bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 589: DNA demethylating agent and histone deacetylation inhibitor synergistically induce paired box 5 gene expression in non-small cell lung cancer cell lines
Authors: Liang Yuanxin , Perez-Soler Roman , Zou Yiyu 
Published: May 2015

Abstract
Epigenetic abnormalities play an important role in carcinogenesis and tumor suppressor paired box 5 gene (Pax5) is one of the most frequently methylated genes in non-small cell lung cancer (NSCLC). Depletion of Pax5 increased malignant characteristics including proliferation, migration and invasion in mammary cancer cells, while overexpression of Pax5 does not lead to cancer in vivo and induces apoptosis in hematological cancer cells. In this study, we found that Pax5 expression was frequently absent or down-regulated in NSCLC cell lines in vitro. We tested whether a combination of DNA demethylating agent Azacytidine and histone deacetylation (HDAC) inhibitor Vorinostat has a synergistic effect on the Pax 5 gene expression and cell growth inhibition of human NSCLC cell lines. We found that the combination induced Pax5 expression synergistically in NSCLC cell lines. Azacytidine decreased global DNA methylation and reduced CpG sites methylation rate in Pax5 promoter region. Vorinostat inhibited HDAC activity, but did not directly enhance the demethylation function of Azacytidine. Further investigation is needed to uncover the mechanism of action of the synergistic effect of these two agents on the Pax5 gene expression. Our results also show that different NSCLC cell lines respond similarly to the combination treatment under our experimental conditions.
Citation Format: Yuanxin Liang, Roman Perez-Soler, Yiyu Zou. DNA demethylating agent and histone deacetylation inhibitor synergistically induce paired box 5 gene expression in non-small cell lung cancer cell lines. [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 589. doi:10.1158/1538-7445.AM2014-589
Abstract 591: LKB1 regulates COX-2 transcription via CRTCs dependent pathway
Authors: Cao Chunxia , Gao Ruli , Zhang Min , Chen Zirong , Wu Lizi , Kaye Maria Zajac , Kaye Frederic 
Published: May 2015

Abstract
Inactivation of the liver kinase B1 (LKB1) gene by somatic mutation is a common event in lung adenocarcinoma. LKB1 was first identified as a tumor suppressor responsible for Peutz-Jeghers syndrome (PJS) and up regulation of cyclooxygenase-2 (COX-2) was detected in a significant percentage of human PJS polyps. In addition, COX-2 has been proposed as a therapeutic target for lung cancer although clinical trial using COX-2 inhibitors have been disappointing.
In the current study, we identified a novel LKB1/CRTC/COX-2 molecular pathway in human lung cancer cells and provided new information for clinical use of COX-2 inhibitors. The Kaye lab cloned the CREB-regulated transcription co-activators (CRTCs) and showed aberrant phosphorylation and activation of CRTC1 exclusively in non-small cell lung cancer (NSCLC) samples carrying LKB1 null mutations. We have now demonstrated that CRTC directly regulates COX-2 expression via evolutionarily conserved CRE sites within the promoter. In addition, we observed that ectopic expression of LKB1 resulted in nuclear export of phosphorylated CRTC with attenuation of COX-2 expression. Alternatively, LKB1 knock-down results in CRTC activation and promotes COX-2 expression in NSCLC cells. Importantly, LKB1 null lung cancer cells were preferentially sensitive to COX-2 inhibitors. In summary, our data defines a CRTCs-mediated transcriptional regulatory mechanism for COX-2 activity in cancer and proposes a possible clinical application of COX-2 inhibitors in patients with lung tumors carrying somatic LKB1 null mutations.
Citation Format: Chunxia Cao, Ruli Gao, Min Zhang, Zirong Chen, Lizi Wu, Maria Zajac Kaye, Frederic Kaye. LKB1 regulates COX-2 transcription via CRTCs dependent pathway. [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 591. doi:10.1158/1538-7445.AM2014-591
Abstract 601: Essential role of LRF in mesenchymal stem cell differentiation and tumorigenesis through Dlk1 and Sox9 repression
Authors: Guarnerio Jlenia , Lunardi Andrea , Pandolfi Pier Paolo 
Published: May 2015

Abstract
The regulatory factors governing the initial steps of mesenchymal stem cell (MSC) commitment and differentiation are largely unknown, and the role of MSCs in the genesis of mesenchymal tumors (sarcomas) has not been fully elucidated. In recent years, several genes and pathways have been characterized as important regulators of these cells’ differentiation into adipocytes, chondrocytes and osteoblasts. Although extremely valuable, these data have been mainly generated using cell lines or mouse embryonic fibroblasts (MEFs), leaving a more reliable model, such as one based on primary multi-potent MSCs, completely unexplored. To fill this gap, we have established new conditions enabling us to manipulate in vitro primary MSCs while maintaining their stemness properties, and have taken advantage of a series of genetically engineered mouse models to unravel a new role for LRF as both a master regulator of MSC differentiation and a tumor suppressor gene in mesenchymal tumors through the repression of two major pathways: DLK1/MAPK and SOX9. Mesenchymal tumors, although rare, have an extremely high rate of mortality, due to a lack of knowledge of the molecular mechanisms responsible for their genesis and progression, and consequently a limited number of available drugs. Our recent findings, however, significantly advance our knowledge of the mechanisms underlying sarcoma pathogenesis, and identify new LRF/DLK1/MAPK and LRF/SOX9 pathways that could prove fundamental to the stratification and targeted therapy of LRF-negative sarcomas.
Citation Format: Jlenia Guarnerio, Andrea Lunardi, Pier Paolo Pandolfi. Essential role of LRF in mesenchymal stem cell differentiation and tumorigenesis through Dlk1 and Sox9 repression. [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 601. doi:10.1158/1538-7445.AM2014-601
Abstract 629: Combination hypoxia-specific chemotherapy and immunotherapy of prostate cancer
Authors: Ai Midan , Bartkowiak Todd , Jaiswal Ashvin R. , Shah Krishna , Ager Casey , Lerman Beatrisa , Curran Michael A. 
Published: May 2015

Abstract
Tumor hypoxia contributes to chemotherapy and radiotherapy resistance, and helps foster metastasis. Hypoxia likely also supports tumor immune resistance by supporting development of suppressive myeloid and T cell populations by activating immunosuppressive signaling pathways in the tumor and stroma, and by creating a metabolically hostile environment for immune effector cells. TH-302 is a hypoxia-specific chemotherapeutic drug which is activated only in the hypoxic cores of tumors and remains harmless in the periphery. We hypothesized that concurrent combination therapy with TH-302 and T cell checkpoint blockade would promote inside-out tumor destruction with the drug killing at the core, releasing antigen, and diminishing suppression, while the antibodies helped expand and protect the T cells activated as a result. In the TRAMP-C2 prostatic adenocarcinoma model, we found that antibody blockade of CTLA-4 and PD-1, used in conjunction with TH-302 administration, promoted tumor rejection in a significantly larger percentage of mice than either therapy alone. The combination therapy promoted uniquely advantageous ratios of effector T cells to MDSC within the prostate cancer microenvironment. This novel combination of immunotherapy and hypoxia-specific chemotherapy has the potential to offer profound anti-tumor responses to a much greater percentage of patients than either chemotherapy or immunotherapy alone with the same or fewer side effects.
Citation Format: Midan Ai, Todd Bartkowiak, Ashvin R. Jaiswal, Krishna Shah, Casey Ager, Beatrisa Lerman, Michael A. Curran. Combination hypoxia-specific chemotherapy and immunotherapy of prostate 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 629. doi:10.1158/1538-7445.AM2014-629
Abstract 654: Targeting K-ras mutant cancer cells with a lupus anti-guanosine antibody
Authors: Young Melissa R. , Noble Philip W. , Weisbart Richard H. , Hansen James E. 
Published: May 2015

Abstract
Aberrant G-protein signaling due to mutations in genes encoding the Ras family of small GTPases is associated with approximately 30% of human cancers, and K-ras is one of the most commonly mutated Ras proteins. Development of targeted therapies that are preferentially toxic to cancer cells harboring K-ras mutations is therefore an important goal in cancer research. We have identified an unusual cell-penetrating lupus autoantibody, 4H2, as a potential candidate for development as a targeted therapy for tumors with activating K-ras mutations. 4H2 is an anti-guanosine antibody that has previously been shown to penetrate living cells and inhibit cAMP formation. Taken together, the ability of 4H2 to bind guanosine (a component of GDP/GTP) and to inhibit cAMP formation suggests that 4H2 perturbs G-protein signaling. We therefore hypothesized that 4H2 would be selectively toxic to cancer cells with aberrant G-protein signaling due to activating K-ras mutations compared to cells without mutations in K-ras. To test this hypothesis, we evaluated the effects of 4H2 on a panel of isogenic pairs of cells with and without activating K-ras mutations, including Cal12T lung cancer cells (with and without a G12C activating K-ras mutation), NCI-H1975 lung cancer cells (with and without a G12D activating K-ras mutation), and SW48 colon cancer cells (with and without a G12A activating K-ras mutation). Immunofluorescence experiments confirmed that 4H2 penetrates into and localizes to the cytoplasm of cells with and without an activating K-ras mutation. In cell proliferation assays the matched pairs of cells were treated with 4H2 while growing as subconfluent monolayers, and 4H2 was observed to significantly inhibit the proliferation of the cells with activating K-ras mutations but not the cells without K-ras mutations. Next, colony formation assays confirmed that treatment with 4H2 was significantly more toxic to cells with activating K-ras mutations compared to cells without K-ras mutations. Mechanistically, Western blot analyses suggest a differential effect of 4H2 on the MAP kinase and Akt signaling pathways in K-ras mutant and wild type cells, consistent with the hypothesis that 4H2 interferes with G-protein associated intracellular signaling pathways. In summary, this work has demonstrated that 4H2 is an intriguing candidate for further study and development as a potential targeted therapy for tumors with activating mutations in K-ras.
Citation Format: Melissa R. Young, Philip W. Noble, Richard H. Weisbart, James E. Hansen. Targeting K-ras mutant cancer cells with a lupus anti-guanosine antibody. [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 654. doi:10.1158/1538-7445.AM2014-654
Abstract 671: CD38-specific engineered toxin body: Therapeutic potential for multiple myeloma
Authors: Rajagopalan Sangeetha , Brieschke Brigitte , Robinson Garrett L. , Erdman Jennifer , Null William , Higgins Jack P. , Willert Erin K. 
Published: May 2015

Abstract
Multiple myeloma is a malignancy of plasma cells that accounts for 10% of all hematological cancers. Current treatments for multiple myeloma include immunomodulatory agents, protease inhibitors and chemotherapies and, while these therapies are often initially effective, most patients experience relapse. New therapeutics are urgently required. CD38 is a transmembrane glycoprotein absent on most resting leukocytes but expressed on lymphoid malignancies, including multiple myeloma and lymphoma, making it an attractive target for directed therapy. Recent clinical trials with antibodies to CD38 have shown promise in multiple myeloma. While these antibodies rely on the recruitment of an immune response for cytotoxicity, we have developed an engineered toxin body (ETB) comprising a CD38 binding scFv and a de-immunogenized form of Shiga-like Toxin A (MT-4001) capable of specifically recognizing and directly killing CD38 expressing cells. Our results show that MT-4001 is a promising targeted therapeutic agent against CD38 positive cancer cells and is currently under further development.
Citation Format: Sangeetha Rajagopalan, Brigitte Brieschke, Garrett L. Robinson, Jennifer Erdman, William Null, Jack P. Higgins, Erin K. Willert. CD38-specific engineered toxin body: Therapeutic potential for multiple myeloma. [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 671. doi:10.1158/1538-7445.AM2014-671
Abstract 672: Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1
Authors: Wittemer-Rump Sabine , Kopitz Charlotte , Huynh Hung , Lindbom Lars , Beckermann Bernhard , Osada Motonobu , Laurent Dirk , Lippert Jörg 
Published: May 2015

Abstract
BAY 1179470 is a human immunoglobulin (IgG) antibody directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed on cancer cells during tumorigenesis and metastasis. Anti-tumor efficacy of BAY 1179470 has been demonstrated in FGFR2-expressing gastric cancer mouse and rat xenograft models. No toxicologically relevant findings were observed in the repeated dose preclinical safety studies in rats and monkeys. Therefore, toxicity was not an appropriate endpoint for the first-in-man (FIM) study and dose selection was decided to be based on PK/PD modeling and predictions from preclinical efficacy data. All preclinical PK and tumor response data from mouse models were used to create a model framework to describe the PK and PK/PD as functions of BAY 1179470 dose, regimen and time. In a subsequent confirmatory step the PK/PD model derived from mouse efficacy data was applied to predict the efficacy in rats. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure were combined with the PK/PD model developed from mouse models to assess the expected efficacy for a range of human tumor doubling rates. Minimal effective doses, maximum effect and maximum effect doses, and maximal effective doses in humans were derived for various dosing intervals (1 day to 6 weeks). From the maximum effect dose the target AUC in humans was calculated and doses for the FIM study selected accordingly. The FIM study is currently ongoing in Japan (NCT01881217).
Citation Format: Sabine Wittemer-Rump, Charlotte Kopitz, Hung Huynh, Lars Lindbom, Bernhard Beckermann, Motonobu Osada, Dirk Laurent, Jörg Lippert. Pharmacokinetic and pharmacodynamic (PK/PD) modeling of preclinical data of a novel anti-fibroblast growth factor receptor 2(FGFR2) antibody (BAY 1179470) to guide dosing in Phase 1. [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 672. doi:10.1158/1538-7445.AM2014-672
Abstract 694: Different pancreatic cancer cells have their own core signaling pathway
Authors: Kim Eunkyung , Kang Sujin , Kim So Y. , Kang Dongxu , Lee Seungha , Choi Hye J. , Kim Joo-Hang , Song Jae Jin 
Published: May 2015

Abstract
Gemcitabine as the standard chemotherapy agent to pancreatic cancer has proved effective; however, the response rate remains at 5.4% and the 5-year survival rate is extremely poor. Due to the shortcomings of gemcitabine and the presence of gemcitabine-resistant pancreatic cancer, the development of targeted agents into an anti-neoplastic agent remains a viable option.
We have investigated the transforming growth factor-beta (TGF-β), which is known to play a central role in pancreas cell function. We have already observed that the suppression of TGF-β2 induced an unexpected down-regulation of both TGF-β1 and TGF-β3 with concomitant decreases of survival-related signals, such as N-caderin, β-catenin, pp65 in melanoma cell line. Here, two different pancreatic cancer cell lines (HPAC, BxPC3), which have opposite genetic backgrounds (K-ras, p53, Smad4, EGFR), have shown differing sensitivities to the down-regulation of TGF-β2. Through transcriptome analysis, HPAC showed a high expression of TGF-β2, MUC4, HSP27, BMP4 which are deeply related to tumor progression and metastasis and are composed to core signaling complex initiating from TGF-β2. This was confirmed by TGF-β2 down-regulation with gemcitabine to show a greater decrease in survival potential compared to BxPC3. On the contrary, BxPC3, which has more of the mutant type p53, exhibited greater down-regulation of MUC4 by downregulation of p53 compared to that of TGF-β2. Such observations suggest that BxPC3 is composed of a different core signaling pathway, p53-MUC4 rather than TGF-β2-related signalings.In conclusion, it is necessary that the core signaling pathways which are implicated in individual pancreatic carcinogenesis are more specifically considered so that the various gemcitabine-resistant pancreatic cancer cells on the basis of customized treatment can be controlled.
Citation Format: Eunkyung Kim, Sujin Kang, So Y. Kim, Dongxu Kang, Seungha Lee, Hye J. Choi, Joo-Hang Kim, Jae Jin Song. Different pancreatic cancer cells have their own core signaling pathway. [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 694. doi:10.1158/1538-7445.AM2014-694
Abstract 703: Highly selective HSV virotherapy for glioblastoma
Authors: Li Aofei , Marzulli Marco , Mazzacurati Lucia , Uchida Hiroaki , Cohen Justus , Glorioso Joseph , Grandi Paola 
Published: May 2015

Abstract
Glioblastoma Multiforme (GBM) is an aggressive brain cancer for which there is no effective treatment. Oncolytic HSV vectors (oHSV) are attenuated lytic viruses that have shown promise in the treatment of human GBM models in animals. Although proven safe for treatment of GBM in patients, oHSVs efficacy has been limited, a consequence of poor intra-tumoral virus replication and spread. To counter these limitations, we have developed oHSVs whose selective replication in GBM cells does not rely on defective genes. This was accomplished by (i) full retargeting of oHSV to utilize the epidermal growth factor receptor (EGFR) for infection of human GBM tumor cells and (ii) further vector engineering to modify the essential HSV immediate early gene (ICP4) for sensitivity to repression by the microRNA mir-124. Mir-124 is highly expressed in neurons but virtually absent in GBM and highly conserved among different species. The mir-124-regulated vector was unable to replicate in nude mice following intracranial inoculation supporting vector safety and was shown to be effective in the treatment of human GBM in nude mice. To enhance vector intra-tumor vector spread, our EGFR retargeted-mir-124 controlled vector was further modified by vector arming with the matrix metalloproteinase gene encoding MMP9. MMP9 degrades collagen type IV, a major component of the extracellular matrix (ECM) and basement membranes of glioblastomas but absent in normal brain tissue. Studies are ongoing to determine whether MMP9 expression enhances vector spread in GBM neurospheres and as a therapeutic agent for enhanced treatment of human GBM in animals
Citation Format: Aofei Li, Marco Marzulli, Lucia Mazzacurati, Hiroaki Uchida, Justus Cohen, Joseph Glorioso, Paola Grandi. Highly selective HSV virotherapy for glioblastoma. [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 703. doi:10.1158/1538-7445.AM2014-703
Abstract 707: Tumor-targeted delivery of siRNA using stabilized calcium phosphate nanoparticles based on bio-inspired hyaluronic acid conjugate
Authors: Lee Min Sang , Lee Jung Eun , Byun Eunkyoung , Kim Nak Won , Lee Haeshin , Jeong Ji Hoon 
Published: May 2015

Abstract
Purpose : Low cytotoxicity and high cellular gene delivery capability are among the most important prerequisites for the selection of a non-viral carrier. In this study, we report the development of calcium phosphate (CAP) nanoparticles stabilized by a conjugate of the biological adhesive molecule, 3,4-dihydroxy-L-phenylalanine (dopa), and a nontoxic hydrophilic natural polymer, hyaluronic acid (HA), for targeted siRNA delivery to cancer cells.
Methods : Dopa-conjugated HA (dopa-HA) was synthesized by EDC/NHS chemistry and analyzed by spectrometry and 1H-NMR. Stabilized calcium phosphate nanoparticles containing siRNA (CAP/siRNA/dopa-HA) was prepared by simply mixing CaCl2 solution containing siRNA with a HEPES buffer containing Na2HPO4 and subsequent addition of a solution containing dopa-HA. The particles were characterized by using light scattering method and transmission electron microscope (TEM). The gene silencing and cancer cell-targeting ability of CAP/siRNA/dopa-HA was evaluated by monitoring cellular reporter activity (luciferase) in human colon carcinoma cells permanently expressing firefly luciferase. Confocal microscopy and FACS analysis were performed to assess CD44-specific cellular delivery. Bio-distribution and in vivo gene silencing of CAP/siRNA/dopa-HA nanoparticles were studied in an animal model bearing tumor xenograft.
Results : CAP/siRNA/dopa-HA can form compact nanoparticles that effectively protect siRNA from enzymatic degradation despite the structural drawbacks of siRNA, such as low charge density and short and rigid structure. In addition, stabilized CAP nanoparticles were able to maintain their colloidal stability in a physiological salt condition for over a week. The superior ability of CAP/siRNA/dopa-HA to maintain the integrity of encapsulated siRNA and the stability in solution of the nanoparticles allow this formulation to achieve improved intratumoral accumulation of siRNA and a high level of target gene silencing in solid tumors after systemic administration.
Conclusion Considering its biocompatibility, transfection efficacy, and tumor targeting capability, this stabilized organic-inorganic hybrid gene delivery platform should be considered a promising candidate carrier for systemic siRNA delivery and targeted cancer therapy.
Citation Format: Min Sang Lee, Jung Eun Lee, Eunkyoung Byun, Nak Won Kim, Haeshin Lee, Ji Hoon Jeong. Tumor-targeted delivery of siRNA using stabilized calcium phosphate nanoparticles based on bio-inspired hyaluronic acid conjugate. [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 707. doi:10.1158/1538-7445.AM2014-707