bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-316: Pharmacokinetic modeling optimizes direct inhibition of the ‘undruggable’ target EWS-FLI1 of Ewing Sarcoma
Authors: Hong S. Peter , Gamble S. Ellen , Hong Sung-Hyeok , Kobs Christina L. , Elsass Karen E. , South Natalie L. , Monroe Philip J. , Üren Aykut , Toretsky Jeffrey A. 
Published: August 2012

Abstract
Chimeric transcription factors have long been considered ideal anti-cancer targets since they are only present in tumor cells, however, their lack of enzymatic activity has placed them in a category of ‘undruggable’ proteins. The EWS-FLI1 fusion protein of Ewing Sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified the small molecule YK-4-279 as a specific inhibitor of EWS-FLI1 by blocking the interaction with RHA. Blocking this interaction leads to apoptosis. Data suggests that relatively long exposures of drug are necessary to keep EWS-FLI1 and RHA apart. We have modeled YK-4-279 treatment using cell lines (TC71, TC32, A4573, SK-ES, and RD-ES) to establish the duration of YK-4-279 exposure that leads to apoptosis. Apoptosis was measured by caspase-3 cleavage. A validated plasma detection method allows for HPLC measurement of YK-4-279. Pharmacokinetic (PK) models of YK-4-279 for both intraperitoneal (IP) and intravenous (IV) administration were developed in SD rats and BL6 mice. ES cell lines were exposed to YK-4-279 over a time-course, followed by a caspase-3 activity assay that demonstrated a minimum of 16 hours exposure was necessary to achieve maximal apoptosis using either 3 or 10 microM compound. A dose-dependency assay demonstrated that while apoptosis could be achieved with 30 - 80 microM YK-4-279 after 4 hours of treatment, caspase-3 activity was less than or equal to 3 microM for 16 hours. Rat PK modeling demonstrated a t1/2 of 30 minutes following IV administration. BL6 mice demonstrated similar kinetics to the rat. SCID/bg mice, which are necessary for tumor efficacy studies, demonstrated approximately 50% faster clearance than either rat or BL6 mice. Absolute bioavailability for IP administration was 41%. Models that use cell culture based targets for plasma levels and duration of exposure will be created to optimize IP dosing regimen. The optimized IP dosage and dosing intervals will be evaluated in tumor bearing animals in order to advance development of YK-4-279. The results of these studies will be used to guide toxicology studies in animals. In addition, pharmacodynamics models are being developed to compare YK-4-279 levels with functional activity. The combined results of these investigations will lead to human clinical trials for this first-in-chemical class, first-in-mechanism drug candidate.
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 LB-316. doi:1538-7445.AM2012-LB-316
Abstract LB-353: Development of thymidylate synthase ternary complex-specific antibody: A new way to tailor 5-fluorouracil dosing
Authors: Patel Kalpesh , Yerram Sashidhar R. , Kern Scott E. 
Published: August 2012

Abstract
Introduction: 5-Fluorouracil (5FU) is a fluorinated nucleoside analogue used in cancer treatment. 5FU metabolites modify thymidylate synthase (TS) to form a ternary complex and inhibit its activity. Despite its benefits, major side effects are common and can lead to discontinuation of 5FU therapy. Although dose, schedule, and mode of application of 5FU can be adjusted to minimize toxicity, there has been a little done to tailor 5FU dosage for cancer therapy. Aims: To develop a ternary complex-specific monoclonal antibody. To develop a test quantifying drug-complexed TS level so as to measure the action of 5FU at the cellular level. Methods: Recombinant TS was produced in E. coli. In-vitro, the ternary complex was created. A specific rat monoclonal antibody was raised against drug-complexed TS. ELISA and immunoblot (IB) assays were validated using 5FU-treated cells. Tumors were developed in nude mice by injection of RKO and MiaPaCa2 cells. We treated tumors in mice with 5FU at different doses and assayed the tumor upon harvest. Results: The drug-complexed TS migrates slower than native TS in protein gels. Our novel ternary complex-specific rat monoclonal antibody (10C4) specifically recognized drug-complexed TS in ELISA and IB in both cultured cells and tumors treated with 5FU. Commercially available TS-specific antibody recognized both forms of TS. Conclusion: We developed and characterized the first thymidylate synthase ternary complex-specific rat monoclonal antibody. Implications: Quantification of drug-complexed TS may be possible with use of the new antibody. The actual action of 5FU at the cellular level can now be determined readily. It may become possible to calculate individualized 5FU doses in the clinic using advances in the technology. Such developments might decrease the incidence of toxicity and increase drug effectiveness during 5FU 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 LB-353. doi:1538-7445.AM2012-LB-353
Abstract LB-370: Genetically engineered oncolytic Edmonston strain of measles strain harboring the wild-type N, P, L genes (MV-NPL) effectively target lung cancer stem cells
Authors: Inoue Hiroyuki , Hijikata Yasuki , Yasunari Keisuke , Sakamoto Akira , Miyamoto Shohei , Nosaki Kaname , Matsumura Yumiko , Takayama Koichi , Nakanishi Yoichi , Tani Kenzaburo 
Published: August 2012

Abstract
Increasing evidence suggests that only a small percentage of cancer cells in solid tumors have tumorigenic potential. These highly tumorigenic cells share with normal stem cells the ability to proliferate and give rise to diversified tumor cell types including those with the capacity for self-renewal. These cells are termed cancer stem cells (CSCs) and are believed to contribute to CSCs resistance to conventional therapies. Therefore, specific targeting of CSCs is an attractive and novel therapeutic approach. Measles virus Edmonston strain (MV-Edm) is thought to possess remarkable oncolytic activity that selectively destroys human tumor cells. Recently, we succeeded and reported the development of novel oncolytic measles virus (MV) by genetic engineering of MV-Edmonston strain (MV-Edm), that have demonstrated its remarkable oncolytic activity against wide ranges of human tumor cells, with the N, P, and L genes of wild-type MV (MV-NPL). The oncolytic activities of the MV-NPL on human renal cell carcinoma were superior to those of MV-Edm both in vitro and in vivo studies even in the presence of IFN[[Unsupported Character - &#8208;]]α[[Unsupported Character - &#61472;]](Xing, M. et. al. Mol Ther 2010). Here, we demonstrated that lung CSCs, side population fraction of human lung cancer cells of A549 (A549-SP), expressed high level of CD46 required for MV-NPL infection and MV-NPL had a superior oncolytic capacity against both A549-SP and A549-NSP (non SP) cells in a time and dose-dependent manner without damaging normal lung cells. Our results of pan-caspase inhibiton assays showed the partial contribution of caspases-dependent apoptosis in the oncolysis of A549-SP cells by MV-NPL, even though the expression levels of anti-apoptotic protein of both XIAP and Mcl-1 were higher in A549-SP cells than A549-NSP cells. Additionally, we demonstrated that an addition of either PI3K inhibitor or MEK inhibitor further enhanced the oncolytic effects of MV-NPL. Furthermore, our in vivo studies using nude mice bearing A549 xenografts revealed that serial intratumoral MV-NPL administrations exhibited significant antitumor effects without severe side effects. Collectively, these data suggested that genetically engineered MV-NPL could be a promising oncolytic agent to effectively eradicate lung CSCs.
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 LB-370. doi:1538-7445.AM2012-LB-370
Abstract LB-373: Parp1 dependent regulation of chromatin remodeling by the ALC1 (Amplified in Liver Cancer) oncogene
Authors: Gottschalk Aaron J. , Trivedi Rushi D. , Conaway Joan W. , Conaway Ronald C. 
Published: August 2012

Abstract
The human ALC1 (Amplified in Liver Cancer 1) gene was originally identified as a gene present on a human chromosome 1q21 region amplified in a large fraction of hepatocellular carcinomas. Subsequent studies found that overexpression of the ALC1 protein was found to be oncogenic in human cells and mice, although the mechanism of action of ALC1 in oncogenesis is not known. The human ALC1 gene encodes a member of the SNF2 superfamily of ATPases. The ALC1 protein is unique among SNF2 family members because it includes a macrodomain that is capable of binding selectively to poly(ADP-ribose) (PAR). We and others have also previously demonstrated that ALC1 possesses DNA-dependent ATPase and ATP-dependent nucleosome remodeling activities that are strongly dependent on the presence of poly(ADP-ribose) polymerase PARP1 (or the closely related PARP2) and NAD+ within in vitro assays. Our preliminary investigation of the mechanism of PARP1- and NAD+-dependent activation of ALC1 DNA-dependent ATPase and nucleosome remodeling activities revealed (i) that both the ALC1 SNF2 ATPase domain and an intact macrodomain capable of binding PAR are essential for activation by PARP1 and NAD+, (ii) that activation of ALC1 in the presence of PARP1 and NAD+ results in increased affinity of ALC1 for DNA and nucleosomes, and (iii) that autoPARylated PARP1 is most likely the source of PAR required for activation of ALC1. These preliminary observations provided some insight into basic features of the function of the ALC1 protein, but they left unresolved major questions concerning the mechanism by which ALC1 is activated by PARP1 and NAD+ to remodel nucleosomes. In our recent studies, we extend our investigation of the mechanism by which ALC1 is “activated” to remodel nucleosomes by PARP1 and NAD+. Our findings argue that (i) ALC1 activation requires assembly of a stable ALC1.autoPARylated PARP1.nucleosome intermediate, (ii) that ALC1 regulates association of autoPARylated PARP1 with this intermediate, and (iii) stable binding of the ALC1 macrodomain to autoPARylated PARP1 is critical for ALC1 activation. Taken together, our findings are consistent with the model that a stable ALC1.autoPARylated PARP1 heterodimer is the active species in ALC1-dependent ATPase and nucleosome remodeling. These findings provide further important insight into the mechanism of action of this poorly understood oncogene.
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 LB-373. doi:1538-7445.AM2012-LB-373
Abstract LB-380: Distinct methylation pattern in early-onset colorectal cancer patients without detectable germline mutation
Authors: Chan Tsun-Leung , Li Carmen , Yuen Siu-Tsan , Chan Anthony KW , Tsui Wendy WY , Chan Annie SY , Leung Suet-Yi 
Published: August 2012

Abstract
Colorectal cancer (CRC) is currently the second most common cancer and mortality rate of all cancers in Hong Kong. We have previously reported a higher incidence of early-onset colorectal cancer patients compare with other ethnic groups, which may be caused by genetic or epigenetic predisposition in the Chinese population. Despite we confirmed Lynch Syndrome (LS) plays a significant role in it, pathogenic event of roughly 20% of young patients with MSI tumour cannot be identified. These patients are still susceptible to novel genetic or epigenetic predisposition of CRC. In this study, we compared the epigenetic signature of CRC patients below and above the age of 50 years old, who developed High level of microsatellite instability (MSI-H) and loss of MLH1 expression. The CpG island methylator phenotype (CIMP), regional methylation events, Braf and Kras mutation status have been examined. Among 12 cases of the early-onset patients, unexpectedly 5 of them showed constitutive MLH1 promoter hypermethylation versus 1 in 26 cases of the late-onset control patients by pyrosequencing (p-value &lt; 0.01). CIMP-High status, which has been frequently reported in late-onset patients, was found to be 25% and 77% in the early and late-onset groups respectively (p value &lt; 0.001). Strikingly, regional methylation coincides with the CIMP-High cases and MLH1 promoter methylation was the unique epimutation event in the chromosomal region encompass MLH1 in most of the early-onset patients. We are the first to demonstrate that CIMP status and MLH1 regional methylation are a distinct phenotype in the patient with early-onset CRC irrespective of the constitutive status of MLH1 promoter methylation event. Our data suggest that the tumorigenesis of early-onset CRC is significantly different from patients with late-onset CRC despite they are all classified as MSI-H and loss of expression of MLH1. Lastly, epigenetic signature of most of the early-onset CRC patients is indistinguishable from the patient with constitutive MLH1 promoter methylation. It is unclear epigenetic predisposition contribute to the high incidence of early-onset CRC. Further investigation for additional markers should be performed as routine Kras and Braf mutation status were uninformative.
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 LB-380. doi:1538-7445.AM2012-LB-380
Abstract LB-389: The function of histone demethylase RBP2 in breast cancer metastasis and drug resistance
Authors: Cao Jian , Liu Zongzhi , Zhao Minghui , Nguyen Don , Yan Qin 
Published: August 2012

Abstract
Metastasis and drug resistance are two major challenges in cancer therapies. The occurrence of these two events requires cancer cells to gain new mutations or change their expression profiling, or both, adapt to new environment (i.e. distal organs or drug treatments). These changes likely follow Darwin's evolutionary theory: heterogeneous of cancer cells are generated randomly and more aggressive cells are selected by the tissue environment. Stable inheritance of genome and epigenetic states could delay metastasis and drug resistance. Trimethylated lysine 4 in histone H3 (H3K4me3) is the epigenetic marker for transcriptionally active promoters and the binding site for transcriptional activators. Removing the methyl groups from trimethylated H3K4 on gene promoter regions is a common epigenetic strategy for gene silencing. The JARID1 family members are to date the only known proteins responsible for catalyzing demethylation of trimethylated H3K4. Therefore they are essential in cell differentiation and development. Even though JARID1A (RBP2) was implicated in tumorigenesis of certain cancer types, its exact roles are still poorly understood. I hypothesized that RBP2 contributes to changes of epigenetic states during the occurrence of metastasis and drug resistance. Consistent with my hypothesis, I found that RBP2 is highly expressed in metastatic breast cancer cells and Herceptin tolerant population. Loss of RBP2 decreased lung metastatic gene signature and increase drug sensitivity.
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 LB-389. doi:1538-7445.AM2012-LB-389
Abstract LB-4: Preclinical development of spherical nucleic acids, a novel RNAi-based nanomedicinal platform, as anti-glioma therapeutics
Authors: Stegh Alexander H. 
Published: August 2012

Abstract
Patients with Glioblastoma (GBM) survive for a mere 14-16 months. Conventional and targeted therapies, foremost inhibitors of receptor tyrosine kinases (RTK-Is) have been ineffective in glioma clinical trials, contributing to a near 100% failure rate of GBM drug development. Impediments to clinical successes are the lack of systematic identification of genes with critical roles in therapy (apoptosis) resistance, and the dearth of innovative technologies to deliver therapeutics to glioma elements, and to effectively target important apoptosis regulators in established gliomas. Here, we describe the development and pre-clinical characterization of a novel RNAi-based nanomedicinal platform (termed spherical nucleic acids, SNAs) to target aberrantly expressed oncogenes in GBM. SNAs consist of polyvalent gold nanoparticles with diameters of ∼13 nm, which are densely functionalized with RNAi molecules via oligoethylene glycol-thiol linkers. Our detailed physico-chemical and cell biological characterization revealed that SNAs exhibit highly efficient cellular uptake and robust serum stability without the use of auxiliary transfection strategies or chemical modifications, less induction of innate immune responses, reduced off-target effects, and minimal systemic toxicity in rodents. In proof-of-priciciple studies, we utilized SNAs to neutralize the expression of anti-apoptotic Bcl-2 proteins, i.e., canonical family members, such as Bcl-2, Bcl-xL, and the atypical member Bcl2L12. We show highly efficient uptake of SNAs into various primary and transformed glial cell lineages in vitro, including patient- and glioma mouse model-derived tumor neurospheres (TNS). Importantly, SNAs provoked robust and persistent knockdown of Bcl-2 family members on mRNA and protein levels, and robustly sensitized glioma cells toward therapy-induced apoptosis. Finally, Magnetic Resonance Imaging and Inductively Coupled Plasma Mass Spectrometry of SNAs co-functionalized with gadolinium revealed that intravenously administered SNAs penetrated the blood-brain- and blood-tumor-barriers, and robustly disseminated xenogeneic glioma explants. High-level accumulation of Bcl2L12-targeting SNAs within glioma elements was associated with increased intratumoral apoptosis, and consequently resulted in reduced glioma formation and prolonged survival of xenografted mice. Thus, silencing of anti-apoptotic signaling driven by members of the Bcl-2 family using nano-RNAi represents a novel therapeutic approach to overcome therapy resistance and to halt progression of GBM.
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 LB-4. doi:1538-7445.AM2012-LB-4
Abstract LB-400: The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients
Authors: Zhang Zemin 
Published: August 2012

Abstract
Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC). HBV integration into the host genome has been reported but its scale, impact and contribution to HCC development is not clear. Here, we sequenced the tumor and nontumor genomes (&gt;80X coverage) and transcriptomes of four HCC patients and identified 255 HBV integration sites. Increased sequencing to 240X coverage revealed a proportionally higher number of integration sites. Clonal expansion of HBV-integrated hepatocytes was found specifically in tumor samples. We observe a diverse collection of genomic perturbations near viral integration sites, including direct gene disruption, viral promoter-driven human transcription, viral-human transcript fusion and DNA copy number alteration. Thus, we report the most comprehensive characterization of HBV integration in hepatocellular carcinoma patients. Such widespread random viral integration will likely increase carcinogenic opportunities in HBV-infected individuals.
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 LB-400. doi:1538-7445.AM2012-LB-400
Abstract LB-402: New fusion genes in lung adenocarcinoma revealed from next generation RNA-seq
Authors: Ju Young Seok , Lee Won-Chul , Shin Jong-Yeon , Kim Jong-Il , Kang Jin-Hyoung , Kim Young Tae , Seo Jeong-Sun 
Published: August 2012

Abstract
Cancer is a genomic disease. A subset of somatic driver mutations has been reported in lung adenocarcinoma in the past few years, such as somatic mutations in EGFR, KRAS and EML4-ALK fusion gene. Identification of driver mutations in lung cancer is very important, since several anti-cancer drugs targeting them (gefitinib, erlotinib, and crizotinib) have shown dramatic clinical outcomes for the treatment of lung adenocarcinomas. However, a large proportion of lung cancer patients have been observed to have none of them in their cancer genome. More than 40% of lung adenocarcinoma patients appear to be driven by unknown genetic events. Gene fusions represent a subset of genetic alteration in human cancer. We recently identified a fusion gene joining KIF5B and RET transforming tyrosine kinase in tumor tissues of lung adenocarcinoma patients as a driver mutation using integration of whole-genome and transcriptome sequencing of cancer tissue [1]. We expanded our study by sequencing more transcriptomes of lung adenocarcinomas with paired normal tissues. Overall, we obtained transcriptome sequences from 88 primary lung adenocarcinomas, 53.5% (n=47) of them were negative for EGFR, KRAS and EML4-ALK. Our approach identified many novel fusion events in lung adenocarcinoma, such as CD74-ROS1, SLC34A2-ROS1, and additional fusions of cancer related genes. Majority of these fusion genes and known somatic mutations were mutually exclusive (p=0.001), suggesting these fusion genes are highly likely to be the driver mutations of lung adenocarcinoma. Overall, fusion genes account for ∼15% of genetic causes of lung adenocarcinoma according to our dataset. We will discuss those fusion genes and frequent somatic mutations of lung adenocarcinoma revealed from transcriptome sequencing of 88 lung adenocarcinomas. REFERENCE 1. Fusion of KIF5B and RET transforming gene in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Research (2012), Advance online publication Dec 22 2011.
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 LB-402. doi:1538-7445.AM2012-LB-402