bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1562: Choosing the right preclinical model for cancer immunotherapy: The “SyngenOmic” toolbox..
Authors: Harper James A. , Prime John , Herath Athula , Howell Jane , Papaspyridonos Marianna , Popple Amy , Anderton Judith , Morrow Michelle , Lewis Arthur , Henley Liz , McCourt Matthew , Sainson Richard 
Published: August 2014

Abstract
Recent FDA approvals of ipilimumab and sipuleucel-T for the treatment of metastatic melanoma and castrate-resistant prostate cancer respectively have validated the approach to modulate the immune system for the clinical treatment of cancer. MedImmune Oncology, has an extensive pipeline and expertise in investigational Immune Mediated Therapy in Cancer (IMT-C) drugs (e.g. tremelimumab and MEDI4736), and is heavily invested in this novel era of cancer therapeutics. Pre-clinical assessment of the validity of potential IMT-C drugs can be enabled by the use of syngeneic tumours established in immuno-competent animals. MedImmune's pharmacology team has lead efforts to develop such models, to a point that a panel of 15 different validated syngeneic tumour types is available in house for studies to progress projects. The intention of selecting relevant models and of minimizing animal experimentation, reduces the number of models tested for each project, and allows for detailed genetic and proteomic characterization of treatment dependent effects within our models. Utilising both in vitro and in vivo approaches, we have generated transcriptomic and genomic data for our cell lines, the resulting implanted tumours and for the relevant lymphatic organs (draining lymph node and spleen). Using key proteomic/cell markers through IHC and FACS analysis, we are also evaluating the immune profile/status of our tumour bearing animals in parallel. Finally, in order to establish the disease relevance and prognostic value of our models we are analyzing our cell panel for the presence of somatic mutations in 50 genes previously implicated in human cancers. Once completed, the resulting dataset will hopefully help pre-clinical scientists to refine their in vivo plans and deliver more clinically-relevant pharmacology packages for the progression of cancer immunotherapy drug candidates.
Citation Format: James A. Harper, John Prime, Athula Herath, Jane Howell, Marianna Papaspyridonos, Amy Popple, Judith Anderton, Michelle Morrow, Arthur Lewis, Liz Henley, Matthew McCourt, Richard Sainson. Choosing the right preclinical model for cancer immunotherapy: The “SyngenOmic” toolbox. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2013-1562
Abstract 1565: Significance of elemental content and distribution profiles in assessing established cell lines as surrogates for cancer tissues from two different organs.
Authors: Farah Ibrahim O. , Arslan Zikri , Ayensu Wellington K. 
Published: August 2014

Abstract
Studies have shown that defective metal homeostasis is very essential to the development of the cancer phenotype in many cancers including lung and liver carcinomas. Low Zn levels as well as overexpression of metalothioneins were implicated in the development and progression of various cancers. Wider elemental profiles that relate cancer and normal phenotypes with regards to metal homeostasis were not well elucidated in the literature. To this end, established cell lines are currently used as accepted models for studying cancer but the level of their representation of actual cancer tissues was not clear. This study is attempting to assess the relevance of cell lines currently is use as surrogates for cancer and establish their relationship to actual normal and cancer tissues from humans. We hypothesize that elemental content and distribution profiles in cancer and normal tissue are significantly different from those possessed by established cell lines. We used Inductivity Coupled Plasma (ICP-Mass Spectroscopy) for lung and liver samples obtained from normal and cancer human cadaver tissues (US Biomax) and cell models of lung and liver carcinomas; the A549 and HepG2 cell lines (ATCC), to analyze for elements and test the hypothesis. Samples prepared using standardized digestion procedures were loaded onto the ICP-MS equipment to test for a profile consisting of 12 elements, namely, Zn, Cu, Fe, Mg, Mn, Ca, Al, Co, Ba, Cr, Ni and Se. Analysis of data showed significant variations in elemental content and distribution profiles between the cell models and actual tissues consistent with the hypothesis. It is concluded that elemental homeostasis is essential for normal tissue function and that shifts in their distribution and content are essential in determining the use of cell models as surrogates for studying cancer. These results are promising and warrant further studies to confirm the relevance of cell line models in relation to their use as screening tools for examining targeted cancer therapeutics.
Citation Format: Ibrahim O. Farah, Zikri Arslan, Wellington K. Ayensu. Significance of elemental content and distribution profiles in assessing established cell lines as surrogates for cancer tissues from two different organs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1565. doi:10.1158/1538-7445.AM2013-1565
Abstract 1570: Novel strategy for eradicating lymph node metastasis of early-stage colorectal cancers using telomerase-dependent replicating adenoviral agent.
Authors: Kikuchi Satoru , Kishimoto Hiroyuki , Tazawa Hiroshi , Hashimoto Yuuri , Uno Futoshi , Nishizaki Masahiko , Kagawa Shunsuke , Urata Yasuo , Hoffman Robert M. , Fujiwara Toshiyoshi 
Published: August 2014

Abstract
One of the biggest challenges in endoscopic therapeutic approach for early colorectal cancer with submucosal invasion is how to treat regional lymph nodes (LNs) possibly metastasized. The rate of LN metastasis in submucosal invasive colorectal cancer are estimated approximately 10%. Since endoscopic treatment can't clean LNs outside the bowel physically, open or laparoscopic surgical treatment is still gold standard for submucosal invasive colorectal cancer. We previously reported that in an orthotopic rectal tumor mouse model, a telomerase-dependent tumor killing adenoviral agent (OBP-301) spreads to the regional LNs, selectively replicates in cancer cells in metastasized LNs, and inhibits LN metastasis, when administered into the primary advanced rectal tumor. In this study we evaluated the effectiveness of novel less invasive treatment against submucosal invasive colorectal cancer, using local tumor resection such as endoscopic submucosal dissection (ESD) and OBP-301. HCT-116-GFP human colon cancer cells were orthotopically implanted into the submucosal layer of nude mouse rectum with resultant submucosal invasive early rectal tumor. LN metastasis was observed in 78.5% of mice as early as 7 days after cancer cell inoculation, and the rectal tumor of mice with LN metastasis got locally excised with prior peritumoral injection of OBP-301 solution, mimicking ESD technique. Seven days after tumor resection, treatment of OBP-301 showed a significant inhibition in LN metastasis status compared to control group. Moreover, LN metastatic recurrence was not detected in OBP-301 treated group even 4 weeks after tumor resection. The combination of ESD and OBP-301 has promising potential to take place of the conventional surgical approach in treating submucosal invasive colorectal cancer.
Citation Format: Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara. Novel strategy for eradicating lymph node metastasis of early-stage colorectal cancers using telomerase-dependent replicating adenoviral agent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1570. doi:10.1158/1538-7445.AM2013-1570
Abstract 1571: Tumor cell panels: New tools in genomic era.
Authors: White Chris , Volpe Lysa-Anne , Chen Luping , Bal Anupreet , Jackson Michael , Foulke John , Tian Fang 
Published: August 2014

Abstract
Increased understanding of cancer genome is affecting every corner of cancer research. Although human tumor cell lines have been used as essential tools for decades, there are only a few cell line panels have been developed for drug screening. The most widely used NCI60 human tumor cell line panel was composed by selecting cell lines to represent nine subtypes of cancer. The rising of targeted therapeutics has led to new generation anticancer agents. However, it's difficult to predict clinical response to these agents because of the genetic diversity and genomic heterogeneity in human cancers. Therefore, there is a gap between the new knowledge of cancer genome and the cell line based platforms for both basic and translational research.
Here, we show that new generation tumor cell panels are filling the gap. The panels were generated by selecting authenticated cell lines derived from variant cancer types, and annotated with genetic alteration information generated by large scale sequencing projects such as the Catalog of Somatic Mutations in Cancer (COSMIC) and the Cancer Cell Line Encyclopedia (CCLE). There are more than 25 tumor cell line panels, which include hundreds of cell lines, have been developed in this initiative. They cover 18 most common cancer types, such as lung, breast, colon, pancreatic cancer and so on. To capture the genetic diversity of cancer, each panel includes cell lines with varying gene mutation complexity. To further facilitate targeted drug discovery, the molecular signature tumor cell line panels focus on individual driver genes, critical protein kinases, transcription factors and cell signaling pathways. Those panels have been analyzed to verify gene mutation, gene expression, protein expression and bio-functions.
Therefore, the new generation tumor cell panels provide powerful tools to accelerate the discoveries in basic cancer research, compound screening, biomarker selection, pathway analysis, and targeted therapeutic development.
Citation Format: Chris White, Lysa-Anne Volpe, Luping Chen, Anupreet Bal, Michael Jackson, John Foulke, Fang Tian. Tumor cell panels: New tools in genomic era. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1571. doi:10.1158/1538-7445.AM2013-1571
Abstract 1572: Influence of apc and med12 mutations on embryonic liver development in zebrafish: a potential model for investigating the role of Mediator in Wnt/β-catenin-dependent cancers.
Authors: Lescott Chamille J. , Glasgow Eric 
Published: August 2014

Abstract
Mutations in adenomatus polyposis coli (APC) result in overactive Wnt signaling and have been linked to colon cancer and hepatoblastoma in humans. Therefore, the Wnt pathway is an attractive target for developing cancer therapeutics. APC directs β-catenin degradation; thus, APC loss results in β-catenin accumulation and an increase in β-catenin-induced transcription. Heterozygous apc mutant zebrafish present enlarged livers at 3 days post-fertilization, and as adults they are predisposed to tumor development. Recently, the Mediator co-activator complex component, Med12, was linked to Wnt signaling. Without med12, canonical Wnt/β-catenin signaling is significantly impaired. We hypothesized that heterozygous med12 mutants will have smaller livers due to a decrease in Wnt activity. Moreover, a reduction in Wnt/β-catenin signaling due to lower levels of Med12 in double heterozygous med12;apc mutant embryos will be sufficient to rescue the large liver phenotype observed in heterozygous apc mutant embryos. In situ hybridization with lfabp probe confirmed the increased liver size in apchu745/+ embryos and showed smaller livers in med12y82/+ embryos. Importantly, the med12y82/+ mutation rescued the large liver phenotype of apchu745/+ embryos. The data suggest that med12 and apc genetically interact to regulate liver development. This interaction between med12 and apc is also likely to also play a role in the development and progression of Wnt/β-catenin-dependent cancers. Therefore, rescue of liver hyperplasia in apc mutants may serve as a model for developing anti-cancer drugs targeting WNT/β-catenin signal transduction through its interaction with MED12.
Citation Format: Chamille J. Lescott, Eric Glasgow. Influence of apc and med12 mutations on embryonic liver development in zebrafish: a potential model for investigating the role of Mediator in Wnt/β-catenin-dependent cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1572. doi:10.1158/1538-7445.AM2013-1572
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1574: The Hippo pathway regulates liver development and tumorigenesis in zebrafish.
Authors: Cox Andrew G. , Beltz Sebastian , Evason Kimberley , Stainier Didier Y. , North Trista E. , Goessling Wolfram 
Published: August 2014

Abstract
The Hippo pathway is a novel signaling cascade that regulates cell proliferation, organ size and tumorigenesis in mammals. In mice, deregulation of the Hippo pathway in the liver has been shown to potently induce tumor formation. However, the molecular mechanism by which the Hippo pathway regulates hepatic growth is not well understood. In this study, we have examined liver development in NF2-/- mutant zebrafish, which exhibit systemic activation of Yap, and found that liver size was increased by 5 days post fertilization (dpf). Histological evaluation of the NF2-/- mutant zebrafish embryos revealed that the enlarged liver was composed of an extended biliary network. In order to examine the cell-autonomous effects of Yap activation in hepatocytes, we generated Tg(fabp10a:YapS87A) fish and found that liver size increased dramatically by 5 dpf. In contrast to the NF2-/- mutant, histological and FACS analysis revealed that the enlarged liver in the Tg(fabp10a:YapS87A) embryos was composed of a greater number of hepatocytes. Chemical exposure to the γ-secretase inhibitor DAPT or erlotinib rescued the hepatomegaly phenotype in 5 dpf Tg(fabp10a:YapS87A) embryos, indicating dependence on Notch and EGFR signaling pathways. To gain greater insight into how these developmental studies relate to tumorigenesis, we compared NF2+/- mutants and Tg(fabp10a:YapS87A) adults and found that both lines were predisposed to liver tumor formation, developing predominantly intrahepatic cholangiocarcinomas. Together, these studies reveal an evolutionarily conserved role of the Hippo pathway at the interface between liver development and tumorigenesis in zebrafish.
Citation Format: Andrew G. Cox, Sebastian Beltz, Kimberley Evason, Didier Y. Stainier, Trista E. North, Wolfram Goessling. The Hippo pathway regulates liver development and tumorigenesis in zebrafish. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1574. doi:10.1158/1538-7445.AM2013-1574
Abstract 1575: Zebrafish embryos as a model for studying the role of estrogen receptor β in cancer metastasis.
Authors: Hao Ruixin , Thomas Christoforos , Dey Prasenjit , Ström Anders , McCollum Catherine W. , Nikolos Fotis , Bondesson Maria , Gustafsson Jan-Ake 
Published: August 2014

Abstract
Estrogen receptor β (ERβ) has been reported to impede cancer metastasis while estrogen receptor α (ERα) can promote cancer metastasis. Several splice variants of ERβ exist in humans and they may have different functions in different tissues, but the role of these differently spliced isoforms in cancer metastasis has not been well studied. Various model systems such as xenografting of cancer cells in mice and dogs have been used to study cancer metastasis. However, difficulties in monitoring living cancer cell metastasis in large non-transparent animals have been a limitation in these studies. Zebrafish embryos are transparent and their immune system is not fully developed until several days after post fertilization. These features make zebrafish a useful model for xenografting cancer cells and monitoring their migration. In addition, the large number of offspring and small size of the embryos make the zebrafish model amendable for high throughput screening and anti-metastasis drug discovery. In our studies, we co-microinjected breast cancer cell lines bearing ERβ constructs or control constructs, expressing fluorescent proteins of different colors, into zebrafish embryos at 48 hours post fertilization (hpf). After 2 hours recovery, fish embryos with cells circulating in the blood system were removed. Embryos that contained cells only in the original injection sites were incubated at 32°C to monitor the cancer cell migration daily using a fluorescence microscope. We found that ERβ expressing breast cancer cells were less migratory than the control cells and they remained at the original injection site to a large extent. We also examined the metastasis of prostate cancer cell lines expressing ERβ splice variants in our zebrafish xenograft model and found that cells with different ERβ splice variants exhibited different migration patterns. In conclusion, zebrafish embryos work as an effective model for studying the role of ERβ and its splice variants for cancer metastasis of diverse cancer cell lines.
Citation Format: Ruixin Hao, Christoforos Thomas, Prasenjit Dey, Anders Ström, Catherine W. McCollum, Fotis Nikolos, Maria Bondesson, Jan-Ake Gustafsson. Zebrafish embryos as a model for studying the role of estrogen receptor β in cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1575. doi:10.1158/1538-7445.AM2013-1575
Abstract 1578: Small molecule HIF-2a inhibitors down regulate its activity in vivo and ameliorate the vhl zebrafish phenotype.
Authors: Metelo Ana , Xiang Li , Baker Rania , Kamentsky Lee , Carpenter Anne , Peterson Randall 
Published: August 2014

Abstract
Hypoxia Inducible Factor (HIF) target genes are involved in several cellular processes including angiogenesis, erythropoiesis, metabolism and stem cell proliferation. The von Hippel-Lindau (VHL) tumor suppressor protein targets HIF for degradation in conditions of normal oxygen tension. Loss-of-VHL leads to constitutive expression of HIF. We have discovered small molecules that repress HIF-2α translation by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to the Iron-Responsive Element (IRE) within the 5’-UTR of HIF-2α mRNA and showed that these small molecules specifically down-regulate HIF-2α expression in vitro.
To validate the HIF-2α inhibitors in vivo, first we tested their efficacy to inhibit acute hif induction in wild-type (wt) zebrafish embryos challenged with the hypoxia mimetic DMOG. Treatment of wt embryos with 100μM of DMOG up-regulated the expression of zebrafish HIF-target genes, such as vascular endothelial growth factor (vegf), erythropoietin (epo) and prolyl-hydroxylase 3 (phd3). Pre-treatment of embryos with the small molecule HIF-2α inhibitor 76 (10nM) significantly decreased the DMOG-induced up-regulation of HIF target genes and resulted in decrease of DMOG-induced erythrocytosis and blood vessel sprouting.
Furthermore, we tested the efficacy of this HIF-2α inhibitor in a vhl zebrafish model (homozygougous mutants harbouring inactivating vhl mutations), which recapitulates aspects of human VHL disease (erythrocytosis, abnormal vascular proliferation in sites such as retina and brain, early lethality). Treatment with inhibitor 76 (10nM, 100nM and 1μM) down regulated the expression of the HIF-target genes phd3, epo and vegf in a dose response manner and rescued the erythrocytosis and sprouting phenotype of vhl embryos. To image and quantify the blood vessel abnormalities of vhl embryos, we generated a Fli-GFP::vhl+/- line and showed that compound 76 improves the abnormal connections between the intersegmental vessels of the Fli-GFP::vhl embryo tail, as well as their human hemangioblastoma-resembling brain vessel proliferation. Finally, we showed that treatment of vhl embryos with compound 76 rescues early lethality.
Our data demonstrate that HIF-2α inhibitor 76 is active in vivo at low concentrations and encourage further development and preclinical testing of this HIF-2α inhibitor for treatment of VHL-associated lesions, such as renal cell carcinoma, hemangioblastoma and neuroendocrine tumors.
Citation Format: Ana Metelo, Li Xiang, Rania Baker, Lee Kamentsky, Anne Carpenter, Randall Peterson. Small molecule HIF-2a inhibitors down regulate its activity in vivo and ameliorate the vhl zebrafish phenotype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1578. doi:10.1158/1538-7445.AM2013-1578