bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3742: P7170: A potent and oral phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) inhibitor with anti-tumor and anti-angiogenic activity
Authors: Agarwal Veena R. , Joshi Asavari , Venkataraman Magesh , Desai Nikesh , Bhatia Dimple , Chaudhari Sarika , Bose Julie , Kolla Lakshmi Sireesha , Deore Vijaykumar , Yewalkar Nilambari , Kumar Sanjay , Sharma Rajiv , Damre Anagha , More Avinash , Gill Parkash , Sharma Somesh 
Published: August 2012

Abstract
The PI3K/mTOR pathway plays an important role in regulating cancer cell proliferation, growth, survival and metabolism. Activation of the PI3K/mTOR pathway by multiple mechanisms is one of the most frequently observed defects in human malignancies. The objective of these studies was to identify a small molecule that has anti-angiogenic activity in addition to PI3K and mTOR activity. P7170, a novel small molecule, inhibits PI3Kα and mTOR enzyme activity with IC50 value of 2.2 nM and 4.4 nM respectively. P7170 also inhibits a number of PI3Kα mutants. The Inhibition of PI3K-mTOR pathway in different cancer cell lines was demonstrated by 80 to 100% inhibition of the expression of phosphorylated AKT (pAKT), S6 ribosomal protein (pS6), and 4EBP1 (p4EBP1) upon treatment with P7170 in a western blot assay. P7170 also inhibited ALK1, an important enzyme involved in angiogenesis, and DNA-PK, an enzyme involved in DNA repair with the IC50 values of 47 and 1.5 nM, respectively. P7170 exhibited potent cytotoxic activity with IC50 values ranging from 2 to 22 nM in a number of cancer cell lines eg. ovarian (A2780), prostate (PC3), triple negative breast (MDA-MB-231 and MDA-MB-468), ER positive breast (MCF7), hepatocellular (HuH-7), renal (786-O), pancreatic (Panc1, AsPC1, and BxPC3), and colon (HCT116, HCT115, SW480) cancer cell lines. More interestingly, P7170 inhibited pAKT and pS6 in stem-like cells isolated from tumor samples of colon, breast, and head and neck cancer patients. P7170 also inhibited anchorage independent colony formation of tumor cells isolated from 39 different human tumor xenografts derived from tumors of patients with different cancers. In addition, P7170 inhibited angiogenesis in vitro in a tube formation assay, and in a matrigel plug assay in animals. It also inhibited metastasis of breast cancer cells. P7170 demonstrated significant in vivo efficacy when administered orally in three human xenograft tumor models. Tumor growth inhibition of 79% at 15 mg/kg in prostate (PC3), 78% at 10 mg/kg in ovarian (A2780), and 64% at 10 mg/kg in triple negative breast (MDA-MB-231) xenografts. Conclusion: P7170 has a unique profile of PI3K-mTOR pathway inhibition along with anti-angiogenic and anti- DNA repair activities. Combined with its effect on stem-like cells, P7170 may prove to be an effective anti-cancer drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3742. doi:1538-7445.AM2012-3742
Abstract 3748: NVP-BYL719, a novel PI3Kalpha selective inhibitor with all the characteristics required for clinical development as an anti-cancer agent
Authors: Fritsch Christine M. , Schnell Christian , Chatenay-Rivauday Christian , Guthy Daniel A. , Pover Alain De , Wartmann Markus , Brachmann Saskia , Maira Sauveur-Michel , Huang Alan , Quadt Cornelia , Hofmann Francesco , Caravatti Giorgio 
Published: August 2012

Abstract
Most of the current oncology drug discovery and development work has shifted towards molecularly targeted therapies. A key focus has been on identifying inhibitors against components of pathways that drive tumor cell proliferation, survival, and metastasis such as the PI3K/mTOR pathway, reported to be implicated in many human cancers through various mechanisms, such as, somatic PIK3CA missense mutations that occur at high frequency. These mutations are largely point mutations predominantly clustered within three hotspots in the helical and kinase domains of p110α: E542K, E545K and H1047R, which represent about 80% of the mutations observed, and confirmed to be oncogenic gain-of-function mutations. Based on these findings cancer-specific mutants of p110α appear to be ideal targets for drug development and p110α specific inhibitors, such as NVP-BYL719, could then have potential anti-cancer activity without causing the potential side effects that could be expected from interference with other Class I PI3K isoforms or other members of the PIKK family. NVP-BYL719 is best described as a PI3Kalpha inhibitor as in biochemical assays, it inhibits p110α as well as p110α most common somatic mutations (IC50=5 nM) much more potently than p110α and ≤ and has weak or no activity against p110α, Vps34 and mTOR and is selective against a wide range of protein kinases (&gt; 50-fold). The potency and selectivity profile of NVP-BYL719 is confirmed at the cellular level, is correlated with inhibition of various PI3K/Akt downstream signaling pathway components and is associated with anti-proliferation of breast cancer cell lines harboring PIK3CA mutations. In vivo, NVP-BYL719 shows dose and time-dependent inhibition of the PI3K/Akt pathway which correlates with compound exposure and is associated with good tolerability and significant dose-dependent anti-tumor efficacy in PIK3CA mutant tumor xenograft models in rodents. Moreover, plasma insulin levels are significantly increased while blood glucose levels remained normal at all tested doses and time points indicating on-target effects of NVP-BYL719 on the regulation of metabolism. Overall, as a PI3Kalpha inhibitor, NVP-BYL719 has good drug-like and pharmacological properties and presents all the characteristics required for its ongoing Phase I clinical development in adult patients with advanced solid malignancies whose tumors have an alteration of the PIK3CA gene.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3748. doi:1538-7445.AM2012-3748
Abstract 3807: Regulation of pancreatic, gliosarcoma and non-small cell lung cancer via CPI-613, a novel anticancer therapeutic agent
Authors: Perera Candida N. , Rodriguez Robert , Shorr Robert 
Published: August 2012

Abstract
While the novel anticancer agent CPI-613, currently in clinical trials, is primarily known to affect multiple cancer cell energy metabolic processes and pathways, here we demonstrate that CPI-613 also shows cancer-cell-cycle-specific effects on BxPC3 (human pancreatic) cancer cells, SF539 (human gliosarcoma) cells, and H460 (human non-small cell lung cancer) cells but not on non-transformed NIH3T3 (murine fibroblast) cells. Specifically, gene microarray data demonstrates that CPI-613 affects signal transduction pathways and genes related to cell cycle maintenance and progression as well as energetic metabolic processes and pathways. The total RNA production was also significantly reduced in cancer cells treated with CPI-613 compared to non treated controls. Multiple cyclins, p27, p19, and CDK2 are specifically noted to be downregulated in cancer cells treated with this drug, thereby halting the cell cycle at multiple points. Further study of this phenomenon may lead to additional indications for CPI-613 treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3807. doi:1538-7445.AM2012-3807
Abstract 3821: Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines
Authors: Kitazono Miyako , Takiguch Yuichi , Kitazono Satoru , Ashinuma Hironori , Kitamura Atsushi , Tada Yuji , Kurosu Katsushi , Sakaida Emiko , Sekine Ikuo , Tanabe Nobuhiro , Tagawa Masatoshi , Tatsumi Koichiro 
Published: August 2012

Abstract
Background: Malignant pleural mesothelioma (MPM) is one of the most lethal cancers with a rapidly increasing incidence worldwide. Although cisplatin and pemetrexed are recognized as key drugs, and their combination chemotherapy is a standard therapy for MPM, their drug-to-drug interactions, cross-resistance, and resistance mechanisms are not well understood. Methods: The interaction between cisplatin and pemetrexed was evaluated by colonogenic assays followed by isobologram analysis in 4 human MPM cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase (TS) mRNA expression was evaluated by RT-PCR, and gene expression profiles were assessed by cDNA microarray analysis and gene ontology analysis using Ingenuity Pathway Analisis (IPA) in the drug-resistant sublines. Results: Cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar sensitivity to pemetrexed in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High TS expression did not correlate with natural pemetrexed resistance and its elevatedexpression correlated with acquired pemetrexed resistance in 2 sublines. Microarray analysis disclosed that the genes which related to “cellular development”,” small molecule biochemistry,” “cellular movement,” “cell death, and “cellular growth and proliferation” affected drug-resistant mechanisms deeply, and that this tendency was common to cisplatin-resistant sublines and pemetrexed-resistant sublines. Conclusion: Cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 MPM cell lines, suggesting the clinical relevance of their combination chemotherapy. TS expression did not necessarily correlate with pemetrexed resistance. Multiple mechanisms of molecular and cellular functions may underlie acquired resistance to cisplatin and pemetrexed in MPM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3821. doi:1538-7445.AM2012-3821
Abstract 3974: A comprehensive resequence-analysis of 250kb region of 8q24 in Africans
Authors: Chung Charles C. , Hsing Ann W. , Yeager Meredith , Yeboah Edward , Biritwum Richard , Tettey Yao , Adjei Andrew , Marzo Angelo De , Netto George J. , Isaacs William B. , Isaacs Sarah D. , Boland Joseph , Chanock Stephen J. 
Published: August 2012

Abstract
To date, genome-wide association studies (GWAS) have identified more than 45 prostate cancer susceptibility variants, of which at least 5 independent loci were identified within a 654kb region on 8q24. This region also harbors additional loci associated with cancers of the breast, colon, bladder, and chronic lymphocytic leukemia. Previously, the linkage disequilibrium (LD) pattern and recombination hotspots (chr8:128050768-128300801, hg19) defined a 250kb span (region 2) harboring multiple prostate cancer susceptibility loci identified in multiple distinct populations, as well as a locus rs2456449 associated with chronic lymphocytic leukemia in Europeans. Because GWAS identify genetic markers, fine-mapping using sequence analysis in diverse populations is necessary for defining the optimal variants for biological follow-up. Sequence analysis in populations of distinct ancestry can provide important insights into the differences of LD patterns and thus narrow down high interest variants. In the present study, we have resequenced the region in 125 men of African ancestry, which included 78 individuals from a population-based study in Ghana and 47 African-American individuals from the Johns Hopkins Hospital. Upon comparison with 1000 Genomes data (Oct 2011 release), we have identified 365 novel loci and additional surrogates of known susceptibility loci which could be important in establishing priorities for future functional work, designed to explain the biological basis of the association signal for both prostate cancer and perhaps, chronic lymphocytic leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3974. doi:1538-7445.AM2012-3974
Abstract 4017: Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers
Authors: Yun Jiyeon , Song Sang-Hyun , Park Jinah , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Bang Yung-Jue , Kim Tae-You 
Published: August 2012

Abstract
Epiregulin (EREG), a ligand of the epidermal growth factor receptor (EGFR), induces cell growth by binding to the EGFR. Expression of EREG affects sensitivity to cetuximab a chimeric monoclonal antibody that inhibits the EGFR signaling pathway. The mechanism through which EREG is regulated is largely unknown, but a methyl-array study performed by our group revealed that EREG is methylated in gastric cancer cells. In the present study, we found that EREG gene expression was low in seven out of 11 gastric cancer cells and this down-regulation was mediated by aberrant CpG methylation of the EREG promoter. Treatment with 5-aza-CdR restored EREG expression and demethylated the CpG sites in the EREG promoter. Compared to DNMT1, knockdown of DNMT3b significantly increased the expression of EREG mRNA and led to the demethylation of specific CpG sites in the EREG promoter, suggesting that DNMT3b primarily regulates the CpG methylation and silencing of EREG gene. EREG methylation was observed in 30% (4/13) of human primary gastric tumor tissues. In addition to DNA methylation, results from a ChIP assay demonstrated that transcriptional levels of EREG were associated with the enrichment of active histone markers (H3K4me3 and AcH3) and of a repressive marker (H3K27me2). Treatment with 5-aza-CdR dynamically increased the low occupancy of H3K4me3 and AcH3, while decreasing the high enrichment of H3K27me2, indicating that dynamic histone modifications contribute to EREG regulation in addition to DNA methylation. Lastly, the combination of 5-aza-CdR and cetuximab exerted a synergistic anti-proliferative effect on gastric cancer cells. Taken together, the results of our study demonstrated for the first time that EREG is epigenetically silenced in gastric cancer cells by aberrant DNA methylation and histone modification.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4017. doi:1538-7445.AM2012-4017
Abstract 4085: The roles of HDACs in chromatin remodelling and response to chemotherapy in cancer
Authors: Huang Rui , Langdon Simon P. , Harrison David J. , Faratian Dana 
Published: August 2012

Abstract
Background: Chromatin is dynamic in higher-order structure in response to extracellular and environmental signals. We observed nuclear morphological changes in clinical cancer tissues after chemotherapy. Since chromatin structure dictates gene expression, and therefore function, further investigation of this phenomenon may help us to better understand therapeutic responses. We hypothesise that nuclear morphological changes in cancer in response to DNA-damage by chemotherapy are mediated by histone deacetylases (HDACs). Methods: Ovarian cancer cell lines PEO1/PEO4 (platinum sensitive/resistant) were selected as in vitro models, and primary ovarian cancer xenografts OV1002 and HOX424 as in vivo models. Expression levels of HDACs and heterochromatin protein 1 (HP1) were screened by reverse phase protein array (RPPA) and western blot after treatment with cisplatin. Immunofluorescence imaging was undertaken using confocal microscopy and nuclear texture was measured in Image J using GLCM texture analysis plugin. 38 ovarian cancer patient and 175 xenograft samples were assessed for HDAC and HP1 expression in response to chemotherapy by quantitative immunofluorescence. HDAC2 expression was modulated by interfering RNAs (siRNA). Results: We demonstrate nuclear morphological changes in clinical tumours, xenografts, and cell lines in response to platinum chemotherapy. HDACs and HP1 isoforms showed differential expression in a panel of 25 ovarian cancer cell lines associated with response to chemotherapy with increased expression in treated or resistant lines. Expression of HDACs increased in PEO1 cells treated with cisplatin in a time-dependent fashion. This was accompanied by quantifiable changes in nuclear texture (increased heterogeneity), and high expression of HP1s at early time point (4-24h). The proliferation of PEO1 cells was inhibited and HP1 protein expression decreased after HDAC2 knockdown. In clinical specimens, HDAC8 and HP1 gamma expression significantly increased after chemotherapy, and class I HDAC (1, 2, and 8) and HP1 expression were increased after carboplatin treatment in carboplatin-sensitive xenografts. Chromatin conformation, DNA damage response, and cell cycle progression showed sequential changes over time with carboplatin treatment. Conclusion: These results demonstrate alterations in chromatin structure after chemotherapy, and implicate the role of class I HDACs in higher order chromatin changes and the DNA damage response in ovarian cancer in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4085. doi:1538-7445.AM2012-4085
Abstract 4094: Identification of novel breast cancer methylation biomarkers by global demethylation, cDNA microarray, and quantitative methylation analysis
Authors: Ye Chuanzhong , Hu Zhijian , Courtney Regina , Zheng Wei , Cai Qiuyin 
Published: August 2012

Abstract
Aberrant DNA methylation is commonly found in breast cancer. Hypermethylation of CpG islands located in promoter regions of genes may result in translational gene silencing and thus play an important role in carcinogenesis. It has been documented that multiple genes involved in cell cycle regulation, apoptosis, DNA repair, hormone regulation, cell adhesion and invasion, angiogenesis, and cellular growth-inhibitory signaling pathways are hypermethylated in breast cancer. To identify additional hypermethylated genes, we conducted a global demethylation experiment using breast cancer cell lines, followed by gene expression microarray and DNA methylation analyses. Breast cancer MCF-7 cells were treated with 5-aza-2′-deoxycytidine (5-aza-dC) and trichostatin A (TSA). Gene expression profiles between 5-aza-dC/TSA treated and untreated cells were compared using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Expression levels of 195 genes were up-regulated at least two-fold by demethylation treatment of the MCF-7 cells. Expression levels of 16 cancer-related genes were selected for confirmation in six additional breast cancer cell lines using quantitative real-time PCR. Expression of 13 of these genes (APLP1, CARHSP1, CDKN2D, CKMT1A, FSCN1, GPX3, HBEGF, HIC2, HSPA2, NOV, S100A6, SERPINI1, and ZNF238) was confirmed to be significantly increased after 5-aza-dC/TSA treatment. Promoter methylation status of these 13 genes was examined in seven breast cancer cell lines using Sequenom MassARRAY quantitative methylation analysis. Promoter CpG island methylation of 6 genes was observed in all 7 breast cancer cell lines. The ZNF238 and HSPA2 genes had the most methylated CpG sites (each has 11 methylated CpG sites) and highest percentage of methylation in the promoter region tested in the study. In summary, we identified promoter hypermethylation in 6 cancer-related genes, including ZNF238 and HSPA2, in breast cancer cell lines. These genes may play a role in breast carcinogenesis. Further studies using human breast cancer samples are warranted to confirm these findings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4094. doi:1538-7445.AM2012-4094
Abstract 4111: A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers
Authors: Yamamoto Shinsuke , Inoue Jun , Bai Hua , Kawano Tatsuyuki , Inazawa Johji 
Published: August 2012

Abstract
Microtubule-associated protein 1 light chain 3 (MAP1LC3: LC3) has an important role in autophagy. The human LC3 gene family has five members, LC3A (variant-1: v1 and –2: v2), LC3B, LC3B2, and LC3C. While a form of LC3B modified by phosphatidylethanolamine (PE) (form-II) is localized in autophagosomes, it is not clear whether other LC3 proteins also function in autophagy. Here, we examined the association between autophagy and human LC3 proteins during starvation- or p53-induced autophagy in Saos-2 cells. In an analysis of the intracellular distribution of each LC3 protein fused with GFP, GFP-LC3Av1 was frequently localized in autophagosomes with a punctate pattern, similar to GFP-LC3B. Further, endogenous LC3Av1 generated form-II and mostly localized in LC3B-positive autophagosomes during the induced autophagy. Interestingly, LC3Av1, not LC3B, was frequently inactivated at the transcriptional level in various human cancer cell lines (111/244 cell lines, 45.5%) and its inactivation was due to aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC) cell lines and primary tumors. Restoration of LC3Av1 expression in KYSE170 cells, an LC3Av1-inactivated ESCC cell line, showed the inhibition of tumor growth in vivo. These results suggest that LC3Av1, not only LC3B, functions in autophagy and further, LC3Av1 may be crucial in carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4111. doi:1538-7445.AM2012-4111