bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2435: Validation of Cynomolgus monkeys as relevant species for safety assessment of a novel human BiTE antibody platform for cancer therapy
Authors: Rattel Benno , Kischel Roman , Thomas Oliver , Friedrich Matthias , Rau Doris , Ebert Evelyn , Raum Tobias , Wolf Andreas , Mangold Susanne , Kvesic Majk , Baeuerle Patrick A. , Kufer Peter 
Published: February 2011

Abstract
Nonclinical safety assessment of biopharmaceuticals for human use relies on their cross-reactivity with the respective target in other species, the absence of which precludes testing in commonly used animal models. This is the case for a first-generation of T cell-engaging BiTE antibodies, which solely cross-react with T cells of chimpanzee. BiTE antibodies are designed to transiently connect the CD3 subunit of T cell receptors on T cells with an antigen on target cells. This can very effectively activate T cells, leading to a potent redirected lysis of target cells.
Here, we have generated a series of novel human anti-CD3 antibodies that cross-react with non-human primate species, including Cynomolgus monkeys (Macaca fascicularis) and marmoset (Callithrix jacchus). The variable domains of a selected anti-CD3 antibody were used to generate next-generation BiTE antibodies specific for (1) CD33, a target antigen for treatment of acute myelogenous leukemia, (2) melanoma-associated chondroitin sulfate proteoglycan (MCSP), a potential target for treatment of melanoma, and (3) epidermal growth factor receptor 1 (EGFR), a validated target for treatment of colorectal cancer.
In vitro, CD33-, MCSP- and EGFR-specific BiTE antibodies showed comparable binding to CD3 on human and macaque T cells, and to CHO cells expressing CD33, MCSP and EGFR of human or macaque origin. In human and macaque cell-based assays, bispecific binding triggered redirected target cell lysis as well as conditional T cell activation, as previously described for first-generation BiTE antibodies.
When continuously infused for one week to Cynomolgus monkeys, the CD33-specific BiTE antibody caused depletion of CD33-expressing peripheral blood cells at tolerated doses, and reached a maximum tolerated dose (MTD) at 120 µg/m2/day. The EGFR-specific BiTE antibody reached an MTD at 150 µg/m2/kg. In contrast, the MCSP-specific BiTE antibody was well-tolerated up to a dose of 5,000 µg/m2/day. Our primate data suggest that the tolerability and toxicity of CD33-, MCSP- and EGFR-specific BiTE antibodies were apparently determined by target cell-dependent bispecific binding, and not by monovalent binding to CD3 on macaque T cells. Our data validate the Cynomolgus monkey as a relevant species for assessing the safety and tolerability of next-generation BiTE antibodies that use a more broadly cross-reactive anti-CD3 human single-chain antibody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2435.
Abstract 2441: An innovative treatment modality of antibody therapy against intracellular tumor antigens
Authors: Noguchi Takuro , Kato Takuma , Muraoka Daisuke , Ikeda Hiroaki , Kondo Satoshi , Ritter Gerd , Old Lloyd J. , Shiku Hiroshi , Nishikawa Hiroyoshi 
Published: February 2011

Abstract
Therapy with mAb directed against cell surface antigens of cancer is now a well-established treatment modality for human cancer. However, many tumor antigens of great interest have an intracellular location, and therefore not considered suitable targets for antibody therapy. On the other hand, it has been reported that mAbs targeted against specific tumor antigens induce cellular immune response including CD8+ T cells. This raises the possibility that the anti-tumor effects of mAb therapy may partially depend on enhanced cross-priming mediated by APCs following the uptake of antigen released from tumors complexed with Ab (immune-complex). Here, we investigated whether mAb therapy could be applicable to intracellular antigens using a transplantable colon carcinoma CT-26 expressing NY-ESO-1 (a well-studied human cancer/testis antigen), an intracellular antigen lacking cell surface expression. Immune responses to NY-ESO-1 in the murine model closely parallel NY-ESO-1 humoral and cellular immune responses in humans. To accentuate the natural release of intracellular NY-ESO-1 from dying tumor cells to facilitate immune-complex formation, we employed the effect the anti-cancer drug on the response to NY-ESO-1 mAb.
The combination of NY-ESO-1 mAb and 5-fluorouracil exhibited a strong and long-lasting anti-tumor effect that could not be achieved by treatment with either 5-fluorouracil or mAb alone. The anti-tumor effect induced by combination therapy was no longer observed when Fc-depleted Fab antibodies were used, indicating a Fc-dependent action on APCs. Furthermore, augmented anti-tumor effects observed by the combination therapy was associated with strong NY-ESO-1-specific CD8+ T cells in draining lymph nodes and tumor sites, and upregulation of maturation markers on dendritic cells. The opsoniziation of released intracellular tumor antigens with injected mAb facilitates uptake by APC and presentation to CD8+ T cells, leading to accelerated and augmented active immunization. The data indicate that mAb to intracellular molecules of cancer represents a promising approach to cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2441.
Abstract 245: An oncogenic role for CCAAT/enhancer binding protein beta in non-small cell lung cancer
Authors: Thoennissen Nils H. , Iwanski Gabriela B. , Ji Jianfei , Ikezoe Takayuki , Lee Kunik , Adachi Yoshihiro , Takeuchi Tamotsu , Furihata Mutsuo , Park Dorothy J. , Gombart Adrian F. , Koeffler H. Phillip 
Published: February 2011

Abstract
The transcription factor CCAAT/enhancer binding protein (C/EBP) beta is known to be a mediator of cellular transformation and tumorigenesis in human colon, breast and ovary cancer. In this study, we focused on C/EBPbeta and its potential role in non-small cell lung cancer (NSCLC). Immunohistochemical staining of 60 human NSCLC samples (adeno- (31), squamous cell - (25), small cell - (1), large cell - (2), and adeno-squamous cell (1) carcinoma) showed that more than 50% of the tumor samples were significantly positive for nuclear staining of C/EBPbeta compared to healthy airway epithelial cells. Retrovirus-delivered siRNA knock-down of C/EBPbeta expression in human NSCLC cell lines A549, H520, and H460 markedly reduced clonogenic growth, which was accompanied by a significant reduction in cyclooxygenase(COX)-2 expression, increase in G0/G1 cells, and PARP cleavage activity. In contrast, using NSCLC cell line Calu-3 with a moderate intrinsic level of C/EBPbeta, forced expression of this transcription factor even increased clonogenic growth and cell proliferation. Whereas recent studies suggested that family member C/EBPalpha has growth-inhibitory properties in airway epithelial cells, our present data indicate an oncogenic role of C/EBPbeta in NSCLC and may represent a new target for cancer co-therapy to increase response to existing chemotherapeutic regimens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 245.
Abstract 2455: The fjord region (±)-anti-dibenzo[a,l]pyrene-11,12-dihydrodiol-13,14-epoxides ((±)-anti-DB[a,l]PDE), is a powerful and specific inducer of squamous cell carcinoma in the oral cavity of mice
Authors: Chen Kun-Ming , Guttenplan Joseph B. , Aliaga Cesar , Cooper Timothy , Deltondo Joseph , Kosinska Wieslawa , Sharma Arun K. , Sun Yuan-Wan , Zhang Shangmin , Jiang Kun , Bruggeman Richard , Amin Shantu , El-Bayoumy Karam 
Published: February 2011

Abstract
Head and neck squamous cell carcinoma (HNSCC), the sixth most common malignancy, represents a major international public health problem. The vast majority of HNSCC occurs in the oral cavity. Cancer of the mouth strikes about 30,000 Americans each year and less than 50% of patients survive 5 years after diagnosis. Tobacco and alcohol use are considered major causative agents. Current preclinical animal models to study oral carcinogenesis do not accurately mimic the biology of this disease in humans. We have developed a new mouse model by the application of the fjord region diol epoxide, (±)-anti-DB[a,l]PDE, a metabolite of the tobacco constituent dibenzo[a,l]pyrene (DB[a,l]P), to the oral cavity, and we showed for the first time that it is a powerful and specific inducer of oral squamous cell carcinoma (OSCC) in both tongue and oral tissues. Briefly, two groups of B6C3F1 mice (20/group) received doses of (±)-anti-DB[a,l]PDE (6, and 3 nmol) administered into the oral cavity; additional groups received the vehicle or left untreated as controls, 3 time a week for 38 weeks. Mice were sacrificed one year after the first carcinogen administration. The high dose induced 74 % and 100 % OSCC in the tongue and oral tissues, respectively; the corresponding values at the lower dose were 45 % and 89 %. Consistent with the carcinogenicity, we demonstrated powerful mutagenicity in CII gene in big blue mice and the mutation spectra in both tongue and oral tissues revealed similarity in the profiles between DB[a,l]PDE, and that of p53 mutations found in human OSCC. Using immunohistochemistry, we showed that (±)-anti-DB[a,l]PDE resulted in overexpression of p53 protein in malignant tissues compared to normal oral tissues and tongues.
Collectively, we developed a non-surgical whole animal model which is the first to demonstrate the remarkable carcinogenicity and specificity of (±)-anti-DB[a,l]PDE in the oral cavity; this model is an appropriate platform for further exploring the genetic and epigenetic alterations that can truly account for the development of OSCC on humans. In addition, this model can be employed to study efficacies of novel cancer chemopreventive agents.
Supported by NCI grant no. R01 CA 100924.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2455.
Abstract 2456: Mechanism of pancreatic cancer induction by smoking
Authors: Park ChangHwan , Lee In Seok , Abdulsattar Amro M. , Grippo Paul J. , Pandol Stephen J. , Gukovskaya Anna S. , Edderkaoui Mouad 
Published: February 2011

Abstract
Background & Aims: Cigarette smoking is a major risk factor for pancreatic cancer. However, the molecular signaling mechanisms of cigarette smoking remain poorly understood. We studied the effects of the cigarette smoking extract (CSE) and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on apoptosis, proliferation and autophagy and underlying signaling mechanisms both in vitro in human pancreatic ductal cells and in vivo in mouse pancreas. We also studied the effect of K-ras mutation on the smoking-induced cell survival and proliferation. Methods: Immortalized human ductal cells HPDE6 were cultured for up to 1 week in the presence or absence of CSE (0.04-4µg/ml) or NNK (1nM-1µM). Pancreas-specific K-ras transgenic mice EL-K-ras were used as a cancer model. Wild type and EL-K-ras mice were injected with NNK (100mg/Kg) once weekly for 4 weeks and animals sacrificed 72h after the last injection. Apoptosis was assessed by measuring DNA fragmentation with Cell death ELISA or TUNEL and proliferation by 3H-thymidine incorporation into DNA or BrdUrd labeling. Autophagy was measured with its marker LC3 using immunofluorescence staining. Molecular signaling mechanisms were evaluated with Western. Results: Exposure of human ductal cells to CSE and NNK for 24h to 1 week time-dependently decreased apoptosis and autophagy and increased proliferation. Exposure to CSE and NNK decreased AMPK phosphorylation and increased Akt phosphorylation. Akt activation occurred at the times of AMPK inhibition. Pharmacological Akt inactivation reversed the inhibition of AMPK phosphorylation by CSE and NNK and prevented the effects of CSE and NNK on apoptosis and autophagy, indicating a central role of Akt in the prosurvival effects of tobacco compounds. In K-ras mice model of pancreatic cancer NNK injections induced increase in Akt kinase and decrease in AMPK phosphorylation. NNK decreased autophagy and apoptosis and stimulated proliferation in the pancreas. The NNK inhibitory effect on apoptosis and autophagy and the stimulation of proliferation were more pronounced in K-ras mice compared to wild type mice. Conclusion: Our in vitro and in vivo data indicate that smoking compounds create conditions favorable for cancer promotion through activating survival pathways including activation of Akt kinase and inhibition of AMPK activities; this leads to a decrease in apoptosis and autophagy and stimulation of proliferation. Our data suggest that smoking works in concert with K-ras mutation to induce adenocarcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2456.
Abstract 2460: Epstein-Barr virus infection confer stress-resistant property in immortalized nasopharyngeal epithelial cells
Authors: Tsao George Sai-Wah , Tsang CM , Zhang GT , Deng Wen , Hau PM , Man CM , Kenzo Takada , Chen HL , Yip YL , Lo KW , Cao Ya , Cheung LM 
Published: February 2011

Abstract
Epstein-Barr virus (EBV) infection has been postulated to be an early event involved in the pathogenesis of NPC. The lack of representative premalignant nasopharyngeal epithelial cell system for EBV infection has hampered research investigation into the regulation and involvement of EBV infection in NPC pathogenesis. We have compared the efficiency of EBV infection in nasopharyngeal epithelial cells with different biological properties including immortalized, primary and cancerous nasopharyngeal epithelial cells. EBV infection could be achieved in all the nasopharyngeal epithelial cells examined with variable infection rate. TGF-β effectively enhanced EBV infection into nasopharyngeal epithelial cells both in the immortalized and primary nasopharyngeal epithelial cells. Stable infection of EBV was achieved in a telomerase-immortalized nasopharyngeal epithelial cell line, NP460hTert. The expression pattern of EBV-encoded genes and biological properties of this EBV infected cell line upon long term propagation were monitored. The EBV-infected nasopharyngeal epithelial cells acquired anchorage independent growth in soft-agar and exhibited invasive growth properties upon prolonged propagation. A distinguish feature of this EBV-infected nasopharyngeal epithelial cell model was its enhanced ability to survive under growth factor and nutrient starvation. This was evidenced by the suppressed activation of apoptotic markers and sustained activation of pAkt of EBV-infected cells compared to control cells under nutrient starvation. Examination of cytokine profiles of EBV-infected NP460hTert cells to nutrient and growth factor deprivation revealed upregulation expression of MCP-1 and GRO-α. The establishment of a stable EBV infection model of premalignant nasopharyngeal epithelial cells will facilitate research investigation into the pathogenic role of EBV in NPC development.
Acknowlegement: The authors wish to acknowlege the funding support from the Research Grant Council (Hong Kong) and the Area of Excellence on Nasopharyangeal Carcinoma Research Center (Hong Kong).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2460.
Abstract 2463: Overexpression of galectin-7 in mouse skin inhibits tumorigenesis
Authors: Simper Melissa S. , Thomas Megan M. , Clifford John L. , Fischer Susan M. 
Published: February 2011

Abstract
Galectins are a family of proteins that contain conserved sequences in the carbohydrate-binding region that bind to β-galactosides. Galectin expression differs between tissues in addition to different stages of development and also has altered expression during tumor development. Galectin-7 (Gal-7) has been linked to both apoptosis and reduced cell growth in vitro, but conversely, upregulation of Gal-7 in skin has been reported in many transgenic mice that have endogenous skin tumor promoting activity in addition to being associated with an aggressive phenotype in lymphoma cells. To further investigate this conflicting evidence, the role of Gal-7 in skin carcinogenesis was examined. Gal-7 mRNA and protein levels were elevated in mouse skin after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment, while Gal-7 stably-transfected cells showed a decrease in tumor growth when compared to vector stably-transfected cells after injection into nude mice, although no difference in cell growth in vitro was observed. Transgenic mice were then generated that overexpress a flag-tagged Gal-7 protein in the basal layer of the skin under the control of the bovine keratin 5 promoter (K5. Gal-7). These mice display no visible phenotype, but immunohistochemistry shows the transgene is present and expressed. Using a two-stage chemical carcinogenesis protocol, the K5. Gal-7 mice were shown to develop significantly fewer papillomas and squamous cell carcinomas than wild type (WT) mice, though no difference in proliferation or apoptosis was seen in response to TPA treatment. No difference in the inflammatory response to TPA was observed, with the exception of a spike in B cells 36 hours after TPA. However, untreated K5. Gal-7 mice showed a decrease in T and B cells compared to WT mice. This supports data from a reverse phase protein array that indicates annexin, which suppresses phospholipase A2 and inhibits inflammation, is upregulated in the K5. Gal-7 mice. These data suggest that overexpression of Gal-7 in the mouse skin inhibits tumorigenesis, possibly through the inhibition of inflammation. Supported by CA100140.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2463.
Abstract 2466: Tobacco carcinogen-enhanced lung tumorigenesis in Gprc5a knockout mice recapitulates human lung cancer development
Authors: Fujimoto Junya , Kadara Humam N. , Tao Qingguo , Men Taoyan , van Pelt Carolyn , Lotan Dafna , Lotan Reuben 
Published: February 2011

Abstract
Lung carcinogenesis occurs through a multi-step process, which involves the activation or over-expression of oncogenes and the inactivation or silencing of tumor-suppressor genes. Mouse models for human lung cancer have proven to be valuable tools for understanding the basic tumor biology as well as for the development and validation of new approaches to cancer prevention and therapy. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months). To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n=5) of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A signature of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The signature also separated both mouse and human adenocarcinomas from normal lung tissues based on publicly available microarray datasets. A key feature of the signature, up-regulation of UBE2C, MCM2, and FEN-1, was validated in mouse normal lung and adenocarcinoma tissues and cells by immunohistochemistry and western blotting, respectively. Our findings support the following conclusions: 1) lung tumorigenesis in the Gprc5a-KO mouse model is augmented by NNK, 2) gene expression changes induced by tobacco carcinogen(s) are conserved between mouse and human lung epithelial cells, 3) the Gprc5a-KO mouse model recapitulates human lung adenocarcinoma. Thus, the Gprc5a-KO mouse model could be useful for cancer chemoprevention studies. Supported by the Samueal Waxman Cancer Research Foundation and the NCI Cancer Center Core Grant P30-CA16672.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2466.
Abstract 2476: Tumor development in transgenic mice constitutively expressing hypoxia-inducible factor-1α
Authors: Ide Masaru , Sueoka Eisaburo , Aragane Naoko , Sato Akemi , Nakamura Tomoko , Nakamura Hideaki , Hiyama Keiko , Kimura Shinya , Tanimoto Keiji 
Published: February 2011

Abstract
Hypoxia-inducible factor-1α (HIF-1α) has an essential transcription factor for regulation of various genes associated with hypoxic condition in tissues. Elevated expression of HIF-1α has been reported in many cancers associated with tumor progression, invasion and metastasis. To investigate the role of HIF-1α in tumor development and metastasis, we established transgenic mice constitutively expressing HIF-1α gene under regulation of CMV promoter. The transgenic mice showed no gross morphological abnormality until 3 months after birth, but the mice developed tumors in lymphoid, lung and breast tissues. The incidence of tumor bearing in transgenic mice was up to 90% until 18 months after birth. Expression of HIF-1α mRNA and protein was varied among tissues, but the amount of HIF-1α gene was gradually increased in an age-dependent manner. To clarify the molecular mechanism of lymphomagenesis in the transgenic mice, subpopulation of the lymphocytes, mitogenic responsiveness and cytokine production on lymphocyte from transgenic mice were analyzed. We next analyzed the expression of HIF-1α in human lymphoma tissues and found apparent expression of the gene in angioimmunoblastic T cell lymphoma (AILT). Since VEGF expression and marked increase of small vessels in tumor tissues are common features in AILT, HIF-1α may play an important role in pathogenesis of the lymphoma. We present the results concerning the role of HIF-1α in lymphoma occurrence, and will discuss the contribution of the transcription factor in human cancer development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2476.