bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5252: Utilization of TumorGraft technology for personalized breast cancer treatment
Authors: James Meredith , Morris Ronnie , Bruckheimer Elizabeth , Rowinsky Eric , Bacus Sarah , Sidransky David , Paz Keren 
Published: August 2012

Abstract
Breast cancer is the most common cancer among women with over 280,000 new annual cases and 40,000 deaths in the US alone. While hormonal-dependent breast cancer is correlated with good prognosis, an adequate solution for hormonal-independent tumors remains an unmet medical need, largely due to a significant heterogeneity within tumors and their makeover. Various personalized oncology approaches aim at tailoring the optimal regimen for these patients by better understanding their tumor distinctiveness. Champions Oncology focuses on personalizing cancer treatment through the generation of TumorGraft™ models form the patient's own tumor. The current study is focused on the attempt to identify a personalized solution for a patient with HER2-amplified metastatic breast cancer whose disease progressed on Trastuzimab (Herceptin). Using Champions novel and cutting-edge TumorGraft™ technology, the challenge was confronted empirically by preforming a personalized clinical trial in vivo. Tumor fragments, obtained from both the primary breast tumor and lung metastasis, were implanted in immune-deficient mice in a manner that preserves the biological properties of the original tumor and its supporting stroma. Once the TumorGraft™ models were established, panel of drugs and drug combinations were evaluated to help identify treatment regimens that are likely to be most effective for the patient clinically. The drug study encompassed 7 different treatment groups including FDA-approved, as well as investigational agents. Of the 7 treatment arms, 3 demonstrated a significant anti-tumor response with tumor growth inhibition values of 80, 93 and 97% for Lapatinib+Capecitabine, Gemcitabine+Carboplatin and Ixabepilone+Capecitabine, respectively. Molecular analysis of the tumor revealed a truncated HER2 (p95) and a robust HER2 translocation to the nucleus. Additional molecular characterization is ongoing to determine other potential signatures of response. Results from the TumorGraft™ study were recommended to the patient and her medical oncologist and new lines of treatment were commenced subsequently. Herein, we describe the data from the TumorGraft™ drug study, the molecular exploration and the pathway analysis of the primary and the metastatic tumor and the consequences correlation to the clinical outcome.
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 5252. doi:1538-7445.AM2012-5252
Abstract 5257: Manipulating the Noxa/Bim axis undermines the multicellular resistance of 3D tumor spheroids
Authors: Barbone Dario , Cheung Priscilla , Yang Tsung-Ming , Jablons David M. , Sugarbaker David J. , Bueno Raphael , Fennell Dean A. , Letai Anthony G. , Broaddus Courtney V. 
Published: August 2012

Abstract
When grown in 3D cultures as spheroids, cancer cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found in lung cancer and mesothelioma that multicellular resistance lies at the level of mitochondria and can be reduced by manipulating the Bcl-2 repertoire with BH3-mimetics. One mechanism for the multicellular resistance to apoptosis is the lack of up-regulation of the pro-apoptotic sensitizer Noxa upon treatment; Noxa displaces pro-apoptotic Bim from its anti-apoptotic buffering proteins allowing the Bim to induce apoptosis. Interestingly, we have found that, at the same time that cells acquire apoptotic resistance in 3D, they also acquire a pro-apoptotic potential that has been termed “apoptotic priming,” due to an elevated Bim that is sequestered by the anti-apoptotic Bcl-2 proteins. We found that multicellular resistance could be abolished either by restoring Noxa levels using a permeable Noxa peptide or by releasing Bim via inhibition of the anti-apoptotic Bcl-2 proteins using the small molecule inhibitor, ABT-737. Moreover, multicellular resistance was also abolished by the histone deacetylase inhibitor SAHA which upregulated both Noxa and Bim expression. Knockdown of Bim blocked the effect of the Noxa peptide, ABT-737 or SAHA showing the importance of Bim in the chemotherapeutic response. Our results using a clinically-relevant 3D model show that manipulation of the core apoptotic repertoire in order to release Bim may improve chemosensitivity of lung cancer and mesothelioma.
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 5257. doi:1538-7445.AM2012-5257
Abstract 5322: SOD2 enhances cell migration and invasion of tongue squamous cell carcinoma via H2O2-dependent Snail signaling
Authors: Wang Anxun , Liu Zhonghua , Li Su , Cai Yuchen , Zheng Chaoxu , He Qianting , Zhou Xiaofeng 
Published: August 2012

Abstract
In previous studies, we demonstrated that dysregulation of manganese superoxide dismutase (SOD2) is a frequent event in tongue squamous cell carcinoma (TSCC) and is associated with lymph node metastasis. Here, we further investigated the mechanism of SOD2-mediated cell migration and invasion in paired TSCC cell lines with different metastatic potential. The UM1 and UM2 are paired cell lines from a single TSCC patient, where UM1 is more aggressive than UM2 in term of cell migration and invasion. Compared to UM2 cells, UM1 cells exhibited significantly higher SOD2 activity, increased intracellular H2O2 and higher levels of Snail, MMP-1 and pERK1/2 protein, and lower level of E-cadtherin protein. Upon knockdown of SOD2 by RNA interference, UM1 cells displayed significantly reduced cell migration and invasion abilities. This is accompanied by reductions in SOD2 activities, intracellular H2O2, levels of Snail, MMP-1 and pERK1/2 proteins, as well as increase in the level of E-cadtherin protein. Cell migration and invasion of the UM2 and the SOD2 shRNA-treated UM1 cells were enhanced by H2O2 treatment. This H2O2-mediated cell migration and invasion is accompanied by increased levels of Snail, MMP-1 and pERK1/2 protein, and decreased level of E-cadtherin protein. Thus, we conclude that the SOD2-dependent production of H2O2 contributes to both cell migration and invasion of TSCC via the Snail signaling pathway through increased Snail, MMP-1 and pERK1/2 expression, and the repression of the E-cadtherin.
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 5322. doi:1538-7445.AM2012-5322
Abstract 5324: H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM
Authors: Chen Min Wei , Hua Kuo-Tai , Kao Hsin-Jung , Chi Chia-Chun , Wei Lin-Hung , Hsiao Michael , Kuo Min Liang 
Published: August 2012

Abstract
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.
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 5324. doi:1538-7445.AM2012-5324
Abstract 5326: ID3 contributes to cerebrospinal fluid seeding and poor prognosis of medulloblastoma
Authors: Phi Ji Hoon , Choi Seung Ah , Lim Sang-Hee , Wang Kyu-Chang , Cho Byung-Kyu , Park Sung-Hye , Park Chul-Kee , Lee Ji Yeoun , Kim Seung-Ki 
Published: August 2012

Abstract
Seeding of medulloblastoma is the most influential prognostic factor for survival, but little has been known about the molecular mechanism of seeding in medulloblastoma. Inhibitor of differentiation (ID) genes are implicated as promoter of tumor progression and metastasis in many human cancers. We investigated the expression and functional roles of ID genes in terms of seeding and prognosis of medulloblastoma. Significantly higher ID3 expression was observed in medulloblastoma with seeding than in tumors without seeding. In vitro studies using D283 medulloblastoma cells and ID3-siRNA showed that ID3 knockdown resulted in decreased proliferation, enhanced apoptosis, and suppressed migration. We made a seeding model of medulloblastoma in mice and injected a stable cell line with ID3 knockdown with shRNA. ID3 knockdown in vivo inhibited growth of primary tumor and development of leptomeningeal seeding and prolonged survival of animals compared with controls. A mRNA mini-array revealed that ID3 knockdown leads to up-regulation (TIMP3, ITGB4, COL12A1, ADAMTS8) and down-regulation (TNC, CTGF, ICAM1) of several genes related to cellular invasion and migration. High ID3 expression was associated with poor survival of patients with medulloblastoma as with seeding at presentation. These findings indicated that ID3 plays an important role in seeding of medulloblastoma and may be a target of therapeutic intervention for enhancing survival of the patients in the poor-prognostic group.
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 5326. doi:1538-7445.AM2012-5326
Abstract 5331: The effect of heat shock protein 27 (HSP27) on prostate cancer cell adhesion, invasion and metastasis
Authors: Voll Eric , Ogden Irene , Huang XiaoKe , Bergan Raymond 
Published: August 2012

Abstract
Prostate cancer (PCa) is the most commonly diagnosed form of cancer among American men, and the second leading cause of all cancer-related deaths. PCa death is caused by the process of metastasis. In order to metastasize, tumor cells must acquire a series of phenotypic alterations, collectively known as the metastatic cascade. We have demonstrated that the small heat-shock protein, HSP27, affects key early steps of the metastatic cascade, and therefore may be a regulator of human PCa metastasis. HSP27 protein expression increases during PCa progression. It is phosphorylated in response to signaling from transforming growth factor-β (TGF-β), which in turn increases matrix metalloproteinase 2 (MMP-2) and cell invasion in vitro. We now demonstrate that HSP27 does not affect human PCa cell adhesion, cell detachment or cell migration, all of which contribute to the composite function of cell invasion. We went on to show that proteolysis by MMPs is necessary for HSP27-driven cell invasion by demonstrating that it was abrogated Marimastat, a broad-spectrum MMP inhibitor. By orthotopically implanting HSP27 variant human PCa cell lines, we demonstrated that HSP27 increases metastasis in a murine model. We also found that HSP27 increased tumor size. HSP27 increases human PCa metastasis and tumor growth in vivo. These findings provide a mechanistic explanation for the poor prognosis associated with increased HSP27 expression in human prostate tissue.
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 5331. doi:1538-7445.AM2012-5331
Abstract 5332: Snail transcription factor contributes to prostate cancer tumor progression via reactive oxygen species and Rac1 activation
Authors: Barnett Petrina K. , Henderson Veronica , Arnold Rebecca S. , Mezencev Roman , Kundu Kousik , Hudson Tamaro , Murthy Niren , Chung Leland W K , Zayzafoon Majd , Odero-Marah Valerie 
Published: August 2012

Abstract
Epithelial-mesenchymal transition (EMT) represses cell adhesion associated genes, making cells more migratory. Snail is the master gene that regulates the EMT process by down regulating tight junction proteins, such as E-cadherin, and up-regulating mesenchymal genes, such as vimentin. Cell migration can also be regulated by the Rho family of GTPases such as Rac1, which can induce reactive oxygen species (ROS), specifically superoxide, via the NADPH oxidase (Nox) pathways. ROS, specifically hydrogen peroxide has been shown to mediate EMT induced by MMP-3. The objective of this study is to determine whether Snail Transcription factor contributes to tumor progression via ROS and Rac1 and to study the effect(s) of antioxidants on Snail signaling. We utilized androgen-dependent LNCaP and androgen-independent 22Rv1 and ARCaP cell lines overexpressing Snail to examine Rac1 activity in vitro. ROS (superoxide and hydrogen peroxide) levels were examined in vitro and in vivo. Western blot analysis of EMT markers, cell migration on collagen and Real Time PCR Array to assay oxidative stress enzymes was also performed. We found that LNCaP, 22Rv1 and ARCaP cells overexpressing Snail displayed increased Rac1 activity while LNCaP and ARCaP cells with Snail overexpression expressed higher levels of superoxide and hydrogen peroxide in vitro. Furthermore, ARCaP cells overexpressing Snail injected into nude mice showed higher tumorigenicity as compared to ARCaP Neo control cells and excised tumors displayed increased levels of superoxide and hydrogen peroxide ex vivo. Real Time PCR Array revealed significant increase in key enzymes involved in oxidative stress such as aldehyde oxidase I and peroxidasin. Treatment with the hydrogen peroxide scavenger, N-acetyl cysteine (NAC), could partially revert Snail-mediated EMT in ARCaP cells as evidenced by re-expression of E-cadherin after 3 days. The muscadine grape skin extract (MSKE) antioxidant decreased ROS levels and Rac1 activity and reverted Snail-mediated EMT as seen by decreased vimentin, re-induction of E-cadherin, and decreased cell migration. This is the first report of Snail regulation of ROS by regulating oxidative stress enzymes, leading to EMT and tumor progression. We are also showing novel data that Snail can regulate cell motility via Rac1 activation. Therefore, targeting Snail-mediated EMT with antioxidants offers a promising therapy to reduce prostate cancer progression in future. Research supported by NIH Grants: 1P20MD002285 and G12RR03062.
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 5332. doi:1538-7445.AM2012-5332
Abstract 5333: EpCAM overexpression in metastasizing gastric carcinomas
Authors: Ensinger Christian , Reinold Susanne , Galler Daniela , Drach Mathias , Hofer Carina 
Published: August 2012

Abstract
EpCAM, a homophilic Ca2+-independent adhesion molecule, is expressed in various epithelial tissues. Especially proliferating tissues or neoplasias show an increasing expression of EpCAM. Since it is found in large quantities in carcinomas, it seemed to be useful as novel therapeutic target for monoclonal and bispecific antibodies raised against the protein. Due to lack of data in gastric carcinomas, we investigated these tumors and their corresponding metastases. Therefore we evaluated the immunohistochemical reactivity of 104 gastric cancers, and their lymph node as well as distant metastases, using the mouse monoclonal antibody ESA by use of a previously defined scoring system for overexpression. Most of the tumour cells showed distinct membraneous reactivity, while normal gastric epithelium as internal control was EpCAM negative. 104 cases presented with an overexpression in 65,39%, without significant correlation to tumour stage or grade (p=0,339), no significant difference to histological growth patterns (according to Lauren) was found (p=0,186). 46,15 % of 26 mucinous carcinomas showed an overexpression, without mucinous parts they had an overexpression of 68 %, resulting in highly significant differences (p = 0.039 - two tailed) in these two groups. 54 primary tumors with metastases were evaluated. 62.96 % of these primary tumours had an EpCAM overexpression. 52 cases with lymph node metastases revealed a positive correlation with high significance (Pearson, p &lt; 0.05). The paired-samples T-test no significance was found (p = 0.283 - two tailed). Comparing primary tumors with distant metastases a proportional relationship between the values was found (Pearson). The t-test brought no significant differences (p = 0.120). Between the lymph node metastases and distant metastases a positive correlation could be seen (Pearson, p = 0.192), without significance in the t-test (p = 0.121). Our study shows an EpCAM overexpression already in early stages of gastric cancers and a significant correlation between the primary tumors and metastases. So it seems to be possible to conclude from the EpCAM evaluation in available tissue of the primum to its metastases, facilitating clinical use of EpCAM-based immunotherapies and provide higher efficiency in the fight against all kinds of metastasizing gastric carcinomas. Recently designed new bispecific monoclonal antibodies are exerting improved therapeutic effects through antibody-dependent cellular cytotoxicity or complement. Also promising results were described for experimental gene therapy using EpCAM-targeted adenoviral vectors in human gastric and oesophageal carcinomas.
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 5333. doi:1538-7445.AM2012-5333
Abstract 5336: Distinct liver cancer stem cells defined by EpCAM and CD90 in human hepatocellular carcinoma
Authors: Yamashita Taro , Honda Masao , Kawaguchi Kazunori , Takatori Hajime , Sunakozaka Hajime , Wang Xin W. , Kaneko Shuichi 
Published: August 2012

Abstract
Recent evidences suggest that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells: CSCs). Although CSCs have been identified using several CSC markers and are now considered a pivotal target for the eradication of HCC, little information is known about the characteristics of marker-positive cells. Here we explored the expression of CSC markers CD90 and EpCAM in primary HCCs and cell lines to investigate the molecular characteristics of each cell type. Gene expression profiling and immunohistochemistry analyses were used to characterize 340 surgically resected HCC tissues and 11 advanced HCC tissues with distant organ metastasis obtained from autopsy. Magnetic-activated cell sorting was used to isolate EpCAM+ or CD90+ cells from surgically resected 12 fresh HCC specimens, which were tested for hepatic stem cell properties including their tumor initiating capacity in NOD/SCID mice. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene expression analysis of sorted cells suggested that EpCAM+ cells had the features of epithelial stem cells whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum AFP with a tendency of portal vein invasion, while the presence of CD90+ cells was associated with high incidence of distant organ metastasis within two years after surgical resection and advanced TNM stages. Serial xenotransplantation of EpCAM+/CD90+ cells in NOD/SCID mice revealed the rapid growth of EpCAM+ cells in the subcutaneous lesion and highly metastatic capacity of CD90+ cells into the lung. Xenotransplantation experiments of cell lines further demonstrated that EpCAM+ cells had the features of hepatic CSCs with marked tumorigenic capacity whereas CD90+ cells had those of vascular endothelial cells with highly metastatic features. Markedly, CD90+ cells showed the abundant expression of c-Kit and VEGFR1 and chemosensitivity to imatinib methylate (c-Kit inhibitor) and axitinib (VEGFR1/2 inhibitor). Taken together, our data strongly suggest the discrete natures of EpCAM+ and CD90+ cells with specific gene expression patterns and chemosensitivity to the molecularly targeted therapy. The presence of distinct CSCs may determine the clinical outcome of HCC.
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 5336. doi:1538-7445.AM2012-5336