bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1835: Phosphodiesterase 4D (PDE4D) selective inhibitors as candidate drugs for prostate cancer
Authors: Marker Paul C. , Hammer Kimberly D.P. 
Published: August 2012

Abstract
Our laboratory used an insertional somatic mutagenesis screen in mice to identify novel genes that may drive prostate cancer initiation and progression. Using this screen, we have identified candidate prostate cancer genes including the candidate oncogene phosphodiesterase 4D (PDE4D). Investigation of PDE4D showed that it was over-expressed in human prostate cancer cell lines and in human prostate cancers. Stable knockdown of PDE4D by shRNA reduced the growth and migration of prostate cancer cells in vitro and in vivo. Several small molecule PDE4D-selective inhibitors have been developed, including cilomilast and NVP-ABE171, and we have used them as potential anti-prostate cancer drugs in vitro and in vivo. The inhibitors were able to reduce the growth of prostate cancer cells in the context of epithelial mono-cultures or co-cultures that modeled stromal-epithelial interactions. Daily oral administration of PDE4D inhibitors for 6 weeks also reduced the growth of several prostate cancer xenograft lines in vivo through a dramatic induction of apoptosis. Interestingly, NVP-ABE171 and cilomilast also reduced the size of the prostates of treated mice without impacting overall animal health or the sizes of other organs. Under in vitro conditions in which prostate cancer cell growth was inhibited by either NVP-ABE171 or cilomilast, we also observed changes in the activation of potential downstream molecular targets of PDE4D inhibition including the sonic hedgehog and mitogen-activated protein kinase pathways. We are continuing studies with these inhibitors to further support the use of NVP-ABE171 and cilomilast as anti-prostate cancer drugs and to understand their mechanism(s) of action in the prostate.
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 1835. doi:1538-7445.AM2012-1835
Abstract 1836: p38α MAPK interacts with and inhibits RARα: Suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells
Authors: Garattini Enrico , Gianni’ Maurizio , Terao Mineko , Kurosaki Mami , Paroni Gabriela , Loparco Maria Immacolata , Peviani Marco 
Published: August 2012

Abstract
All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being employed in the treatment of acute promyelocytic leukemia (APL). The use of ATRA in other types of acute myelogenous leukemia (AML) calls for the identification of novel strategies aimed at increasing its therapeutic activity. One possible strategy to improve the efficacy of retinoids is to identify non-retinoid compounds that enhance the activity of ATRA, focusing on the mechanisms controlling the stability/activation of the nuclear retinoid receptors expressed in the AML blast. An important mechanism modulating the activity of the RAR-containing transcriptional complexes is phosphorylation of RARs and accessory proteins, such as co-repressors and co-activators. The mitogen activated kinase p38alpha, cyclin-dependent kinase 7 (CDK7) and mitogen-and stress-activated kinase (MSK1) stand out as critical determinants in the process. p38alpha is often increased and/or activated in AML blasts and it represents an important pharmacological target as well as a potential determinant of ATRA sensitivity in these cells. Here, we provide evidence that pharmacological inhibition of the mitogen-activated- protein-kinase, p38alpha, or silencing of the corresponding gene sensitizes APL and AML cell lines, as well as primary cultures of AML blasts to the anti-proliferative and cyto-differentiating activity of ATRA and synthetic retinoids. P38alpha inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARalpha, and the derived chimeric protein expressed in the majority of APL cases, PML-RARalpha. Inhibition is the consequence of ligand-independent binding of p38alpha which results in stabilization of RARalpha and PML-RARalpha via blockade of their constitutive degradation by the proteasome. Our data indicate that p38alpha inhibition causes a preferential increase in the relative amounts of RARalpha over those of PML-RARalpha. The inhibitory effect requires a catalytically active p38alpha and direct physical interaction with RARalpha and PML-RARalpha. Ser-369 in the E-region of RARalpha is essential for the binding of p38alpha and the ensuing functional effects on the activity of the receptor. In conclusion, our results add a further layer of complexity to the mechanisms controlling retinoid receptors’ activity and provide the rationale for the use of novel strategies in the treatment of AML patients with a cyto-differentiating approach.
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 1836. doi:1538-7445.AM2012-1836
Abstract 1844: CD43 normally expressed on the surface of leukocytes is expressed in the cytoplasm and nucleus of breast cancer and is a novel therapeutic target
Authors: Shelley Carl S. , Fu Qiangwei , Cash Steven E. , Andersen Jeremiah J. , Kennedy Colin R. , Dietrich Leah L. , Agger William A. 
Published: August 2012

Abstract
One in eight of the female population of the United States will be diagnosed with breast cancer in their lifetime. This statistic defines breast cancer as the most common cancer affecting American women. Advances in breast cancer treatment will be facilitated by the identification and targeting of the causative molecular defects. We have found that breast cancer is characterized by expression of CD43. This sialoglycoprotein is normally only produced by leukocytes. Strikingly, an N-terminal domain of CD43 that is extracellular in leukocytes is expressed predominantly in the cytoplasm of breast cancers. The C-terminal domain that is expressed in the nucleus of leukocytes only upon activation exhibits constitutive nuclear localization in breast cancer. Segregation of the N and C terminal domains of CD43 between different subcelluar compartments suggests that in breast cancer it is subjected to specific proteolytic cleavage events. The normal function of CD43 is to regulate leukocyte adhesion, apoptosis and migration. We reasoned that if these normal functions are extrapolated to breast cancer, then CD43 could contribute to disease progression and, therefore, represent a novel therapeutic target. We tested this hypothesis by using small-interfering RNA to target CD43 expressed by the breast cancer cell line MCF7. This targeting resulted in cancer cells exhibiting increased susceptibility to apoptosis and increased vulnerability to lysis by natural killer cells. In addition, targeting demonstrated that CD43 likely facilitates metastasis by inhibiting homotypic adhesion and driving transendothelial migration. Using an othrotopic mouse model, we demonstrate that CD43-targeting reduces the size of primary tumors by 76%. Taken together, our results indicate that expression of CD43 is a robust breast cancer biomarker and its targeting has the potential to be developed into a new breast cancer therapy.
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 1844. doi:1538-7445.AM2012-1844
Abstract 185: Alteration of microRNA expression profiles in HPV-associated squamous cell carcinoma of the head and neck (SCCHN)
Authors: Oh Ji-Eun , Kim Jeong-Oh , Shin Jung-Young , Zhang Xiang-Hua , Chun Sang-Hoon , Won Hye-Sung , Jung Chan-Kwon , Hong Sook-Hee , Lee Myoung-Ah , Kang Jin-Hyoung 
Published: August 2012

Abstract
Background High-risk type of human papillomavirus (HPV) has recently been found to be etiologically associated with 20 to 25% of SCCHN, particularly common in or pharyngeal tumors. We investigated the protein expression of PTEN/PI3K/AKT/mTOR signal pathway on HPV 16 +/− tonsillar squamous cell carcinomas. And, we analyzed microRNA expression profile in tongue cancer cell line transfected with HPV 16 E6/E7 oncogene. Method Tonsil cancer patients who had been treated at Seoul St. Mary's Hospital between 2000 and 2009 were reviewed. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded tumor tissues of 65 surgical specimens, and stained with antibodies against PTEN, PIK3CA, phosphorylated AktSer473, and phosphorylated mTORSer2448. High-risk HPV infection status was determined by in situ hybridization. The protein expression of EGFR, PIK3CA, pAkt, mTOR, and PTEN was assessed by immunohistochemistry. MicroRNA expression was studied using microarrays (PANArray™ miRNA expression profiling kit) in two tongue cancer cell lines (YD8 and YD10B) transfected with HPV 16 E6/E7 oncogene. Results Of the 65 pts, 26 (40%) pts were HPV positive. Overall survival and relapse-free survival were significantly different between two groups (P = 0.05 and P = 0.036, respectively). PTEN expression was significantly higher in HPV-positive- than in HPV-negative patients (P = 0.02). PIK3CA, phosphorylated AktSer473, and phosphorylated mTORSer2448 expression was negatively correlated with HPV status, yet not significantly. HPV status (P = 0.03) and nodal stage (P = 0.05) were found to significantly affect overall survival, as determined by multivariate analysis. The expression profile of miRNAs was different in HPV 16 E6/E7 transformed cells compared with vector alone cells. In the final round, 8 of 158 miRNAs were selected to be most differently expressed miRNAs; let-7b, miR-1, miR-107, miR-122, miR-127-5p, miR-95, miR-23b and miR-370 (&gt;1.2-fold). Conclusion We observed the higher expression of PTEN in HPV 16 positive tonsil tumor than HPV 16 negative tumor. Our data suggest that some microRNAs induced by E6/E7 oncogene might directly affect PTEN expression level independent of p53. We are underway on the experiments confirming that PTEN is regulated by which among these miRNAs.
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 185. doi:1538-7445.AM2012-185
Abstract 1854: Lysophosphatidic Acid Acyltransferase-Beta contributes to proliferation and anchorage-independent growth in pancreatic adenocarcinoma
Authors: Blaskovich Michelle , Gevariya Harsukh , Lawrence Nicholas J. , Sebti Saïd M. , Springett Gregory 
Published: August 2012

Abstract
Abstract: Lysophosphatidic acid acyltransferase-beta (LPAAT-α) catalyzes the production of phosphatidic acid (PA) from lysophosphatidic acid (LPA). PA is a lipid cofactor that contributes to the activation of c-Raf, BRAF, mTOR and PKC-α. LPAAT-α expression is a prognostic factor in gynecologic malignancies and is being investigated as a therapeutic target in a variety of tumor types. We previously reported that LPAAT-α is expressed in pancreatic cancer cell lines and in human pancreatic adenocarcinoma tissues. We employed siRNA knockdown of LPAAT-α expression in pancreatic cancer cells in vitro. We find that reduction in the expression of LPAAT-α protein is associated with decreased proliferation and impairment in anchorage dependent growth of pancreatic cancer cells. Methods: MiaPaCa and Panc-1 cells were transfected with two different siRNAs targeted to LPAAT-α at 10 nM and 25 nM for 48 hrs and 72 hrs. A non-targeting siRNA was used as a control. The cells were then plated on tissue culture dishes or in soft agar and allowed to proliferate. Proliferation on plastic dishes was measured using Alamar Blue. Colony formation in soft agar was determined by directly counting macroscopic colonies. Results: Transfection of MiaPaCa and Panc-1 cells with siRNA at 25 nM for 72 hours achieved almost 100% inhibition of LPAAT-α protein expression by Western blotting. Under these conditions there was a 50% reduction in proliferation and colony formation. Studies to determine the effects of depleting LPAAT-α on the levels of p-PKC-α, p-MEK, p-4E-BP1 and p-S6Kinase are ongoing and will be presented. Conclusions: Suppression of expression of LPAAT-α protein in pancreatic cancer cell lines reduces proliferation and anchorage independent growth. This contributes to the validation of LPAAT-α as a therapeutic target in pancreatic cancer.
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 1854. doi:1538-7445.AM2012-1854
Abstract 1861: EPHB4 as a potential therapeutic target for esophageal cancer
Authors: Hasina Rifat , Mutreja Karun , Kawada Ichiro , Kanteti Rajani , Arif Qudsia , Liu Ren , Li Xiuqing , Zhou Yue , Hyjek Elizabeth , Lingen Mark W. , Mueller Jeffery , Waxman Irving , Villaflor Victoria , Ferguson Mark , Vokes Everett E. , Gill Parkash , Salgia Ravi 
Published: August 2012

Abstract
Despite substantial improvements in screening, diagnosis, and treatment of esophageal cancer, the prognosis of this disease remains bleak. Survival at 5 years for all esophageal cancer patients taken together, with amenable treatments and with or without surgery ranges from 5-20% (Cancer Facts and Figures. American Cancer Society 2011). Although a multidisciplinary approach to include surgery, radiation, and chemotherapy, alone or in combination, attempts to improve the survival of this aggressive disease, these statistics underscore the continued need for attention to this disease and for identification of new targets in its treatment. We have been studying the role of receptor tyrosine kinases (RTKs) in cancer, particularly the EphB4 receptor, which has become increasingly associated with the pathobiology of adult cancers over the past several years. It has been shown to be aberrantly expressed and/or to play an oncogenic role in cancers of the breast, bladder, ovary, uterus, colon, head and neck, and prostate through its effects on cellular motility, growth, and migration, as well as on tumors’ ability to induce neoangiogenesis. To date, its role and potential as a target for therapy in different cancers have not been thoroughly investigated and remain poorly understood. Targeted inactivation of EphB4 and its ligand Ephrin-B2 have demonstrated that both are essential for angiogenic remodeling and embryonic survival (Adams and Klein 2000; Kim, Hu et al. 2008). In this report, we determine that EphB4 is overexpressed, has increased gene copy number and is involved in enhanced motility and migration in esophageal cancer. Archival patient samples consisting of 93 squamous cell carcinoma, 100 adenocarcinoma and 25 adjacent normal control samples as well as four adenocarcinoma and nine squamous cell carcinoma cell lines were used for the studies. Extensive mouse modeling of esophageal cancer was also used. We have reported that there is consistently higher expression of EphB4 in both squamous and adenocarcinoma compared to adjacent normal tissue with a statistically significant correlation between EphB4 expression and higher grades of squamous cell carcinoma. In a chemically induced esophageal squamous cell carcinoma model in mice, EphB4 was found overexpressed compared to normal controls. This study identifies EphB4 to be an important pathway in esophageal neoplastic lesions. It would now be useful to bring this to clinical fruition.
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 1861. doi:1538-7445.AM2012-1861
Abstract 1866: Genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-small cell lung cancer
Authors: Han Ji-Youn , Shin Eun Soon , Ghang Ho Young , Lee Yeon-Su , Lee Jin Soo 
Published: August 2012

Abstract
Purpose: We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with severe diarrhea and neutropenia in patients treated with irinotecan for advanced non-small cell lung cancer (NSCLC). Patients and Methods: We performed a case-control GWAS using the Affymetrix 5.0 array set in 103 patients enrolled in two phase II studies of with irinotecan and cisplatin. A subsequent replication study was conducted to validate major GWAS findings in an independent series of 146 patients enrolled in another phase II study of irinotecan-based chemotherapy. Cases were defined as patients with grade 3 diarrhea (G3D) or grade 4 neutropenia (G4N) according to the National Cancer institute's Common Terminology Criteria for adverse events v3.0. Results: The GWAS included 11 G3D (control 90) and 24 G4N (control 77). The replication set included 13 G3D (control 133) and 21 G4N (control 125). GWAS identified 49 and 32 SNPs putatively associated with G3D and G4N, respectively. In the replication series, SNPs, rs1517114 (C8orf34), rs1661167 (FLJ41856), and rs2745761 (PLCB1) were confirmed for G3D, and rs11128347 (PDZRN3), rs11979430 and rs7779029 (SEMAC3) were confirmed for G4N. Conclusion: This GWAS screen along with subsequent validation indentified novels SNPs associated with irinotecan-related severe toxicities.
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 1866. doi:1538-7445.AM2012-1866
Abstract 1879: The exomes of the NCI60 and their implications for cancer pharmacogenomics
Authors: Abaan Ogan D. , Davis Sean R. , Bilke Sven , Polley Eric C. , Walker Robert L. , Pineda Marbin , Zhu Yuelin J. , Reinhold William , Holbeck Susan L. , Simon Richard M. , Doroshow James H. , Pommier Yves , Meltzer Paul S. 
Published: August 2012

Abstract
Acquired and constitutional genetic variations in cancers have a substantial influence on response to therapy. The NCI60 panel of cell lines provides a unique opportunity to investigate this problem. These 60 human tumor cell lines represent 9 cancer types, and are richly characterized as the result of many previous studies which have collected various biochemical and genomics data [1]. In addition, there exists a comprehensive dataset of sensitivity and resistance profiles of over 100,000 compounds with potential antineoplastic activity. However, characterization of coding region DNA sequence variants has been lacking. In this study, we sequenced the whole exomes of the NCI60 cell lines and identified single nucleotide variants and short insertions/deletions. Variants found by sequencing were in excellent agreement with variants previously identified by SNP analysis or targeted capillary sequencing. Even though most cell lines displayed similar mutation counts, cell lines with microsatellite instability displayed a hypermutator phenotype. In addition, observation from ti/tv ratio and nature of base changes revealed preservation of possible carcinogen specific DNA mutation signatures. Deleterious variants were identified at higher frequency in known cancer genes while TP53 mutations where the most frequent event among the NCI60. Finally, notable instances of correlation between gene/pathway mutations with sensitivity to certain drug/compounds was identified. For example, sensitivity to vemurafenib was highly correlated with BRAF mutation. This comprehensive dataset enhances the value of cell lines widely used as disease models in many laboratories by adding depth to the existing genomic data. Our analysis identifies a large number of genomic variants correlated with drug responsiveness, including a number of genes known to be targeted by specific agents as well as numerous candidates for future investigation. 1. Shankavaram, U.T., et al., CellMiner: a relational database and query tool for the NCI-60 cancer cell lines. BMC Genomics, 2009. 10: p. 277.
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 1879. doi:1538-7445.AM2012-1879
Abstract 1892: Identification of differentially methylated genes associated with cetuximab and erlotinib resistance
Authors: Ogawa Takenori , Chang Xiaofei , Koch Wayne , Sidransky David 
Published: August 2012

Abstract
Anti-EGFR therapy is among the most promising molecular targeted therapies against cancer developed in the past decade. Two classes of EGFR-directed therapeutic inhibitors are currently in clinical use: anti-EGFR monoclonal antibodies, such as cetuximab, and small-molecule tyrosine kinase inhibitors (TKIs) of EGFR, such as erlotinib. Although both classes of drugs are capable of inducing an initial therapeutic response, primary as well as acquired drug resistance is frequently observed. Emerging evidence has linked epigenetic changes, such as DNA methylation at CpG islands, to the development of cytotoxic chemotherapeutic drug resistance. To identify genes that are specifically methylated during the evolution of resistance to anti-EGFR therapeutic agents, we employed two parental NSCLC and HNSCC cell lines and their resistant derivatives to either erlotinib or cetuximab. DNA from each pair was used for methylation-specific array containing a panel of 64 genes that are commonly known to be regulated through promoter methylation. We found that death-associated protein kinase 1 (DAPK1) was hypermethylated in drug resistant cells generated from both parental cell lines. Restoration of DAPK1 into the resistant cells by stable transfection re-sensitized the cells to both erlotinib and cetuximab. Conversely, siRNA-mediated knockdown of DAPK1 induced resistance in the parental sensitive cells. These results demonstrate that DAPK1 plays an important role in both cetuximab and erlotinib resistance in NSCLC and HNSCC cancer cells, and that promoter methylation of its gene frequently occurs during the chronic treatment of anti-EGFR agents. In conclusion, DAPK1 could be a novel target for the improvement of therapeutic benefit of anti-EGFR therapy.
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 1892. doi:1538-7445.AM2012-1892