bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2760: Identification of ET-743 analogs with improved selectivity and potency for EWS-FLI1 and Ewing sarcoma cells.
Authors: Harlow Matt , Maloney Nichole , Segars Laura , Woldemichael Girma , Helman Lee J. , Grohar Patrick J. 
Published: August 2014

Abstract
BACKGROUND: Ewing sarcoma is a pediatric malignancy characterized by the fusion of the EWS and FLI1 genes, which creates a constitutively activated transcription factor, EWS/FLI1. The transcriptional program of EWS/FLI1 drives malignant transformation as well as high-risk features such as increased angiogenesis, resistance to apoptosis, and increased metastatic potential. It is well known that perturbing the transcriptional activity of EWS/FLI1 leads to cell death in vitro and should be considered as a possible site of therapeutic intervention in Ewing sarcoma patients. To that end, we identified ET-743 (trabectedin, Yondelis), a natural product, which inhibits EWS/FLI1 activity in vitro. Using ET-743 as a lead compound, we have characterized a number of structural analogs of ET-743 to identify more potent and/or more selective inhibitors of EWS/FLI1 activity.
METHODS: We evaluated the potency of the ET-743 structural analogs using MTS viability assays using Ewing sarcoma, alveolar rhabdomyosarcoma, and osteosarcoma cell lines. The specific inhibition of EWS/FLI1 downstream transcriptional activity was measured using a luciferase-based approach and western blotting. We also evaluated each analog's ability to suppress a gene signature of EWS/FLI1, which included more than 20 genes known to be deregulated by EWS/FLI1 using a novel microfluidic based assay and the Fluidigm platform.
RESULTS: Several analogs proved to be more potent than ET-743 and selective for transcriptional suppression of EWS/FLI1. All of the analogs induced varying degrees of DNA damage and cell death, which were detected by biochemical and metabolic assays. We also show that the analogs sensitize ES cells to treatment with camptothecins to a variable degree based on analog relative to the parent compound.
CONCLUSIONS: In comparison to ET-743, we have shown that its structural analogs confer better pharmacological properties such as increased potency and specificity towards Ewing sarcoma cell lines. We are currently working to further characterize the mechanism of action for these analogs and evaluate the compounds in an in vivo model. The ultimate goal would be to translate these compounds to the clinic and improve patient outcomes with Ewing sarcoma.
Citation Format: Matt Harlow, Nichole Maloney, Laura Segars, Girma Woldemichael, Lee J. Helman, Patrick J. Grohar. Identification of ET-743 analogs with improved selectivity and potency for EWS-FLI1 and Ewing sarcoma cells. [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 2760. doi:10.1158/1538-7445.AM2013-2760
Abstract 2775: Establishment of patient primary gastric cancer xenograft models for test of anticancer agents.
Authors: Zhang Ning , You Shengyi , Li Wenwei , Zhou Wen , Liu Yong , Zhou Rui , He Fang , Liu Changnian 
Published: August 2014

Abstract
Background. Human xenograft tumor models established by inoculating human tumor cell lines into immunodifficient mice have been routinely used for preclinical test of anticancer agents. But tumor cell lines have a relatively low transplantability, which resulted in a limited number of tumor models available for selection of right tumor modes for test of targeted therapeutics. Recently, we have developed a large number of patient primary gastric cancer xenograft models by transplanting human fresh gastric tumor fragments into nude mice, which have been employed for preclinical test of clinically used drugs and novel anticancer agents for their chemosensitivity screening. Mehtods. The fresh gastric tumor samples were collected from local hospitals. The tumor fragments of 2-3 mm were subcutaneously implanted in the flanks of nude mice by trocar needle. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue (passage 0). The clinically used drugs included 5-FU, gemcitabine, and doxorubicin. The histology and gene sequence of the established primary gastric tumor models were analyzed and compared with patients’ original tumors. Results. A total of 110 patient gastric cancer samples were implanted into nude mice; and 30 primary tumor models have been established with a tumor taking rates of 27% for the first passage. The tumor taking rates were higher in the later passages ranged from approximately 70-95%. The therapeutic efficacy of the test anticancer drugs was consistent with their clinical findings. The patients’ primary gastric cancer xenografts from all 5 passages retained a similarity in architecture, histopathological morphology, and genomic mutation status to their patients’ original tumors. Conclusions. The patient primary tumor model system can provide a larger number of models within same tumor histological type for selection of right models for preclinical testing novel agents based on their anticancer mechanism. The primary tumor models retain a similarity in histology and genomic mutation status to their patients’ original tumors. They may predict more relevant clinical response rate and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs discovery and development programs.
Citation Format: Ning Zhang, Shengyi You, Wenwei Li, Wen Zhou, Yong Liu, Rui Zhou, Fang He, Changnian Liu. Establishment of patient primary gastric cancer xenograft models for test of anticancer agents. [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 2775. doi:10.1158/1538-7445.AM2013-2775
Abstract 2792: Characterization of spontaneous in vivo cachexia models in Champions TumorGraft™ models.
Authors: Anderson Nathan , Khor Tin Oo , Feldhaus Andrew , Olson Katie , Latham John , Sidransky David , Bruckheimer Elizabeth M. 
Published: August 2014

Abstract
Cachexia, defined as a loss of adipose tissue and skeletal muscle mass not reversible by nutritional support, is present in the majority of patients with advanced cancer progression. This reduces the patient's quality of life and impacts their ability to function normally and undergo treatments. Reversing cachexia has been problematic due to a lack of quality pre-clinical models. Traditional xenograft models using cell lines are limited due to their inability to accurately replicate the whole body response to cancer. Champions Oncology overcomes this challenge through the use of its innovative Champions TumorGraft™ platform, where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. Champions has identified a panel of three TumorGraft models which spontaneously induce cachexia when implanted subcutaneously into nude mice: 1) CTG-0282, a pancreatic cancer model, 2) CTG-0765, a NSCLC model, and 3) CTG-0804, a renal cell carcinoma model. All three models have shown a greater than 90% cachexia rate, as demonstrated by lost body weight, over multiple passages. In addition, loss of body weight correlates with an increase in tumor volume size. Mice that have little or no tumor growth show no loss of body weight. Past studies have indicated a function for pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6) and interferon gamma (IFNγ), in the cachexia process. Champions is currently investigating the roles of these possible tumor-mediated factors in the aforementioned models. Principle among these factors is IL-6, which has been shown to be required in the regulation of cachexia in tumor-bearing mice and is correlated with weight loss and survival in patients. Preliminary results from our studies suggest a correlation between IL-6 levels and spontaneous cachexia in Champions TumorGraft models. In summary, we demonstrate that the Champions TumorGraft platform preserves the biological properties of the original human tumor, including spontaneous cachexia behavior in these models, and is therefore ideal for oncology drug development programs focused on the inhibition of cachexia.
Citation Format: Nathan Anderson, Tin Oo Khor, Andrew Feldhaus, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Characterization of spontaneous in vivo cachexia models in Champions TumorGraft™ models. [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 2792. doi:10.1158/1538-7445.AM2013-2792
Abstract 2793: Development of an androgen-dependent prostate Champions TumorGraft™ cancer model.
Authors: Khor Tin Oo , Paz Keren , Tiruchinapalli Dhanrajan , Sidransky David , Bruckheimer Elizabeth M. 
Published: August 2014

Abstract
Prostate cancer (PCa)is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, with the highest incidence rates recorded in developed countries such as those in North America (Jemal et al., 2011). While the five year-survival rate for PCa patients with localized disease is 100%, it is only 30.6% once the cancer metastasizes (Vishnu et al., 2010). One of the biggest challenges for finding a better treatment for metastatic PCa is the lack of predictable and accurate preclinical models that closely recapitulate different stages of the pathogenesis of human PCa. Champions Oncology focuses on the development of Champions TumorGraft™ models derived from the direct implantation of patient tumors into immunocompromised mice. Compared to traditional cell line-based xenograft models, the patient-derived TumorGraft models maintain stable gene-expression patterns and mutational status and correlate to clinical predictability. To overcome the challenge for PCa, Champions Oncology has utilized its TumorGraft technology to establish and characterize a new androgen-dependent prostate cancer TumorGraft model, CTG-0488. This involved the implantation of a primary human prostate tumor in immunocompromised mice in a manner that preserves the biological properties of the original human tumor. In this preliminary work, the characteristics of Champion TumorGraft™ model CTG-0488 are showcased, including tumor histology, mutational status, and chemosensitivity profiles to several standard of care compounds. Overall the development of an androgen-dependent prostate cancer Champions TumorGraft™ model will significantly aid in the development of oncology compounds focused on androgen-dependent prostate cancer.
Citation Format: Tin Oo Khor, Keren Paz, Dhanrajan Tiruchinapalli, David Sidransky, Elizabeth M. Bruckheimer. Development of an androgen-dependent prostate Champions TumorGraft™ cancer model. [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 2793. doi:10.1158/1538-7445.AM2013-2793
Abstract 2804: Anti-tumor and anti-metastatic efficacy of TCM on prostate cancer in orthotopic model of metastatic cancer.
Authors: Zhang Lei , Wu Chengyu , Zhao Ming , Zhang Yong , Hoffman Robert M. 
Published: August 2014

Abstract
We report here on the efficacy of TCM formula TCM-formula LQ on patient-like orthotopic nude-mouse models of metastatic human cancer. The anti-tumor and anti-metastatic activity of LQ was determined on orthotopic models of human prostate and colon cancer. In the present study, human cancer cell lines PC-3 prostate and HCT-116 colon, labeled with green fluorescent protein (GFP), were used. The cells were initially implanted subcutaneously. Subcutaneous tumors were harvested to obtain tissue fragments which were implanted orthotopically in nude mice. The herbal mixture LQ (gavage, 600 mg/kg/day) significantly inhibited prostate cancer tumor growth as measured by imaging, tumor size and weight in subcutaneous, and orthotopic models. LQ was efficacious against primary and metastatic cancer without weight loss and cachexia. Fifty percent of mice in control group got the ascites, but only 20% had ascites in the LQ group. Survival of tumor-bearing mice was also prolonged by LQ treatment. The results indicate that LQ can have non-toxic efficacy against metastatic prostate cancer in clinically relevant orthotopic mouse models.
Citation Format: Lei Zhang, Chengyu Wu, Ming Zhao, Yong Zhang, Robert M. Hoffman. Anti-tumor and anti-metastatic efficacy of TCM on prostate cancer in orthotopic model of metastatic cancer. [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 2804. doi:10.1158/1538-7445.AM2013-2804
Abstract 2823: Molecular response of the axillary lymph node microenvironment to metastatic colonization.
Authors: Ellsworth Rachel E. , Valente Allyson L. , Kane Jennifer L. , Ellsworth Darrell L. , Shriver Craig D. 
Published: August 2014

Abstract
Breast stroma plays an active role in tumorigenesis, undergoing both phenotypic and molecular changes to facilitate and promote tumor development and growth. The metastatic microenvironment also plays a role in successful colonization; however, the genetic changes in these secondary microenvironments are not well described.To improve understanding of the molecular changes associated with metastatic colonization of a foreign tissue, gene expression data was generated from lymph node tissues from women with at least one lymph node with macrometastases and one lymph node with no detectable metastases. Lymph node tissue was microdissected and hybridized to U133A 2.0 gene expression arrays. Differential expression was detected using Partek® Genomics Suite™6.5 with P&lt;0.001, &gt;2-fold change defining significance. Thirty-four genes were differentially expressed, 23 genes, including EPCAM, KRT19 and MUC1, were expressed at significantly higher levels in colonized lymph nodes and 11 genes, such as CXCL2 and HPGDS, were expressed at significantly higher levels in non-metastatic lymph nodes. Thus, lymph node tissue differs in gene expression between those harboring metastatic tumors and those without metastasis. Genes expressed at higher levels in colonized lymph nodes are involved in tumorigenesis, suggesting that like the breast stromal microenvironment, the metastatic microenvironment undergoes cross-talk with the tumor cells, while genes involved in immune function are down-regulated in colonized lymph nodes, suggesting that suppression of proper immune response may be required for successful metastatic colonization.
Citation Format: Rachel E. Ellsworth, Allyson L. Valente, Jennifer L. Kane, Darrell L. Ellsworth, Craig D. Shriver. Molecular response of the axillary lymph node microenvironment to metastatic colonization. [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 2823. doi:10.1158/1538-7445.AM2013-2823
Abstract 2826: Expression of HBEGF enhances breast carcinoma cell motility, invasion and metastasis.
Authors: Zhou Zhen Ni , Sharma Ved P. , Beaty Brian T. , Kenny Paraic , Wiley H. Stephen , Condeelis John S. , Segall Jeffrey E. 
Published: August 2014

Abstract
Despite advances in screening and prevention, breast cancer is still associated with a high mortality rate that predominantly results from the development of metastatic disease. One of the key steps of the metastatic cascade is invasion. Previous work in our lab has discovered a paracrine loop between tumor cells and macrophages in which tumor cells are capable of stimulating macrophages through the secretion of CSF-1 and the tumor associated macrophages in turn aid in tumor cell invasion by secreting EGF. The goal of our project is to explore how expression of EGFR ligands, specifically HBEGF, by tumor cells affects the paracrine loop, invasion and metastasis. Previous studies have shown that HBEGF is often found to be coexpressed with the EGFR and that HBEGF expression in tumors is correlated with more biologically aggressive disease and poorer patient prognosis. An initial Oncomine cancer gene expression analysis showed that HBEGF expression was correlated with more rapid recurrence of disease in breast cancer upon removal of the primary breast tumor. Based on the published data, we decided to focus our study on this particular ligand. Using MTLn3 rat mammary adenocarcinoma cells and human MDA-MB 231 breast adenocarcimona cells that were transduced to overexpress HBEGF, we have shown that HBEGF expression enhanced tumor cell invasion by increasing tumor cell motility, invadopodium formation and matrix degradation. We have also discovered that expression of HBEGF enhanced metastasis by making tumor cell invasion independent of the paracrine loop. Our studies suggest that for tumors that express HBEGF, therapies that target tumor associated macrophages using CSF-1R inhibitors may not be effective in inhibiting tumor cell invasion. In addition, we have found that HBEGF expression causes an increase in the recruitment of tumor associated macrophages and tumor angiogenesis along with increased expression of VEGF, which suggests that anti-VEGF treatment could be particularly useful for treating patients whose tumors overexpress HBEGF.
Citation Format: Zhen Ni Zhou, Ved P. Sharma, Brian T. Beaty, Paraic Kenny, H. Stephen Wiley, John S. Condeelis, Jeffrey E. Segall. Expression of HBEGF enhances breast carcinoma cell motility, invasion and 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 2826. doi:10.1158/1538-7445.AM2013-2826
Abstract 2834: Cancer testis antigens-specific CD4+ T-cell immunity augmented by CTL-epitopes vaccination in cancer patients.
Authors: Tomita Yusuke , Yuno Akira , Yoshitake Yoshihiro , Tsukamoto Hirotake , Irie Atsushi , Senju Satoru , Yoshida Koji , Tsunoda Takuya , Nakamura Yusuke , Shinohara Masanori , Nishimura Yasuharu 
Published: August 2014

Abstract
We identified novel cancer testis antigens (CTAs) including CDCA1, LY6K (URLC10) and KIF20A that are overexpressed in lung cancer, head and neck cancer (HNC), and other various malignancies, but not expressed in many adult normal tissues except for testis and fetal organs by using genome-wide cDNA microarray analyses. We identified CTAs-derived peptides that can activate tumor-reactive and HLA-A2 or -A24-restricted CTLs in both in vitro preclinical and in vivo clinical studies of peptide vaccine. It is well known that IL-2 and IFN-γ produced by Th1 cells have pivotal roles in efficient induction of memory CTLs and efficient infiltration of CTLs into the tumor. We identified these CTAs-derived promiscuous 20∼26-mer long peptides (LPs) that can induce both Th1 cells restricted by several frequent HLA class II and tumor-reactive CTLs restricted by HLA-A2 or -A24. The LPs were naturally processed from CTAs and presented by dendritic cells. In addition, these LPs induced propagation of CTA-specific CTLs by cross presentation in both human in vitro and HLA-class I transgenic mice in vivo. Furthermore, these LPs and Th1-cell clone enhanced induction of CTA-specific CTLs in vitro. Significant frequencies of CTA-specific Th1 cells were detected after short-term in vitro stimulation with LPs in HNC patients vaccinated with CTA-derived CTL-epitope peptides and cancer patients before vaccination but not in healthy donors; responses were augmented by repeated vaccinations. These results show for the first time the presence of novel CTAs-specific Th1 cell responses in cancer patients and suggest the potential utility of these LPs for propagation of CTAs-specific Th1 cells and CTLs.
Citation Format: Yusuke Tomita, Akira Yuno, Yoshihiro Yoshitake, Hirotake Tsukamoto, Atsushi Irie, Satoru Senju, Koji Yoshida, Takuya Tsunoda, Yusuke Nakamura, Masanori Shinohara, Yasuharu Nishimura. Cancer testis antigens-specific CD4+ T-cell immunity augmented by CTL-epitopes vaccination in cancer patients. [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 2834. doi:10.1158/1538-7445.AM2013-2834
Abstract 2853: Monoclonal antibodies derived in neuN mice following successful T cell therapy of spontaneous breast tumors are specific for tumor progenitor cells.
Authors: Wang Li-Xin , Patel Mona , Berk Michael , Plautz Gregory E. 
Published: August 2014

Abstract
There is considerable interest in developing approaches to specifically target tumor progenitor cells. Our previous results demonstrated that adoptive transfer of CD4+ and CD8+ T cells primed with a breast cancer progenitor vaccine inhibited the progression of spontaneous primary tumors in neuN mice. Interestingly, post-treatment serum but not pre-treatment serum was reactive with surface molecules on the vaccine cells. This indicates that the transferred T cells resulted in uptake of tumor antigens and stimulation of host B cells. To characterize the antigenic targets, we generated hybridomas from spleen cells derived from treated mice. Three candidate clones which were strongly reactive with a neu-negative variant tumor line were subjected to two rounds of limiting dilution cloning. The mAb prepared from hybridoma #1 (IgG1) and hybridoma #2 (IgG2b) were each reactive against two independent tumor lines derived from spontaneous breast tumors in neuN mice (C2D1 and MMC5) when these cells were maintained in serum-free culture medium as tumorspheres. There was no reactivity against the same tumor cell lines when cultured as adherent monolayers in serum-containing medium nor was there reactivity against 3T3 adherent or tumorsphere cultures. Our previous analysis of tumorsphere cultures of C2D1 and MMC5 indicated that they express a panel of markers associated with tumor progenitor cells and have markedly enhanced per-cell tumorigenicity. Two of these antibodies have been purified by protein G or Protein A columns and retain binding to C2D1-tumorsphere cells, but not to C2D1 adherent cells. Importantly, these two antibodies can also bind to cultured 4T1-tumorsphere cells, an additional breast cancer cell line arising initially in BALB/c mice. These studies will allow us to identity corresponding antigens and determine expression on a broader array of spontaneous breast carcinomas in neuN mice. The epitopes recognized by these mAbs, which are expressed on progenitor cells from multiple tumor lines, might have importance as an immunotherapy target.
Citation Format: Li-Xin Wang, Mona Patel, Michael Berk, Gregory E. Plautz. Monoclonal antibodies derived in neuN mice following successful T cell therapy of spontaneous breast tumors are specific for tumor progenitor cells. [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 2853. doi:10.1158/1538-7445.AM2013-2853