bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2875: ATAD2 overexpression indentifies aggressive endometrial carcinomas
Authors: Krakstad Camilla , Tangen Ingvild Løberg , Raeder Maria B. , Hoivik Erling , Kusonmano Kanthida , Zou June X. , Øyan Anne M. , Trovik Jone , Chen Hongwu , Kalland Karl Henning , Salvesen Helga B. 
Published: May 2015

Abstract
Background
Upregulation of the gene ATAD2 has been implicated in cancer development and progression in a number of tissues, and reported to be a member of prognostic gene-signatures in breast (van 't Veer et al, 2002; Wang et al, 2005) and endometrial cancers (Salvesen et al, 2009). We have investigated ATAD2 protein expression in relation to prognosis and gene expression alterations relevant for potential biological driver mechanisms and treatment targets in endometrial cancer.
Methods:
A total of 564 endometrial carcinoma primary lesions were prospectively collected and explored for ATAD2 protein expression in relation to survival and established markers for aggressive disease. Transcriptional alterations related to ATAD2 protein level were investigated by microarray analysis for 236 freshly frozen samples in parallel. Differentially expressed genes were identified using the significance analysis of microarray (SAM) method, and GSEA analysis was performed using the MSigDB version 4.0 C2 collection http://www.broadinstitute.org/gsea/msigdb/index.jsp).
Results:
High ATAD2 expression is significantly associated with the established clinical-pathological variables for aggressive endometrial cancer high FIGO stage, non-endometrioid subtype, high grade, aneuploidy, loss of hormone receptors and poor overall survival (all P-values≤0.001), also in the subset of ERα positive tumors. mRNA and protein expression for ATAD2 was highly correlated (p&lt;0.001), suggesting that immunohistochemical staining may represent a more clinically applicable measure for mRNA levels for ATAD2 level in routinely collected formalin fixed paraffin embedded specimens. Gene expression alterations in samples with high ATAD2 expression revealed upregulation of several cancer-related genes (CDCs, E2Fs) and gene sets that previously has been linked to aggressive disease and potential for targeting new therapies.
Conclusion:
Our results support that immunohistochemical staining for ATAD2 may be a clinically applicable biomarker reflecting clinical phenotype and targetable alterations in endometrial carcinomas to be further explored in controlled clinical trials.
Salvesen HB et al (2009) Proc Natl Acad Sci U S A 106(12): 4834-9
van 't Veer LJ et al (2002) Nature 415(6871): 530-6
Wang Y et al (2005) Lancet 365(9460): 671-9
Citation Format: Camilla Krakstad, Ingvild Løberg Tangen, Maria B. Raeder, Erling Hoivik, Kanthida Kusonmano, June X. Zou, Anne M. Øyan, Jone Trovik, Hongwu Chen, Karl Henning Kalland, Helga B. Salvesen. ATAD2 overexpression indentifies aggressive endometrial carcinomas. [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 2875. doi:10.1158/1538-7445.AM2014-2875
Abstract 2877: Focal adhesion kinsase (FAK) protein overexpression and gene copy number gain correlate with better outcome in patients with surgically resected NSCLC tumors
Authors: Tang Ximing , Cai Yiran , Behrens Carmen , Lin Heather , Lee J. Jack , Wistuba Ignacio. I. 
Published: May 2015

Abstract
Purpose: Cancer cell migration mechanisms are important for invasion and metastasis development. Focal adhesion kinase (FAK) is a critical cancer-related signaling molecule that regulates cell motility and migration. We investigated the effect of tumor FAK protein expression and gene copy number gain in the prognosis of patients with surgically resected non-small cell lung cancer (NSCLC).
Material and Methods: We studied FAK protein expression by immunohistochemistry (IHC) in 216 NSCLC stages I-III archival tumors, including 151 adenocarcinomas (ACs) and 65 squamous cell carcinomas (SCCs). In 190 of these tumors (132 ACs and 58 SCCs), we examined FAK gene copy number by fluorescence in situ hybridization (FISH). FAK IHC expression was examined using the H-score, and a score &gt;150 was defined as overexpression. We examined the correlation of FAK abnormalities with tumors' clinic-pathological and molecular features, and with patients' outcome, including recurrence free and overall survivals.
Results: FAK cytoplasmic protein expression score (P&lt;0.0001) was significantly higher in AC (143 ± 71) compared to SCC (70 ± 42) histology, and in never smokers than smokers. FAK protein overexpression was more frequently (P=0.0005) detected in stage I (46%) than stage II (22%) and III (23%) tumors. In ACs, FAK protein overexpression was significantly higher (P=0.003) in tumors with EGFR mutation (11/13, 85%) compared with wild-type tumors (40/97, 41%). We found that ≥4 FAK gene copies in ≥20% of malignant cells were detected in 28.8% of ACs and 22.4% of SCCs. We did not find correlation between protein expression and gene copy number. After adjusting for stage and adjuvant therapy, NSCLC and AC patients with FAK expression higher than the median had better overall survival (NSCLC, HR 0.51 [CI 0.29-0.86], P=0.017; AC, HR 0.43 [CI 0.23-0.82], P=0.011) compared with patients without protein overexpression. Also, we found that, after adjusting for stage and adjuvant therapy, FAK gene copy number ≥4 in ≥20% of tumors cells correlated with better overall survival (HR 0.34 [CI 0.16-0.95], P=0.039) in patients with AC histology.
Conclusion: FAK protein overexpression and gene copy number gain were frequently detected in NSCLC tumors, and, interestingly, they correlated with better outcome in patients with surgically resected tumors.
Citation Format: Ximing Tang, Yiran Cai, Carmen Behrens, Heather Lin, J. Jack Lee, Ignacio. I. Wistuba. Focal adhesion kinsase (FAK) protein overexpression and gene copy number gain correlate with better outcome in patients with surgically resected NSCLC tumors. [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 2877. doi:10.1158/1538-7445.AM2014-2877
Abstract 2885: Therapeutic microparticle-based tumor lysate vaccination reduces spontaneous lung metastases in a murine breast cancer model
Authors: Gross Brett P. , Wongrapanich Amaraporn , Francis Meghan , Joshi Vijaya B. , Salem Aliasger K. , Norian Lyse A. 
Published: May 2015

Abstract
Although existing interventions are highly efficacious for the treatment of localized breast cancers, disseminated tumors remain incurable. Therapeutic induction of systemic anti-tumor immunity is a promising approach for treating metastatic disease. We have developed a novel heterologous prime/boost vaccination protocol that significantly reduces metastatic tumor burdens in a pre-clinical murine model of breast cancer.
In our studies, mice were orthotopically challenged with Luciferase-expressing 4T1 adenocarinoma cells. Six days later, mice received a priming therapy that consisted of parental 4T1 tumor lysates encapsulated in poly(lactic-co-glycolic) acid microparticles administered contralateral to the established tumor. On day eleven, mice received a boost therapy that consisted of 4T1 lysates and a cocktail of Toll-like receptor agonists. At the conclusion of the assay (day twenty-five), tumor burdens from excised lungs were quantified using bioluminescent imaging. Therapy-receiving mice showed a significant reduction in lung tumors (Student's T-test: p = 0.002, n = 37 control mice vs. 25 treated mice) with an average 46.66% decrease relative to no therapy control mice. Independent quantification of lung metastases was also performed using a standard 6-thioguanine assay. There was a strong correlation (R^2 = 0.8803) between bioluminescent intensity and 6-thioguanine colony number, demonstrating that the decrease in bioluminescence signal due to therapy is not merely explained by the in vivo loss of Luciferase expression by 4T1 cells.
We are currently characterizing the vaccination-induced differences in the localized immune environment of metastatic lung tumors. Effector T cell activation/exhaustion kinetics and the influx of immunosuppressive cell populations (myeloid-derived suppressor cells and regulatory T cells) are now being explored. These studies will help elucidate the immunological mechanism(s) responsible for the diminished metastatic tumor outgrowth observed with our therapy. In conclusion, our data demonstrate that therapeutic vaccination of tumor lysates is efficacious in controlling spontaneous lung metastases in an aggressive model of murine breast cancer.
Citation Format: Brett P. Gross, Amaraporn Wongrapanich, Meghan Francis, Vijaya B. Joshi, Aliasger K. Salem, Lyse A. Norian. Therapeutic microparticle-based tumor lysate vaccination reduces spontaneous lung metastases in a murine breast cancer model. [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 2885. doi:10.1158/1538-7445.AM2014-2885
Abstract 2890: Mechanistic evaluation of the anti-tumor activities of 2-fluorofucose alone and in combination with anti-idiotype vaccination
Authors: Okeley Nicole M. , Zeng Weiping , Levengood Matthew R. , McEarchern Julie A. , Jonas Mechthild , Duniho Steven , Senter Peter D. , Law Che L. 
Published: May 2015

Abstract
Fucose is a sugar that is widely incorporated in cellular glycoconjugates and has been implicated for roles in tumor progression and metastasis. An analog of fucose, 2-fluorofucose, has been shown to have activity in vitro and in vivo as an inhibitor of glycoconjugate fucosylation and has shown promising antitumor activity in cancer growth models as well as potentiation of the protective effect of a mouse B cell lymphoma idiotype vaccine against challenge by live A20 lymphoma cells (Okeley N.M. et al, PNAS 110, 5404-5409, 2013). The effects of 2-fluorofucose that mediate these activities was explored in vitro and in vivo. In vitro, we found that 2-fluorofucose is rapidly converted to GDP-2-fluorofucose, the active species that inhibits the de novo pathway for fucosylation of protein glycans. The molecule accumulates within cancer cells, and is retained with a half-life in the range of 20 hours. In vivo, evaluation of the effect of 2-fluorofucose treatment on the fucosylation and proliferation state of xenografts showed reduced LCA lectin binding by western blot and IHC, and reduced Ki-67 staining, suggesting a lower mitotic index in these tumors. Adoptive transfer experiments were undertaken in order to shed light onto potential mechanisms for the antitumor effects of 2-fluorofucose when used in a cancer vaccine setting. These studies were performed in mice that were immunized with an A20 idiotype vaccine in the presence or absence of 2-fluorofucose, prior to tumor challenge. The antitumor effects obtained when serum from 2-fluorofucose treated animals was injected into non-vaccinated mice suggested a role for defucosylated antibodies with enhanced ADCC activities. In addition, T cell depletion studies demonstrated that 2-fluorofucose stimulated a CD4+ T cell involvement in in the protection against tumor engraftment. These results suggest multifactorial roles for the activities of 2-fluorofucose as an anticancer agent and as a stimulator of vaccine activity.
Citation Format: Nicole M. Okeley, Weiping Zeng, Matthew R. Levengood, Julie A. McEarchern, Mechthild Jonas, Steven Duniho, Peter D. Senter, Che L. Law. Mechanistic evaluation of the anti-tumor activities of 2-fluorofucose alone and in combination with anti-idiotype vaccination. [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 2890. doi:10.1158/1538-7445.AM2014-2890
Abstract 2895: Small cell lung cancer cells express the late stage gBK tumor antigen: a possible immunotarget for the terminal disease
Authors: Hoa Neil T. , Ge Lisheng , Tajhya Rajeev B. , Beeton Christine , Cornforth Andrew N. , Abolhoda Amir , Lambrecht Nils , Dacosta-Iyer Maria , Ouyang Yi , Hickey Michelle J. , Erickson Kate L. , Kruse Carol A. , Jadus Martin R. 
Published: May 2015

Abstract
Big Potassium (BK) ion channels have several splice variants. One splice variant initially described within human glioma cells is called the glioma BK channel (gBK). This isoform consists of 33 amino acids inserted into the intracellular region of the BK ion channel. Using a gBK-specific antibody, we detected gBK within 3 human small cell lung cancer (SCLC) lines. Patch clamping revealed that functional membrane channels were found on the SCLC cells. Prolonged exposure to BK channel activators caused the SCLC cells to swell within 20 minutes and resulted in their cytotoxicity within 5 hours. Transfection of BK-negative HEK cells with gBK produced functional gBK channels. Quantitative RT-PCR analysis using primers specific for gBK, but not with a lung-specific marker, Sox11, confirmed that advanced, late-stage human SCLC tissues strongly expressed gBK mRNA. Normal human lung tissue and early, lower stage SCLC resected tissues very weakly expressed this transcript. Immunofluorescence using the gBK antibodies confirmed that SCLC cells taken at the time of autopsy intensely displayed this protein. gBK may represent a late-stage marker for SCLC. HLA-A*0201 restricted human CTL were generated in vitro by one-way mixed lymphocyte reactions or mixed lymphocyte dendritic cell reactions, the latter using gBK peptide pulsed dendritic cells. The exposure of SCLC cells to interferon-γ (IFN-γ) increased the expression of HLA; these treated cells were killed by the CTL better than non-IFN-γ treated cells even though the IFN-γ treated SCLC cells displayed diminished gBK protein expression. Prolonged incubation with recombinant IFN-γ slowed the in vitro growth and migration of the SCLC cells, suggesting it might inhibit tumor growth in vivo. Immunotherapy targeting gBK might possibly impede advancement to terminal state of SCLC.
Citation Format: Neil T. Hoa, Lisheng Ge, Rajeev B. Tajhya, Christine Beeton, Andrew N. Cornforth, Amir Abolhoda, Nils Lambrecht, Maria Dacosta-Iyer, Yi Ouyang, Michelle J. Hickey, Kate L. Erickson, Carol A. Kruse, Martin R. Jadus. Small cell lung cancer cells express the late stage gBK tumor antigen: a possible immunotarget for the terminal disease. [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 2895. doi:10.1158/1538-7445.AM2014-2895
Abstract 2901: Cell surface-associated anti-MUC1-derived signal peptide antibodies: implications for cancer diagnostics and therapy
Authors: Kovjazin Riva , Horn Galit , Smorodinsky Nechama I. , Shapira Michael Y. , Carmon Lior 
Published: May 2015

Abstract
The MUC1 tumor associated antigen is highly expressed on a range of tumors. Its broad distribution on primary tumors and metastases renders it an attractive target for immunotherapy. After synthesis MUC1 is cleaved, yielding a large soluble extracellular alpha subunit containing the tandem repeats array (TRA) domain specifically bound, via non-covalent interaction, to a smaller beta subunit containing the transmembrane and cytoplasmic domains. Thus far, inconclusive efficacy has been reported for anti-MUC1 antibodies directed against the soluble alpha subunit. Targeting the cell bound beta subunit, may bypass limitations posed by circulating TRA domains. MUC1's signal peptide (SP) domain promiscuously binds multiple MHC class II and Class I alleles, which upon vaccination, generated robust T-cell immunity against MUC1-positive tumors. This is a first demonstration of non-MHC associated, MUC1 specific, cell surfaces presence for MUC1 SP domain. Polyclonal and monoclonal antibodies generated against MUC1 SP domain specifically bind a large variety of MUC1-positive human solid and hematological tumor cell lines; MUC1-positive bone marrow derived plasma cells obtained from multiple myeloma (MM)-patients, but not MUC1 negative tumors cells, and normal naive primary blood and epithelial cells. Membranal MUC1 SP appears mainly as an independent entity but also co localized with the full MUC1 molecule. MUC1-SP specific binding in BM-derived plasma cells can assist in selecting patients to be treated with anti-MUC1 SP therapeutic vaccine, ImMucin. A therapeutic potential of the anti-MUC1 SP antibodies was suggested by their ability to support of complement-mediated lysis of MUC1-positive tumor cells but not MUC1 negative tumor cells and normal naive primary epithelial cells. Moreover in preliminary studies, anti-MUC1 SP antibodies delayed tumor growth of murine DA-3 cells transfected with human MUC1. These findings suggest a novel cell surface presence of MUC1 SP domain, a potential therapeutic benefit for anti-MUC1 SP antibodies in MUC1-positive tumors and a selection tool for MM patients to be treated with the anti-MUC1 SP vaccine, ImMucin.
Note: This abstract was not presented at the meeting.
Citation Format: Riva Kovjazin, Galit Horn, Nechama I. Smorodinsky, Michael Y. Shapira, Lior Carmon. Cell surface-associated anti-MUC1-derived signal peptide antibodies: implications for cancer diagnostics and therapy. [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 2901. doi:10.1158/1538-7445.AM2014-2901
Abstract 2903: IMAB362, a novel first-in-class monoclonal antibody for treatment of pancreatic cancer
Authors: Tuereci Oezlem , Woell Stefan , Jacobs Stefan , Mitnacht-Kraus Rita , Sahin Ugur 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most frequent subtype (&gt;80%) of pancreatic cancer (PC) is characterized by a generally lethal progress within a short period of time after primary diagnosis. Despite high efforts, the treatment options are very limited and mainly of palliative nature.
Therefore, we investigated whether IMAB362 might represent a potential treatment option in this patient population. IMAB362 is a highly potent and tumor-cell selective therapeutic antibody which is currently in clinical development in gastro-esophageal cancer (in phase II and IIb trials). IMAB362 is directed against the tight junction molecule CLDN18.2, a proliferation-promoting transmembrane protein, which is maintained during malignant transformation. Our previous studies demonstrated, that CLDN18.2 is expressed in &gt;55% of patients with PDAC and frequently in metastases at considerable levels. To evaluate the anti-tumor activity of IMAB362 we performed in vitro and in vivo experiments on CLDN18.2 expressing PC cell lines.
IMAB362 exerts its anti-tumor function by antibody-dependant cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ADCC was assessed in various cancer cell lines and peripheral blood mononuclear cells (PBMCs) at an E:T-ratio of 40:1 in the presence of IMAB362. The efficacy ranged from 67.1 ± 6.8 to 92.6 ± 5.5%. EC50 was determined between 23.4 ± 12.3 ng/ml and 5.7 ± 4.4 µg/ml. IMAB362's capacity to induce CDC was analyzed by incubation of various tumor cell lines with healthy human serum as source for complement. We observed a dose-dependent lysis with EC50 values ranging from 0.3 - 2.6 µg/ml.
In vivo studies in PC tumor bearing nude mice showed that administration of repeated doses of IMAB362 tends to result in inhibition of tumor growth and prolonged survival. Also, the anti-tumor effect of IMAB362 was strictly dependent on the expression of its target CLDN18.2. These results demonstrate that IMAB362 has antitumoral activity in vitro and in vivo against PC cell lines and PC xenografts. Most promising, the efficacy was due to IMAB362's single agent activity only. Combinations with established chemotherapies (e.g. 5-FU, gemcitabine) might deliver a strong rationale for clinical testing of the highly selective monoclonal antibody drug in patients with PDAC. Results from further in vivo testing of IMAB362 combinations with established chemotherapies will be presented at the meeting.
Citation Format: Oezlem Tuereci, Stefan Woell, Stefan Jacobs, Rita Mitnacht-Kraus, Ugur Sahin. IMAB362, a novel first-in-class monoclonal antibody for treatment of pancreatic 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 2903. doi:10.1158/1538-7445.AM2014-2903
Abstract 2924: MAPK pathway inhibition enhances the efficacy of an anti-endothelin B receptor drug conjugate by inducing target expression in melanoma
Authors: Asundi Jyoti , Polakis Paul , Lacap Jennifer A. , Nannini Michelle 
Published: May 2015

Abstract
Therapies targeting the MAP kinase pathway in melanoma have produced significant clinical responses; however, duration of response is limited by acquisition of drug resistance. Rationale drug combinations may improve outcomes in this setting. We assessed the therapeutic combination of an antibody drug conjugate (ADC) targeting the Endothelin B receptor (EDNRB) with small molecule inhibitors of the MAP kinase signaling pathway in melanoma. Cell lines and tumor models containing either mutant BRAF or NRAS, or wildtype for both, were exposed to small molecule inhibitors or BRAF and MEK. Expression of EDNRB was analyzed and the therapeutic impact of combining the anti-EDNRB ADC with the BRAF and MEK inhibitors was assessed. Increased expression of EDNRB in response to inhibition of BRAF and/or MEK was observed and augmented the antitumor activity of the ADC. Enhanced target expression and ADC anti-tumor activity were realized irrespective of the response of the tumor model to the BRAF or MEK inhibitors alone and could be achieved in melanoma with mutant NRAS, BRAF or neither mutation. Cells that acquired resistance to BRAF inhibition through long-term culture retained drug-induced elevated levels of EDNRB expression. Expression of EDNRB was not enhanced in normal human melanocytes by inhibition of BRAF and the combination of the ADC with MAPK inhibitors was well tolerated in mice. The anti-EDNRB ADC combines well with BRAF and MEK inhibitors and could have therapeutic utility in the majority of human melanoma cases.
Citation Format: Jyoti Asundi, Paul Polakis, Jennifer A. Lacap, Michelle Nannini. MAPK pathway inhibition enhances the efficacy of an anti-endothelin B receptor drug conjugate by inducing target expression in melanoma. [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 2924. doi:10.1158/1538-7445.AM2014-2924