogenesis via up-regulation of Angpt2 by decreasing miR-543 in human osteosarcoma. These findings certify that CTGF functions as a tumor enhancer gene, suggesting that CTGF may be a potential therapeutic target for osteosarcoma patients.
Citation Format: Yu-che Cheng, Hsiao-Chi Tsai, Tzu-Wei Tan, Chih-Hsin Tang. CTGF promotes tumor angiogenesis process in osteosarcoma through induction of angiopoietin-2. [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 3399.
Abstract 34: Monocarboxylate transporters as potential therapeutic targets in human ovarian cancer
Authors: Boyers Amy , Stratford Ian 
Published: July 2016

Abstract
Introduction- Cancer cells have the ability to favour glycolysis for the production of lactate even in the presence of sufficient levels of oxygen. This is known as the ‘warburg effect’ or ‘aerobic glycolysis’. As a consequence of this glycolytic switch, there is an accumulation of lactate within cells. Therefore, cells must remove this excess lactate in order to prevent cell death via intracellular acidosis. In order to do this cells use Monocarboxylate Transporters (MCTs), which are responsible for the transport of lactate in and out of cells. MCT1 and MCT4 have been found to be over expressed in many types of human cancers, including ovarian cancer.
Aims- The aim of this study was to assess how changing the expression levels of MCT1 and MCT4 effects the growth and response to therapy of four Human Ovarian cancer cell lines (Skov3, Caov3, OV90 and Ovcar3).
Methods- Cell lines were stably transfected to either over express MCT1 (Skov3, Caov3, and OV90 cells), MCT4 (OV90 cells) or to contain doxycycline inducible silencing of MCT4 (Skov3, Caov3 and Ovcar3 cells). The effect of changing the expression levels of MCT1 and MCT4 on the function of these cell lines was assessed. Assays to look at changes in cell proliferation, lactate accumulation and release, and the cytotoxicity of Paclitaxel and Carboplatin were determined in both normoxia (21% O2) and hypoxia (0.1/1% O2).
Results- Over expressing MCT1 in the three human ovarian cell lines had no effect on cell growth or lactate release in normoxia or hypoxia. Also when MCT1 was over expressed in Skov3 and Caov3 cells there were no changes in their sensitivity to Carboplatin or Paclitaxel. However, when MCT1 was over expressed in OV90 cells, they became slightly more resistant to Paclitaxel. Over expressing MCT4 in OV90 cells also had no effect on cell growth in normoxia, but significantly more lactate was released by these cells. Secondly, when these cells were grown in hypoxia they survived for a greater period of time than wild type cells. This correlated with a much higher amount of lactate being released by these cells. Finally, these cells were more resistant to Paclitaxel than both the MCT1 over expressing cell lines and their wild type counterparts.
Conclusions- Changing the expression levels of MCT1 and MCT4 in Human Ovarian cancer cells have an effect on normal cell function. This suggests that MCTs could be potential therapeutic targets in ovarian cancer.
Citation Format: Amy Boyers, Ian Stratford. Monocarboxylate transporters as potential therapeutic targets in human ovarian 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 34.
Abstract 3400: An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors
Authors: Craven Kelly E. , Gore Jesse , Wilson Julie L. , Korc Murray 
Published: July 2016

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival of 7%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density, and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting.
By analyzing the recently expanded TCGA (The Cancer Genome Atlas) dataset, we report here that an angiogenesis gene signature is present in ∼35% of PDACs and is mostly distinct from an angiogenesis signature present in PNETs. Additionally, principal component analysis (PCA) of the entire or angiogenic PDAC and PNET transcriptomes from TCGA indicates that there are large differences in gene expression between these two tumor types. For example, PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Functionally, targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib blocks proliferative cross-talk between human pancreatic cancer cells and human endothelial cells. Tumors from the KRC (oncogenic Kras, deleted Rb1) PDAC mouse model show superior enrichment and differential expression of the angiogenic gene signature compared to tumors from the KPC (oncogenic Kras, mutated Trp53) PDAC mouse model. Moreover, treatment of KRC and KPC mice with ruxolitinib suppresses murine PDAC progression in KRC mice but not in KPC mice. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature should be explored in the clinic and that this could lead to improved responses to anti-angiogenic therapy in PDAC.
Citation Format: Kelly E. Craven, Jesse Gore, Julie L. Wilson, Murray Korc. An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors. [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 3400.
Abstract 3402: Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular carcinoma
Authors: Kore Rajshekhar A. , Upreti Meenakshi , Jamshidi-Parsian Azemat , Dings Rudd P.M. , Makhoul Issam , Griffin Robert J. 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is a highly vascularized tumor, which preferentially recruits new blood vessels from the hepatic artery to fuel its growth, through mechanisms not well understood. Here, we examined the intercellular cross-talk of HepG2 (human HCC) and endothelial progenitor cells (EPC) in transwell co-cultures to mimic initial tumor parenchyma and stroma interactions. We present evidence showing that, in culture, HepG2 cells secrete factors to induce an ‘activated’ EPC phenotype, namely, an increase in survival, growth, proliferation and migration rates. EPC cells showed a significant increase in growth (∼40%) and survival (∼80%) when co-cultured with HepG2 cells. Simultaneously, activated EPCs improved the viability of HepG2 cells. A major mediator of intercellular crosstalk are the secreted microvesicles called exosomes. Exosomes constitute a set of distinct nanovesicles (30-100 nm), endosomal in origin, constitutively secreted by many cells. They are involved in intercellular communication by transferring proteins and RNA from one cell to another. Intercellular crosstalk between these HepG2 cells and EPCs cells lead to qualitative and quantitative changes in the exosomal cargo secreted by the respective cells. The exosomal cargo constituting various proteins and genetic material have been demonstrated to be involved in processes which promote remodeling of extracellular matrix (ECM), biological adhesion and pathways modulating developmental processes and progression of inflammation, leading to cancer growth and development. In other work with glioma cell-derived exosomes has shown the presence of Ephrin A and B receptors which suggests a prominent role of secreted exosomes in stimulating and guiding tumor angiogenesis, a hallmark characteristic of glioblastoma multiforme (GBM). Additionally, our results with co-cultures of tumor and endothelial cells show that angiogenesis signaling in EPC appears to be induced by HepG2 cells via elevated endothelial Ephrin B2 and DLL-4 expression. Overall, our results demonstrate the co-dependence of HCC and EPC intercellular crosstalk, likely accomplished via secreted exosomes, in the initial stages of HCC establishment and stimulation of angiogenesis and development, thus a promising target for new clinical strategies.
Citation Format: Rajshekhar A. Kore, Meenakshi Upreti, Azemat Jamshidi-Parsian, Rudd P.M. Dings, Issam Makhoul, Robert J. Griffin. Ephrin B2 and Dll-4 mediated co-dependence of tumor and endothelial progenitor cells in human hepatocellular 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 3402.
Abstract 3408: Oncogenic SOX2 signaling in bladder cancer
Authors: Wu Chia-Chang , Chiu Yu-Fan , Chou Yu-Ting , Wang Yuan-Hung 
Published: July 2016

Abstract
The intriguing phenomenon that cancer cells have biological features similar to stem cells suggests that cancer and stem cells may share the same regulatory signaling pathway. We found that SOX2, a master transcriptional factor controlling self-renewal of stem cells, was highly expressed in a subgroup of transitional cell carcinoma of bladder cancer, correlating with the advanced pathological grade. Moreover, SOX2 expression was associated with poor overall survival and recurrence-free survival outcomes in patients with bladder cancer. Knockdown of SOX2 in SOX2-high 5637 bladder cancer cells attenuated cell growth. Consistently, ectopic expression of SOX2 in SOX2-low T24 bladder cancer cells endowed cells with increased cell proliferation. Spheroid assay showed that SOX2 expression encouraged spheroid-forming ability of bladder cancer cells in low serum condition, demonstrating the involvement of SOX2 signaling in the maintenance of stemness in bladder cancer cells. Immunoblotting revealed that the expression of SOX2 induced phosphorylation of AKT in the serum-free condition, supporting that SOX2 regulates bladder cancer cell survival. Gene expression microarray analysis showed that SOX2 expression induced IGF2, which was further confirmed by Q-PCR analysis in bladder cancer cells. Chi-square test assay showed that IGF2 expression correlated with the advanced tumor stages in bladder cancer. Pharmacological inhibition of IGF2 signaling attenuated cell growth in SOX2-postive bladder cancer cells. Our findings support the notion that SOX2-IGF2 signaling axis confers aggressiveness in bladder cancer cells with potentials as biomarkers and therapeutic targets for bladder cancer intervention.
Citation Format: Chia-Chang Wu, Yu-Fan Chiu, Yu-Ting Chou, Yuan-Hung Wang. Oncogenic SOX2 signaling in bladder 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 3408.
Abstract 3411: Role of mucin gene variations in microRNA binding sites in modulating colorectal cancer susceptibility and clinical outcomes
Authors: Bendova Petra , Vymetalkova Veronika , Pardini Barbara , Rosa Fabio , di Gaetano Cornelia , Vodickova Ludmila , Buchler Tomas , Naccarati Alessio , Vodicka Pavel 
Published: July 2016

Abstract
Mucins, high molecular weight glycoproteins predominantly expressed at the epithelial surface of tissues, provide protection for colon surface under normal physiological conditions. Mucinous colorectal carcinoma is generally defined as having greater than 50% of the tumor area with a mucinous differentiation by histologic examination.
MiRNAs have recently emerged as important regulators for altered mucin expression during malignant development. MiRNAs are short non-coding RNAs that regulate gene expression by binding to the 3’untranslated regions (3’UTR) of target mRNA thereby hampering protein translation or inducing mRNA destabilization. Aberrant miRNA expression and/or function are frequently observed in colorectal cancer (CRC). Polymorphisms in miRNA binding sites may affect miRNA binding to target genes, resulting in differential mRNA and protein expression and susceptibility to common diseases. We hypothesize that variations in mucin genes may modulate signaling response affecting cancer susceptibility, cancer survival and efficacy of chemotherapy.
Thirteen polymorphisms in nine mucin genes (MUC6, MUC7, MUC13, MUC14, MUC15, MUC17, MUC20, MUC21 and MUC24) were analyzed in DNA samples of 1111 cases and 1469 controls from the Czech Republic. Investigated variants were also studied in association with clinical outcome in all patients provided with detailed information on follow up.
Genetic variations in mucin genes were associated with clinical outcome. In particular, CRC patients carrying the CC genotype for rs886403 in MUC21 gene displayed a shorter survival and higher recurrence risk (HR 1.69; 95% CI 1.13-2.46; p = 0.01 and EFS: HR 1.99; 95% CI 1.38-2.84; p = 0.0002, resp.). The observed association was strikingly pronounced in colon cancer patients while individuals with rectal cancer and carrying variant CC genotype of rs4729655 in MUC17 displayed better overall survival (HR 0.27; 95% CI 0.14-0.54; p = 0.0002).
Expanding our knowledge on mucin involvement in CRC may help us better understand the etiopathogenesis of this disease and thereby contribute to the development of new treatment strategies. The present results identified plausible candidate SNPs potentially affecting miRNAs that target mucin genes in relation to CRC patients’ survival.
Work supported by IGA MZ: NT 15-26535A
Citation Format: Petra Bendova, Veronika Vymetalkova, Barbara Pardini, Fabio Rosa, Cornelia di Gaetano, Ludmila Vodickova, Tomas Buchler, Alessio Naccarati, Pavel Vodicka. Role of mucin gene variations in microRNA binding sites in modulating colorectal cancer susceptibility and clinical outcomes. [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 3411.
Abstract 3423: Overweight and obesity predict better overall survival rates in cancer patients with distant metastases
Authors: Tsang Ngan M. 
Published: July 2016

Abstract
Background: Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status.
Methods: Between 2000 and 2012, a total of 4,010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis.
Results: The median OS time was 3.23 months (range: 0.1−122.17) for underweight patients, 6.08 months (range: 0.03−149.46) for normal-weight patients, 7.99 months (range: 0.07−158.01) for overweight patients, and 12.49 months (range, 0.2−164.1) for obese patients (log-rank: P &lt; 0.001). Compared with normal-weight patients, both obese (HR = 0.676; 95% P &lt; 0.001) and overweight individuals (HR = 0.84; P &lt; 0.001) had a reduced risk of all-cause mortality in multivariable analysis. Conversely, underweight patients had a significantly higher risk of death from all causes (HR = 1.41; P &lt; 0.001).
Conclusions: Overweight and obesity are independent predictors of better OS in metastatic patients with a good performance status. Increased BMI may play a role to identify metastatic patients with superior survival outcome and exhibit a potential to encourage aggressive management in those patients even with metastases.
Citation Format: Ngan M. Tsang. Overweight and obesity predict better overall survival rates in cancer patients with distant metastases. [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 3423.