bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4575: Structure-based design, synthesis and biological testing of highly potent semi-synthetic epipodophyllotoxin-derived hybrid etoposide analogs
Authors: Hasinoff Brian B. 
Published: May 2015

Abstract
Drugs that target DNA topoisomerase II and interact with DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Using a structure-based design approach a series of epipodophyllotoxin-derived hybrid etoposide analogs were designed, synthesized and biologically characterized. It was hypothesized that combining an epipodophyllotoxin moiety that could interact with specific protein residues on topoisomerase II and DNA-interacting moieties in the same molecule would produce much stronger binding and yield more potent and wide spectrum cytotoxic anticancer drugs. Because the hybrids have unique dual targeting mechanisms, cancer cells should be much less able to develop resistance. The most potent hybrid had a mean GI50 in the NCI-60 cell screen much lower than etoposide. The compounds were much less cross-resistant to a K562-derived etoposide-resistant cell line. All of the hybrids tested targeted topoisomerase II as evidenced by their ability to inhibit kDNA decatenation, to produce linear DNA in a DNA cleavage assay and to form covalent topoisomerase II-DNA covalent complexes in a cellular ICE assay. The DNA double strand breaks the hybrids produced in a cellular γH2AX assay and the G2/M cell cycle blocks were also characteristic of topoisomerase II-targeted drugs. Cell cycle analysis was also used to characterize the targets. A COMPARE analysis indicated that the hybrids had NCI 60-cell growth inhibition profiles of both etoposide and the DNA-interacting moieties from which they were derived. This data supports the conclusion that the hybrids displayed characteristics that were consistent with having targeted both topoisomerase II and DNA. Support: CIHR and a Canada Research Chair in Drug Development.
Citation Format: Brian B. Hasinoff. Structure-based design, synthesis and biological testing of highly potent semi-synthetic epipodophyllotoxin-derived hybrid etoposide analogs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4575. doi:10.1158/1538-7445.AM2014-4575
Abstract 4597: Characterization and targeting of radiation-inducible neoantigens in multiple cancer types
Authors: Muhoro Lincoln , Yan Heping , Hunn Jeremy , Thotala Dinesh , Ferraro Daniel , Hallahan Dennis 
Published: May 2015

Abstract
Targeted therapy remains one of the biggest challenges in the effective treatment of cancer. Due to their heterogeneity, not all tumors respond to a particular treatment regimen with similar efficacy. Thus, there is an urgent need to develop targeted therapies that are not only highly specific to cancer subtypes but also have minimal toxicity towards normal tissue. Currently, development of anti-cancer antibodies is limited to antigens that are either overexpressed or antigens that are only expressed in a few patients. This limits both the number of available targets and their selectivity for tumors. Using phage display technology, we have identified proteins that are induced by clinical doses of ionizing radiation (IR): tax-interacting protein 1 (TIP-1) and TATA box-associated factor 15 (TAF-15). Following IR treatment, cell surface expression of both TIP-1 and TAF-15 is enhanced in a number of human cancers, including brain, lung, breast and pancreatic cancer. The underlying premise is that IR induces a stress response resulting from DNA strand breaks and activation of ATM repair pathways. After IR stress, these antigens translocate to the surface where they can be targeted for therapeutic purposes. These radiation-inducible neoantigens present a new synergistic model for the treatment of cancer using IR. In this study, we characterized both radiation-inducible targets in vitro and in vivo. Western blotting, immunohistochemistry and flow cytometry data all demonstrated increased cell surface expression of both TIP-1 and TAF-15 after irradiation. We also developed a monoclonal antibody and a single chain antibody against TIP-1 and are currently in the process of developing antibodies against TAF-15. ELISA and near infra-red whole mouse imaging results demonstrate high affinity and high specificity of our lead anti-TIP-1 antibody and anti-TAF15 peptide in lung, brain, breast and pancreatic cancer. Dosimetry studies using immunofluorescence and Western blot analysis show a dose-dependent increase in expression of TIP-1 and TAF15, suggesting that these proteins may play a key role in the cancer cell's response to radiation stress. We are currently in the process of characterizing the mechanisms of how these proteins contribute to radioresistance and cancer survival processes such as proliferation, apoptosis and metastasis.
Citation Format: Lincoln Muhoro, Heping Yan, Jeremy Hunn, Dinesh Thotala, Daniel Ferraro, Dennis Hallahan. Characterization and targeting of radiation-inducible neoantigens in multiple cancer types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4597. doi:10.1158/1538-7445.AM2014-4597
Abstract 4598: GP130 as a novel therapeutic target in il-6-dependent cancers
Authors: Xiao Hui , Bian Yang , Zhao Chengguang , Lin Li , Jou David , Li Huameng , Li Chenglong , Lin Jiayuh 
Published: May 2015

Abstract
The IL-6/GP130 signaling pathway is critical for the survival and progression of cancer cells of multiple cancer types. We report here the new discovery of Raloxifene (Marketed as Evista by Eli Lilly and Company) and Bazedoxifene [Marketed as Duavee (conjugated estrogens / bazedoxifene) by Pfizer] as novel inhibitors of IL-6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into binding hot spots of GP130 D1 domain by multiple ligand simultaneous docking to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compounds. Similarity searches of virtual hits on drug databases identified Raloxifene and Bazedoxifene as potential inhibitors of IL-6/GP130 interaction. Both Raloxifene and Bazedoxifene are known as selective estrogen receptor modulators and we identified their novel function as GP130 inhibitors. Raloxifene and Bazedoxifene inhibited IL-6 mediated induction of STAT3 phosphorylation in cancer cells, which confirm their ability to inhibit IL-6/GP130 signaling. In contrast, Raloxifene and Bazedoxifene did not inhibit the induction of STAT1 phosphorylation by IFN-γ in cancer cells indicating their selectivity. Raloxifene and Bazedoxifene also inhibited STAT3 phosphorylation and resulted in apoptosis in cancer cells expressing elevated IL-6 levels. In addition, addition of excess IL-6 reversed the expression level of STAT3 phosphorylation which was decreased by Raloxifene or Bazedoxifene supporting that both FDA-approved drugs act through IL-6/GP130 signaling. Compared with an original GP130 inhibitor MDL-A whose IC50 values were 108-216 µM in cancer cell lines, Raloxifene and Bazedoxifene were found more potent in inhibiting cell viability which the IC50 values for Raloxifene and Bazedoxifene were 6.9-8.9 µM and 3.4-4.4 µM respectively in the same cancer cell lines expressing elevated IL-6 levels. Furthermore, both Raloxifene and Bazedoxifene significantly suppressed the tumor growth of human RH30 sarcoma cells in mouse xenograft model in vivo. These findings suggest that FDA-approved drugs Raloxifene and Bazedoxifene may serve as novel GP130-targeting therapeutic drugs in IL-6 dependent cancers.
Citation Format: Hui Xiao, Yang Bian, Chengguang Zhao, Li Lin, David Jou, Huameng Li, Chenglong Li, Jiayuh Lin. GP130 as a novel therapeutic target in il-6-dependent cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4598. doi:10.1158/1538-7445.AM2014-4598
Abstract 4607: Stathmin is involved in the maternal embryonic leucine zipper kinase pathway and impacts in the outcome of glioblastoma
Authors: Uno Miyuki , Oba-Shinjo Sueli Mieko , Silva Roseli , Gimenez Marcela , Rosa Jose Cesar , Marie Suely Kazue Nagahashi 
Published: May 2015

Abstract
INTRODUCTION: Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine kinase involved in several cell processes, including the cell cycle, differentiation, proliferation, and apoptosis. MELK has also shown multiple features consistent with the potential utility as an anticancer target, including in astrocytomas. However, the detailed downstream signaling pathway of MELK in cancer cells is still not fully understood and the putative role of MELK in astrocytomas remains unclear. The discovery of proteins involved in the MELK pathway might be important to develop additional small molecular compound to improve effectiveness. PURPOSE: This study aim to analyze proteins and/or genes involved in the MELK pathway in the tumorigenesis of gliomas. MATERIAL AND METHODS: Analysis of the expression profile of a panel of protein relevant to the process of tumorigenesis that MELK is involved was performed by Proteomic analysis by two dimensional electrophoresis and mass spectrometry for human glioma cell line U87MG transfected with siRNA for the MELK compared to U87MG transfected with non-target control (NTC) cells. Analysis and validation of gene expression was performed by Quantitative real time PCR (qRT-PCR) using SYBR Green method in a series of 153 astrocytomas of different malignant grade (23 AGI, 26 AGII, 18 AGIII and 86 AGIV or glioblastoma - GBM) and 22 non neoplastic (NN) brain samples. RESULTS: We identified Stathmin/oncoprotein 18 (STMN1) involved in the cell cycle, as one of twelve proteins differentially expressed, with lower expression when MELK was silenced. A significant higher expression of STMN1 in malignant diffusely infiltrative astrocytomas when compared to non-invasive pilocytic astrocytoma was found (p&lt;0.0001). Strong correlation for MELK and STMN1 associated expression was observed (r=0.741, p&lt;0.0001) in GBM. STMN1 hyperexpression alone impacted at GBM outcome with an overall survival of 5.4 months in contrast to 13.4 months when both genes were hypoexpressed (log rank=0.002). CONCLUSIONS: Thus, our results showed that STMN1 is downstream in the MELK pathway and might play an important role in astrocytoma tumorigenesis.
Citation Format: Miyuki Uno, Sueli Mieko Oba-Shinjo, Roseli Silva, Marcela Gimenez, Jose Cesar Rosa, Suely Kazue Nagahashi Marie. Stathmin is involved in the maternal embryonic leucine zipper kinase pathway and impacts in the outcome of glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4607. doi:10.1158/1538-7445.AM2014-4607
Abstract 461: Modulation of estrogen receptor (ER) and androgen receptor (AR) by a modified CRISPR-Cas9 system
Authors: Zhou Nanjiang , Mo Yin-Yuan 
Published: May 2015

Abstract
Clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated (Cas) system is a bacterial adaptive immune defense against foreign nucleic acids from viruses, plasmids, and other mobile genetic elements. There are three types of CRISPR systems; type II uses single effector enzyme, Cas9, to cleave double-stranded DNA (dsDNA). Because of this unique feature, CRISPR/Cas9 system has been widely used as a genetic engineering tool from bacteria to mammals. In this system, Cas9 nuclease can bind and cleave genome directed by sequence-specific guide RNA (gRNA). While the wild type Cas9 can cleave double stranded DNA, the mutant Cas9 at D10A and H804A can only bind to but cannot cleave the DNA. Given this unique feature, we tried to repurpose Cas9 as a gene activation or suppression tool. To achieve this, we generated DMCas9 (double-mutant Cas9), and fused it with VP16AD (VP16 activation domain) or VP64AD (VP64 activation domain) to explore its utility for gene activation. To generate a Cas9-based gene silencing tool, we fused DMCas9 with Krab, a well-known protein domain with suppression function. Using a reporter system carrying a specific sequence that was recognized by a given gRNA and mCherry as a readout, we demonstrated that co-expression of VP16AD-DMCas9 and specific gRNAs leads to a at least three-fold induction of mCherry signal; in contrast, DMhCas9-Krab along with the specific gRNA resulted in a significant suppression of mCherry activity. Furthermore, we showed that DMCas9-Krab combined with gRNAs suppressed endogenous expression of AR and ER in MCF-7 cells, causing cell growth inhibition. Together, these results demonstrate the feasibility of Cas9-based gene activation and gene suppression.
Citation Format: Nanjiang Zhou, Yin-Yuan Mo. Modulation of estrogen receptor (ER) and androgen receptor (AR) by a modified CRISPR-Cas9 system. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 461. doi:10.1158/1538-7445.AM2014-461
Abstract 4614: Identification of two salinomycin binding targets in neuroblastoma
Authors: Zhou Shuang , Wang Fengfei , Xiang Shi-Hua , Wong Eric T. , Muhonen Wallace W. , Fonkem Ekokobe , Hsieh Tze-chen , Li David W. , Zhang Ruiwen , Shabb John B. , Wu Joseph M. , Wu Min , Wu Erxi 
Published: May 2015

Abstract
Salinomycin, a widely used anti-coccidial agent isolated from a Streptomyces albus strain, was recently identified from a library of 16,000 natural and commercial chemical compounds based on its highly selective inhibitory effect on breast cancer stem cells (CSCs), with more than 100-fold greater potency than paclitaxel. Salinomycin also exhibits cytotoxic effects on other types of cancer cells and CSCs and overcomes drug resistance. However, the exact mechanism of salinomycin, especially its direct binding target(s), and its effects on neuroblastoma (NB) are yet not known.
NB is one of the most common solid tumors in children and infants, and a leading cause of mortality in children. Despite advances in diagnosis and treatment, currently, 35% of patients with NB remain incurable. In addition, the majority survivors of NB suffer from long-term side effects of current therapies and are at risk for disease relapse or getting a second, different cancer. More effective therapies are pressingly needed. Since the existence of CSCs in human NB cell lines and NB tumors from patients has been well documented, and has been closely associated with chemoresistance or tumor relapse, therapeutic targeting of NB CSCs may be a critical novel approach to conquer the challenges in NB therapy.
Aiming to improve NB therapy, we examined the efficacy and mechanism of salinomycin in human NB cells. Our study showed that salinomycin markedly inhibits NB cell proliferation and tumorsphere formation. Treatment of salinomycin induced G2 cell cycle arrest with an up-regulation of Cyclin A and a down-regulation of p21 protein levels. We further identified TIF1β and NCL as novel direct binding proteins of salinomycin by using comprehensive methods, including chemical proteomics and functional genomics. Furthermore, by analyzing tumor samples from a cohort of 88 NB patients, we found that the elevated level of these proteins is associated with poor prognosis for NB patients. Thus, our results indicate salinomycin is a potential new therapeutic agent and TIF1β and NCL as new therapeutic targets/biomakers for NB therapy.
Citation Format: Shuang Zhou, Fengfei Wang, Shi-Hua Xiang, Eric T. Wong, Wallace W. Muhonen, Ekokobe Fonkem, Tze-chen Hsieh, David W. Li, Ruiwen Zhang, John B. Shabb, Joseph M. Wu, Min Wu, Erxi Wu. Identification of two salinomycin binding targets in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4614. doi:10.1158/1538-7445.AM2014-4614
Abstract 4618: Therapeutic targeting for sphingosine kinase 1 in epithelial ovarian cancer
Authors: Lee Jeong-Won , Ryu Ji Yoon , Jeon Hye-Kyung , Park Young-Ae , Cho Young-Jae , Choi Jung-Joo , Lee Yoo-Young , Kim Tae-Joong , Choi Chel Hun , Kim Byoung-Gie , Bae Duk-Soo 
Published: May 2015

Abstract
Purpose: Sphingosine kinase 1 (SK1) is over-expressed in various human cancers with pro-growth effects and its inhibitors has been suggested potential anti-cancer agents. This study was designed to investigate the therapeutic potential of SK1 inhibitor in epithelial ovarian carcinoma (EOC).
Experimental design: The expression of SK1 protein was evaluated using immunohistochemistry in patients with EOC. EOC cell lines (A2780, SKOV3ip1, A2780-CP20, SKOV3-TR, ES2 and RMG2) were used in this study to test SK1 siRNA or inhibitors. We used two kinds of SK inhibitor including SK inhibitor (for both SK1 and 2) and FTY720 (specifically inhibiting SK1) to check cell proliferation, apoptosis, angiogenesis and invasion using MTT, FACS, ELISA and wound-healing assay, respectively. Furthermore, in vivo experiments were performed to test the FTY720 on tumor growth in orthotopic EOC mouse model.
Results: The expression of SK1 protein in primary EOC tissues was strongly observed in all of patients; however, there was no expression of SK1 protein in the normal ovarian epithelium (n=5). Blocking SK1 by its siRNA or inhibitors significantly affected cell proliferation, apoptosis, angiogenesis and invasion in A2780-PAR and
SKOV3ip1 cells. SK1 inhibitors led to decrease of SK enzymatic activity in cells. Furthermore, utilizing the in vivo animal model (A2780-PAR), FTY720 treatment significantly decreased the total tumor weight compared with control (P &lt; 0.05).
Conclusions: These results show that therapeutic targeting of SK1 with its inhibitor could have potentials of novel therapeutics for EOC.
Citation Format: Jeong-Won Lee, Ji Yoon Ryu, Hye-Kyung Jeon, Young-Ae Park, Young-Jae Cho, Jung-Joo Choi, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Byoung-Gie Kim, Duk-Soo Bae. Therapeutic targeting for sphingosine kinase 1 in epithelial ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4618. doi:10.1158/1538-7445.AM2014-4618
Abstract 462: Chromatin signatures of DLBCL subtypes
Authors: McCord Ron , Field Megan , Jordan Philip , Hunter Ewan , Akoulitchev Alexandre , Mundt Kirsten E. 
Published: May 2015

Abstract
Diffuse Large B-cell Lymphoma (DLBCL) is a common and aggressive type of Non-Hodgkin's Lymphoma. Gene expression profiling long ago identified two distinct subtypes: Activated B-Cell (ABC) and Germinal Center B-Cell (GCB), reflecting the biology associated with the cell of origin of the lymphoma (Alizadeh et al, Nature 2000).
These subtypes are histologically non distinguishable, yet are associated with distinct outcomes. Emerging clinical data also suggests that they are predictive of outcome for novel therapeutics, including a BTK inhibitor, a proteasome inhibitor and an immune modulatory agent. Reliable diagnosis of the DLBLC subtype may therefore become a requirement for choosing the best treatment for DLBCL patients.
Since gene regulation is known to be associated with changes in chromatin structures, we decided to investigate the chromatin conformation around key regulators of ABC/ GCB biology using a Chromatin Conformation Capture Assay (3C). For this assay, chromatin loops are cross-linked; the DNA is digested and re-ligated, joining topologically proximal ends that may be very distant along the length of the chromosome into distinct novel fusion products. After reversing the cross-links, the presence of these novel DNA fusions can be detected by PCR, resulting in a binary read-out. Composites of these PCR products form a signature that may be characteristic of disease, disease state or subtype. The EpiSwitchTM technology has been optimized to identify these epigenetic patterns not only in tissue, but also from blood borne tumor DNA.
To investigate characteristic changes in chromatin conformation in ABC- and GCB- DLBCL cell lines, we focused on key genes known to be differentially expressed in the two sub-types, including Bcl-6, IRF-4 and LMO-2 (Wright et al. PNAS 2003,). We mapped several interactions indicating that these loci are subject to epigenetic regulation. We also applied the assay to blood from DLBCL patients and from healthy volunteers to exclude background signals from normal B-cell maturation. The assay was able to detect the same signatures as seen in cell lines.
These results demonstrate the potential of this technology to detect DLBCL subtype specific chromatin conformation associated biomarkers in patient blood.
Citation Format: Ron McCord, Megan Field, Philip Jordan, Ewan Hunter, Alexandre Akoulitchev, Kirsten E. Mundt. Chromatin signatures of DLBCL subtypes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 462. doi:10.1158/1538-7445.AM2014-462
Abstract 464: Methylase meets phosphatase: roles of PRMT and EYA1 in neuroblastoma
Authors: Li Xingguo , Wang Simeng , Schor Nina F. 
Published: May 2015

Abstract
High-risk neuroblastoma is a lethal childhood tumor characterized by increased oncoprotein MYCN expression. As strategies for modulation of MYCN function itself have proved challenging, targeting of MYCN's downstream effectors may provide an alternative option. Protein arginine methyltransferase 1 (PRMT1) has been reported as a MYCN target gene in neuroblastoma; high expression of PRMT1 is significantly associated with a poor prognosis. Importantly, PRMT1-deficient cells have been shown to be hypersensitive to chemotherapy-induced DNA damage, suggesting that targeting PRMT1 may overcome drug resistance for patients with advanced neuroblastoma. However, the underlying mechanisms of how PRMT1 contributes to chemoresistance and tumor progression are still largely unknown. We report here that PRMT1 forms a novel complex with EYA1, a phosphatase and transcriptional coactivator that may serve as the crucial determinant of survival versus apoptotic responses to DNA damage through dephosphorylation of histones. Interestingly, we found that EYA1 is highly expressed in advanced neuroblastoma and that PRMT1 physically associates with EYA1 through direct interaction. Further, rendering EYA1 refractory to methylation by PRMT1 abolishes its phosphatase activity. These findings suggest that PRMT1 methylase, EYA1 phosphatase, and PRMT1-EYA1 may be druggable targets for the therapy of neuroblastoma.
Citation Format: Xingguo Li, Simeng Wang, Nina F. Schor. Methylase meets phosphatase: roles of PRMT and EYA1 in neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 464. doi:10.1158/1538-7445.AM2014-464