bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 625: Proliferative effects of the phytoestrogens 8-Prenylnaringenin, 6-(1.1-dimethylallyl)naringenin and Naringenin in MCF-7 cells and the rat mammary gland
Authors: Helle Janina , Zierau Oliver , Kräker Kristin , Keiler Annekathrin , Vollmer Günter , Welsh JoEllen , Kretzschmar Georg 
Published: May 2015

Abstract
Evaluation of stimulation of proliferation in female reproductive organs by phytoestrogens of reproductive tract organs is important to estimate their safety/risk profile if used as an alternative to hormone therapy. To assess the proliferative capacity of the flavanones 8-Prenylnaringenin (8-PN), 6-(1.1-dimethylallyl)naringenin (6-DMAN) and Naringenin (Nar) on the mammary gland we compared their estrogenic properties to 17β-Estradiol (E2) in three independent assays. We performed competitive estrogen receptor (ER) ligand binding assays, MCF-7 proliferation studies and a three day exposure experiment in young adult ovariectomized female rats. 8-PN displayed a high relative binding affinity for both ERs with a preference for ERα (19.46 %) compared to ERβ (6.5 %). Among the tested flavanones 8-PN had the strongest mitotic effect on MCF-7 cells. In vivo 8-PN increased the number of terminal end buds (TEB) in the mammary gland and the protein expression of the proliferation markers Ki-67 and PCNA in epithelial ductal cells and further led to an increase of Amphiregulin (Areg) mRNA expression, endpoints correlated to mammary gland proliferation. 6-DMAN also possesses a higher relative binding affinity for the ERα than for the ERβ (1.46 %, 0.84 %) and stimulated the cell proliferation of MCF-7 cells. It enhanced Ki-67 protein expression and β-Casein mRNA expression in vivo. Nar displayed the weakest estrogenic properties and was the only tested compound with a higher affinity for the ERβ than the ERα (0.5 %, 0.08 %). It displayed proliferative effects on MCF-7 cells and slightly induced Ki-67 protein expression in vivo.
Citation Format: Janina Helle, Oliver Zierau, Kristin Kräker, Annekathrin Keiler, Günter Vollmer, JoEllen Welsh, Georg Kretzschmar. Proliferative effects of the phytoestrogens 8-Prenylnaringenin, 6-(1.1-dimethylallyl)naringenin and Naringenin in MCF-7 cells and the rat mammary gland. [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 625. doi:10.1158/1538-7445.AM2014-625
Abstract 645: IGM-55.5, a novel monoclonal human recombinant IgM antibody with potent activity against B cell leukemia and lymphoma
Authors: Duramad Omar , Wang Beatrice , Zheng Fen , Keyt Lena , Repellin Claire , Beviglia Lucia , Bhat Neelima , Bieber Marcia , Teng Nelson , Keyt Bruce 
Published: May 2015

Abstract
IGM-55.5 is an engineered monoclonal human recombinant IgM antibody that was derived from a natural monoclonal antibody 216 isolated at Stanford University from the splenocytes of a patient with Non-Hodgkin's lymphoma. HuMab 216 was previously used in a B-cell acute lymphoblastic leukemia phase I trial and was demonstrated to be well tolerated with significant decrease in peripheral blasts observed (Liedtke et al, Haematologica, 2012). IGM-55.5 has been engineered to be mono-reactive and recognizes a carbohydrate determinant as an epitope on normal human B cells as well as B-cell lymphoma and B-progenitor lymphoblasts.
Here, we report new preclinical studies that describe the mechanism of action and potent activity of IGM-55.5. In-vitro analysis of IGM-55.5 was found to have high surface binding on a broad panel of B cell leukemia and lymphoma cells lines by flow cytometry. IGM-55.5 binding leads to the disruption of the plasma membrane and formation of large membrane pores resulting in cell lysis. This non-classical apoptosis occurs in the absence of complement fixation but in vitro cytotoxicity is increased in assays in the presence of human complement. Studies with aggressive disseminated tumor xenograft models (Namalwa, Granta, & Nalm-6) demonstrate that IGM-55.5 significantly prolongs survival and reduces circulating tumor cells. Peripheral blood samples from chronic lymphocytic leukemia patients demonstrated the potent activity of IGM-55 in eliminating B cell lymphoblasts in comparison with Rituxan when treated in-vitro. These data taken together highlight the potent activity of IGM-55.5 as therapeutic for advanced B cell malignancies, especially indicated for Rituxan resistant or refractory patients.
Citation Format: Omar Duramad, Beatrice Wang, Fen Zheng, Lena Keyt, Claire Repellin, Lucia Beviglia, Neelima Bhat, Marcia Bieber, Nelson Teng, Bruce Keyt. IGM-55.5, a novel monoclonal human recombinant IgM antibody with potent activity against B cell leukemia and lymphoma. [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 645. doi:10.1158/1538-7445.AM2014-645
Abstract 655: Effect of antibody mixtures on HER-family heterodimerization
Authors: Ellebæk Sofie , Bouquin Thomas , Grandal Michael V. , Kragh Michael , Poulsen Thomas T. 
Published: May 2015

Abstract
Members of the human epidermal growth factor receptor (HER)-family, i.e. EGFR, HER2, and HER3, are key oncogenic drivers in numerous cancer forms. Monoclonal antibody therapeutics targeting EGFR and HER2 have been clinically approved and HER3-targeting antibodies are in clinical development. However, resistance to single HER treatment occurs due to mechanisms such as incomplete target elimination and a switch of receptor dependency in the resistant cancer cell population. Another potential escape mechanism for the cancer cells to become resistant and maintain oncogenic signaling is receptor heterodimerization. It is therefore relevant to investigate how heterodimers can be downregulated when targeted with antibodies against a single or multiple HER targets. It is well established that mixtures of two or more antibodies against a single HER family receptor induce superior and rapid receptor downregulation and elimination compared with monoclonal antibodies. However, the effect of antibody mixtures on HER heterodimer distribution has not been investigated.
At Symphogen, we have generated Pan-HER, a combination of two EGFR-, two HER2-, and two HER3-targeting monoclonal antibodies with non-overlapping epitopes in a single drug compound. Detection and quantification of the HER family member distribution in selected cancer cell lines, as well as proliferation assays with combinations of the antibody components comprising Pan-HER have been performed to investigate the effects of 2-, 4- and 6-mixtures of antibodies. Results from studies focusing on characterization of receptor levels, surface expression and heterodimer formation in Pan-HER responsive cancer cell lines will be presented, as well as the effect of Pan-HER on receptor heterodimer distribution, investigated by Co-IP and Duolink Proximity Ligation Assay technology. Our results show that mixtures of antibodies against more than one HER family member potently downregulate the HER family receptor levels and significantly alter the HER family heterodimerization pattern upon short- and long-term exposure to HER-targeting antibodies.
Citation Format: Sofie Ellebæk, Thomas Bouquin, Michael V. Grandal, Michael Kragh, Thomas T. Poulsen. Effect of antibody mixtures on HER-family heterodimerization. [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 655. doi:10.1158/1538-7445.AM2014-655
Abstract 656: A bispecific HER2/CD3 targeting FynomAb with excellent tumor killing and favorable pharmacokinetic properties
Authors: Wuellner Ulrich , Buller Fabian , Klupsch Kristina , Brack Simon , Zbinden Irene , Santimaria Roger , Attinger-Toller Isabella , König-Friedrich Susann , Bertschinger Julian , Grabulovski Dragan 
Published: May 2015

Abstract
There is increasing evidence that T cells are able to control tumor growth and increase survival of cancer patients. However, tumor-specific T cell responses are difficult to mount and sustain in cancer patients, and are limited by numerous immune escape mechanisms of tumor cells. A promising approach in the immunotherapy of cancer is to engage T cells to target tumor cells using bispecific therapeutics targeting a tumor-associated surface antigen and CD3e on T cells. Such therapeutics elicit T cell mediated lysis of tumor cells independent of T cell specificity.
Fynomers are small 7 kDa globular proteins derived from the SH3 domain of the human Fyn kinase (Fyn SH3) that can be engineered to bind with antibody-like affinity and specificity to virtually any target of choice. Fynomers can be fused to N-terminal and/or C-terminal ends of antibodies to generate multispecific therapeutics (FynomAbs) with tailored architectures. FynomAbs can be produced using standard antibody technology (GMP production yield of 3.3 g/L at 1000 L scale achieved), and show IgG-like biophysical properties and pharmacokinetic profiles.
We have generated a novel bispecific FynomAb which can simultaneously bind HER2 on tumor cells and CD3 on T cells. The bispecific HER2/CD3 targeting FynomAb COVA420 potently redirected T cells to HER2 expressing tumor cells showing picomolar tumor cell lysis activity. We present for the first time that a tailored architecture of the FynomAb leads to optimal tumor cell killing properties. The activity of COVA420 was found to be highly specific, as no lysis of cells was observed in the absence of HER2 expression.
In addition, COVA420 demonstrated an antibody-like pharmacokinetic profile in mice. We anticipate that the increased half-life of T cell recruiting FynomAbs compared to other bispecific formats translates into a significant benefit for patients, since it circumvents the need for continuous infusion and prolongs the intervals between successive treatments.
In summary, bispecific T cell recruiting FynomAbs represent a novel platform technology to redirect T cells to tumor cells with optimal biophysical properties, long-half lives and tailored architectures.
Citation Format: Ulrich Wuellner, Fabian Buller, Kristina Klupsch, Simon Brack, Irene Zbinden, Roger Santimaria, Isabella Attinger-Toller, Susann König-Friedrich, Julian Bertschinger, Dragan Grabulovski. A bispecific HER2/CD3 targeting FynomAb with excellent tumor killing and favorable pharmacokinetic properties. [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 656. doi:10.1158/1538-7445.AM2014-656
Abstract 664: Amanitin-based antibody-drug conjugates targeting the prostate-specific membrane antigen
Authors: Hechler Torsten , Kulke Michael , Mueller Christoph , Pahl Andreas , Anderl Jan 
Published: May 2015

Abstract
Antitumoral activity of monoclonal antibodies can be dramatically enhanced by conjugation to toxic small molecules. Beside the recent approval of Kadcyla (T-DM1) and Adcetris (SGN-35) more than 30 antibody-drug conjugates (ADC) have entered clinical trials, promising to strengthen the therapeutic capabilities for cancer treatment in the next decade. Surprisingly most ADCs are based on one of few toxic compounds only and on an even smaller number of toxicity mechanisms: Most antibodies are coupled to the microtubuli-targeting auristatins and maytansines. Toxins that operate through such a mechanism could suffer from limited activity in different cancer indications and in cells expressing resistance mechanisms. Accordingly the use of new drugs that function via alternative toxicity mechanisms could enhance the therapeutic potential of ADCs.
In the present study we evaluated the antitumoral potency of a monoclonal antibody targeting the prostate-specific membrane antigen (PSMA) conjugated to small molecules from the amatoxin family. PSMA is a membrane antigen overexpressed in prostate cancer and an attractive target for an ADC approach, as it shows low expression by most normal tissues and sufficient internalization after antibody binding. Amanitin, the most well-known toxin of the amatoxin family, binds to the eukaryotic RNA pol II and thereby inhibits the cellular transcription at very low concentrations. In our experiments, we tested several random- and site-specific strategies to covalently conjugate amanitin to the antibody and generated conjugates with low aggregation and high affinity for the target antigen. Using a series of PSMA-expressing cells we compared the cytotoxic activity of stable and cleavable linker ADCs and the stability of such constructs in plasma. Overall we observed picomolar activity of ADCs after incubation for three to five days with PSMA-positive prostate cancer cells independent of the hormone-sensitivity status. Moreover we demonstrated high activity of amanitin-based anti-PSMA ADCs in prostate cancer xenograft models. The data encourage the evaluation of these agents in a clinical advanced prostate cancer study.
Note: This abstract was not presented at the meeting.
Citation Format: Torsten Hechler, Michael Kulke, Christoph Mueller, Andreas Pahl, Jan Anderl. Amanitin-based antibody-drug conjugates targeting the prostate-specific membrane antigen. [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 664. doi:10.1158/1538-7445.AM2014-664
Abstract 682: Identification of HSP90 inhibitor sensitizers through pooled RNA interference screen
Authors: Chen Yaoyu , Chen Jinyun , Loo Alice , Mclaughlin Margaret , Pagliarini Raymond , Zhou Wenlai 
Published: May 2015

Abstract
Key words: HSF1, cancer cells, HSP90 inhibitor, Melanoma, HCC, DEDD2.
The molecular chaperone heat shock protein 90 (HSP90) facilitates the appropriate folding of various oncogenic proteins and is necessary for the survival of some cancer cells. HSP90 is therefore an attractive drug target, but the efficacy of HSP90 inhibitor may be limited by HSP90 inhibition induced feedback mechanisms. To identify genes that modulate the efficacy of HSP90 inhibition on tumor cell growth, we performed a large-scale RNA interference (RNAi) genetic screen with a collection of short hairpin RNA (shRNA) vectors targeting 1,000 human genes in A375. A barcoding technique was used to identify genes whose suppression caused resistance or sensitivity to two separate concentrations of NVP-AUY922. 163 and 360 shRNA constructs were significantly depleted form either low- or high-dose NVP-AUY922 treated samples (FDR&lt;=0.15). Among those shRNA hits, 84 hits (including 81 genes) were common shRNA hits as shown in Venn diagram and sensitizing genes or rescuing genes were also shown. Among of these shRNA hits, HSF1 and heat shock protein 90 alpha, class B member 1(HSP90AB1) knockdown scored as the most top sensitizers to HSP90 inhibition in A375 cells, and are known to regulate the cell response to heat shock conditions, which may reflect the potential feedback mechanism of HSP90 inhibition. Taking together, HSF1 is identified as a sensitizer of HSP90 inhibitor through pooled shRNA screening. A striking combinational effect was observed when HSF1 knockdown plus with HSP90 inhibitors treatment in various cancer cell lines: A375, A2058 and HCT116 and tumor mouse models. Interestingly, HSF1 is highly expressed in hepatocellular carcinoma (HCC) patient samples and HCC is sensitive to combinational treatment, indicating a potential indication for the combinational treatment. To understand the mechanism of the combinational effect, we identified that a HSF1-target gene DEDD2 is involved in attenuating the effect of HSP90 inhibitors. Thus, the transcriptional activities of HSF1 induced by HSP90 inhibitors provide a feedback mechanism of limiting the HSP90 inhibitor's activity, and targeting HSF1 may provide a new avenue to enhance HSP90 inhibitors activity in human cancers.
Citation Format: Yaoyu Chen, Jinyun Chen, Alice Loo, Margaret Mclaughlin, Raymond Pagliarini, Wenlai Zhou. Identification of HSP90 inhibitor sensitizers through pooled RNA interference screen. [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 682. doi:10.1158/1538-7445.AM2014-682
Abstract 73: Ewing's sarcoma Ewsa protein regulates Sox9 during skeletogenesis in zebrafish
Authors: Merkes Chris , Turkalo Timothy K. , Wilder Nicole , Park Hyewon , Azuma Mizuki 
Published: May 2015

Abstract
Ewing's sarcoma is the second most common bone cancer in adolescents and is characterized by the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in splicing and transcription, but how these functions affect early development is unknown. To elucidate the function of EWS in early development, we analyzed a mutant ewsa zebrafish line. We generated a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appear to be normal and fertile. The adult MZ ewsa/ewsa mutants display defects in the craniofacial bones (dentary and basihyal). Compared to wt/wt, the MZ ewsa/ewsa mutants have a higher number of craniofacial prehypertrophic chondrocytes, and they fail to mature into hypertrophic chondrocytes possibly due to impaired intercalation at 4 days post-fertilization (dpf). The adult MZ ewsa/ewsa mutants also display curved spines due aberrant differentiation of the nucleus pulposus cells in the intervertebral discs (IVD). These altered differentiation is preceded by increased Collagen type II in the IVD, and Ctgf in the craniofacial chondrocytes in MZ ewsa/ewsa mutants compared to wt/wt at 36 hpf. We further discovered that both Ewsa and Ewsb interact with the master transcriptional factor for chondrogenesis, Sox9, in zebrafish. Consistently, qPCR analysis consistently demonstrated that Sox9 target genes are either upregulated (ctgfa, ctgfb, col2a1a, col2a1b) or downregulated (sox5, nog1, nog2, bmp4) in MZ ewsa/ewsa mutants compared to the wt/wt zebrafish embryos. This study is the first demonstration of Ewsa-dependent regulation of skeletogenesis through modulation of Sox9 target gene expression.
Citation Format: Chris Merkes, Timothy K. Turkalo, Nicole Wilder, Hyewon Park, Mizuki Azuma. Ewing's sarcoma Ewsa protein regulates Sox9 during skeletogenesis in zebrafish. [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 73. doi:10.1158/1538-7445.AM2014-73
Abstract 760: Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 transport
Authors: Patel Atish S. 
Published: May 2015

Abstract
Cancer is a disease whose treatment is often limited due to the development of a phenomenon known as multidrug resistance (MDR) that is its Achilles’ heel. Hence there is an immense demand for development of novel agents that can overcome the emergence of multidrug resistance (MDR) in cancer. A group of transmembrane proteins called ABC (ATP- binding cassette) transporters, present ubiquitously in the human body possesses a modular architecture, contributing immensely towards the development of MDR in various tumor types.
An analysis of structural congeners among a group of compounds led to the discovery of CCTA-1523 that could selectively reverse ABCG2-mediated MDR in cancer cells both in vitro and in vivo. CCTA-1523 at concentrations upto 5 μM sensitized the cancer cells as well as transfected cells overexpressing ABCG2 to the substrate chemotherapeutic drugs. The reversal ability of CCTA-1523 was primarily due to the inhibition of the active efflux function of the transporter; also there was no change in the protein expression of the ABCG2 transporter in the presence of CCTA-1523 at reversing concentrations. Importantly the reversal effect produced by CCTA-1523 was reversible. Co-administration of CCTA-1523 restored the in vivo antitumor activity of doxorubicin in ABCG2 overexpressing tumor xenografts without added toxicity. Taken together, our findings indicate that CCTA-1523 is a potent and reversible, modulator of ABCG2 export function that may offer therapeutic promise for multidrug- resistant malignancies.
Citation Format: Atish S. Patel. Suppression of ABCG2 mediated MDR in vitro and in vivo by a novel inhibitor of ABCG2 transport. [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 760. doi:10.1158/1538-7445.AM2014-760
Abstract 781: Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms
Authors: Matsuoka Kazuaki , Kobunai Takashi , Takechi Teiji 
Published: May 2015

Abstract
Background: TAS-102 is a novel oral nucleoside antitumor agent consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). TAS-102 was found to significantly improve the overall survival of patients with metastatic colorectal cancer who were refractory to treatment with a fluoropyrimidine, irinotecan, and oxaliplatin in a double-blind randomized phase II study. Although significant survival benefits from 5-fluorouracil (5-FU)-based chemotherapy have also been reported in patients with gastric cancer, many patients experience recurrences after several courses of 5-FU-based chemotherapy. The resistance of gastric tumors to 5-FU therapy is thus a major clinical problem. In this study, the efficacy of FTD against 5-FU-resistant human gastric cancer cell lines was investigated. Method: 5-FU-resistant cell lines established by continuously exposing the parent cell lines (MKN-45, MKN-74, and KATOIII) to escalating concentrations (1-5 μM) of 5-FU over a 1-year period were used. The sensitivities of the cell lines to FTD were evaluated using a crystal violet staining assay. To elucidate the mechanism by which resistance is overcome, the mRNA levels of TK1, which converts FTD into an active monophosphate form, and hENT1, which is involved in the cellular uptake of FTD, were determined using RT-PCR. Results: The resistant cell lines KATOIII/5FU, MKN74/5FU, and MKN45/5FU exhibited a 2.0-fold, 4.8-fold, and 14.2-fold resistance to 5-FU, compared with their parent cell lines, respectively. MKN-45/5FU also showed a 3.7-fold resistance to FTD, whereas MKN-74/5FU (1.0-fold) and KATOIII/5FU (1.2-fold) showed no cross-resistance to FTD. The TK1 mRNA level was decreased by 40% in the MKN-45/5FU cells, compared with the parent cell line. Furthermore, this cell line showed a 60% decrease in the mRNA level for hENT1. In contrast, the hENT1 mRNA level increased by 1.6-fold in the KATOIII/5FU cells, with a 50% decrease in the TK1 mRNA level. The TK1 and hENT1 mRNA levels in MKN-74/5FU were increased by 1.9-fold and 1.7-fold, respectively. Conclusion: FTD was able to overcome the resistance to 5-FU in 2 out of 3 resistant cell lines in vitro, with MKN45/5FU exhibiting a partial cross-resistance to FTD. These results suggest that TAS-102 might be a promising chemotherapeutic agent for the treatment of gastric cancer relapses after 5-FU-based treatment. Furthermore, TK1 and hENT1 might be involved in FTD-related cytotoxicity.
Citation Format: Kazuaki Matsuoka, Takashi Kobunai, Teiji Takechi. Efficacy of trifluridine for 5-fluorouracil-resistant human gastric cancer cell lines and their mechanisms. [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 781. doi:10.1158/1538-7445.AM2014-781