bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5461: B7-H3 regulates NF-kB signaling in cancer cells by modulating the degradation and re-synthesis of IkBα
Authors: Glazer Sarah , Gammon Seth , Piwnica-Worms David 
Published: August 2018

Abstract
B7-H3, a B7 homologue, is highly expressed on tumors and tumor vasculature. Although its role as a T cell inhibitor or co-stimulator is still under investigation, high expression of membranous B7-H3 in the tumor compartment is correlated with poor overall survival. NF-kB activation, standing at the intersection between inflammation and cancer, can lead to both the production of cytokines that engage the innate immune system, as well as pro-proliferative signals in cancer. B7-H3 has been shown to enhance and suppress inflammatory signaling by modulating NF-kB. However, the mechanism by which this occurs in cancer cells remains unknown. In this study, we aim to understand how B7-H3 modulates the NF-kB pathway in order to regulate incoming inflammatory signals in cancer cells. The human colon cancer cell line, HCT116, was stably transfected with a transcriptionally-coupled post-translational NF-kB luciferase reporter comprising of the inhibitor of NF-kB, IkBα, fused to firefly luciferase and placed downstream of an NF-kB responsive promoter, kB5. This construct allows for the real-time readout of the degradation of IkBα and NF-kB driven transcriptional re-synthesis of IkBα in response to a stimulus. The reporter cell line was treated with two stimulants, TNFα and flagellin, that activate NF-kB through different pathways and to different degrees with or without treatment with human B7-H3. Treatment of the reporter cell line with B7-H3 alone did not induce IkBα degradation or re-synthesis. However, stimulation of the reporter cell line with TNFα or flagellin in combination with B7-H3 attenuated the degradation of IkBα and its re-synthesis compared to stimulation with TNFα or flagellin alone. Maximal re-synthesis of IkBα when stimulated with TNFα was 8.25 ± 1.51 fold (S.D.) and significantly increased compared to cells additionally treated with B7-H3 (5.83 ± 1.23 fold, p = .01). In addition, peak degradation time of IkBα when cells were stimulated by TNFα was 45 ± 5 min (S.D.), and significantly shorter than when cells were also treated with B7-H3 (61.67 ± 2.89 min, p = .01). Similar trends were observed when cells were treated with both flagellin and B7-H3 compared to stimulation with flagellin alone. These studies show that B7-H3 suppresses the response of colon cancer cells to incoming inflammatory stimuli and attenuates NF-kB signaling by tempering the kinetics and dynamics of IkBα.
Citation Format: Sarah Glazer, Seth Gammon, David Piwnica-Worms. B7-H3 regulates NF-kB signaling in cancer cells by modulating the degradation and re-synthesis of IkBα [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5461.
Abstract 5561: High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T-cells and produce antitumor effects in syngeneic tumor models
Authors: Sinclair Charles , Revenko Alexey S. , Peter Alison , Johnson Robert B. , Hettrick Lisa A. , Taylor Molly , Staniszewska Anna , Hughes Adina , Sandin Lisa , Klein Stephanie , Watt Andrew , Barry Simon , Monia Brett T. , Lyne Paul , Macleod A Robert , Edbrooke Mark 
Published: August 2018

Abstract
Regulatory T-cells (Treg) contribute to cancer progression by suppressing anti-tumor immuity. Tregs specifically require expression of the lineage defining transcription factor Foxp3 for their development and function, but this protein cannot be targeted with conventional small molecule or biologic drugs. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) in an attempt to selectively inhibit Foxp3 expression in mouse Treg cells, and evaluated consequences of ASO-mediated Foxp3 knock-down in vitro and in vivo. Mouse Foxp3-specific ASOs promoted potent dose-dependent reductions in Foxp3 mRNA and protein in vitro, without the use of transfection reagents. Foxp3 knockdown also resulted in loss of immunosuppressive markers and conferred Tregs with a reduced immunosuppressive capacity. Whilst genetic ablation of FOXP3 leads to manifestation of autoimmunity due to a complete loss of Treg function, we observed that the systemic delivery of unformulated mouse Foxp3 ASOs to WT mice resulted in Foxp3 knockdown in vivo, but spared mice from an autoimmune phenotype. Nevertheless, when syngeneic tumor-bearing mice were treated with mouse Foxp3 ASOs tumor growth was significantly attenuated, with a fraction of animals (25%-50%) achieving complete regressions. Anti-tumor activity of mouse Foxp3 ASOs was associated with immunophenotypic changes consistent with an increased anti-tumor immune response. Overall these data demonstrate the therapeutic capacity of mouse ASO to directly target regulatory T-cells, and suggesting that targeting of Foxp3 represents an attractive opportunity in cancer immunotherapy.
Citation Format: Charles Sinclair, Alexey S. Revenko, Alison Peter, Robert B. Johnson, Lisa A. Hettrick, Molly Taylor, Anna Staniszewska, Adina Hughes, Lisa Sandin, Stephanie Klein, Andrew Watt, Simon Barry, Brett T. Monia, Paul Lyne, A Robert Macleod, Mark Edbrooke. High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T-cells and produce antitumor effects in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5561.
Abstract 5586: Circulating tumor cells as the prognostic marker for non-remission and disease-specific mortality of patients with thyroid cancer
Authors: Tseng Ching-Ping , Lin Jen-Der , Liou Miaw-Jene , Hung Wei-Shan , Hsu Hsueh-Ling , Leong Kong-Kit , Chen Yu-Ting , Cheng Ju-Chien 
Published: August 2018

Abstract
Patients with thyroid cancer usually have good prognosis. However, 15-20% of patients ultimately develop recurrence and disease-related death. In this study, we investigate whether the number of circulating tumor cells (CTCs) expressing either epithelial cell adhesion molecule (EpCAM), podoplanin (PDPN, a marker related to poor prognosis in patients with thyroid cancer), or thyroid-stimulating hormone receptor (TSHR, a marker for thyroid cells) is a prognostic marker for non-remission and disease-specific mortality (DSM) of patients with thyroid cancer. Blood samples were collected from patients (n = 128) after thyroidectomy or radioactive iodide therapy. After enrichment of CTCs by a negative selection PowerMag system, enumeration and subtyping of the CD45-depleted cells were performed by immunofluorescence staining using the antibodies aginst EpCAM, TSHR, and PDPN, respectively. Our data revealed that the number of EpCAM+-CTCs (p &lt; 0.001) and PDPN+-CTCs (p &lt; 0.001), and TSHR+-CTCs (p &lt; 0.001) for patients in the non-remission group (n = 43) was significantly higher when compared to the remission group (n = 85). At the cutoff of 40, 14, and 47 cells/mL for EpCAM+-CTCs, TSHR+-CTCs, and PDPN+-CTCs, the accuracy of the assay was equivalent to 80.4%, 76.6%, and 77.3%, respectively. On the other hand, the number of EpCAM+-CTCs (p &lt; 0.001), PDPN+-CTCs (p = 0.013), and TSHR+-CTCs (p &lt; 0.001) for patients in the DSM group (n = 17) was significantly higher when compared to the patients who survived (n = 111). At the cutoff of 27, 25, and 9 cells/mL for EpCAM+-CTCs, TSHR+-CTCs, and PDPN+-CTCs, the accuracy of the assay was equivalent to 69.5%, 67.2%, and 68.5%, respectively. These data together indicate that CTC testing is worthy to be considered as a routine clinical test to benefit clinical care of patients with thyroid cancer.
Citation Format: Ching-Ping Tseng, Jen-Der Lin, Miaw-Jene Liou, Wei-Shan Hung, Hsueh-Ling Hsu, Kong-Kit Leong, Yu-Ting Chen, Ju-Chien Cheng. Circulating tumor cells as the prognostic marker for non-remission and disease-specific mortality of patients with thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5586.
Abstract 5626: Preclinical characterization of Sym022, a novel anti-LAG3 antibody
Authors: Grandal Michael M. , Melander Maria C. , Bhatia Vikram K. , Gjetting Torben , Lindsted Trine , Fröhlich Camilla , Lantto Johan , Horak Ivan D. , Kragh Michael , Kofoed Klaus , Pedersen Mikkel W. 
Published: August 2018

Abstract
Immunotherapy has become a major focus of research in oncology and blockade of immune checkpoints such as cytotoxic T-Lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) has been some of the most successful immunotherapies. Lymphocyte-activation gene 3 (LAG3) belongs to the second-generation immune modulatory targets. LAG3 is expressed by activated T-cells and tumor infiltrating lymphocytes (TILs) and negatively regulates T-cell activity upon ligand engagement. LAG3 binds major histocompatibility complex class II (MHCII) molecules found on the surface of antigen presenting cells and tumor cells. Sym022 is a Fc-inert human monoclonal antibody targeting LAG3. Sym022 binds to human and cynomolgus monkey LAG3 with high affinity and blocks the interaction between LAG3 and MHCII molecules. Functionally, Sym022 increases cytokine production by T-cells in vitro and tumor growth inhibition in vivo. Mechanistically, Sym022 not only blocks ligand binding, but also decreases total LAG3 surface levels through internalization and/or shedding.
Citation Format: Michael M. Grandal, Maria C. Melander, Vikram K. Bhatia, Torben Gjetting, Trine Lindsted, Camilla Fröhlich, Johan Lantto, Ivan D. Horak, Michael Kragh, Klaus Kofoed, Mikkel W. Pedersen. Preclinical characterization of Sym022, a novel anti-LAG3 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5626.
Abstract 5748: Downregulation of glycine decarboxylase renders ovarian cancer cells less proliferative and more chemoresistant
Authors: Shin So-Jin , Chung Hyewon , Kim Jin Young , Kim Hyera , Cho Chi-Heum , Ha Eunyoung 
Published: August 2018

Abstract
Glycine decarboxylase (GLDC) is a very recently identified metabolic oncogene that links glycine metabolism with tumorigenesis. We designed this study to determine the role of GLDC in chemoresistance in ovarian cancer cells. First, we found GLDC is downregulated in paclitaxel-resistant ovarian cancer cells (OVCAR3/PTX). Prompted by decreased glucose transport in OVCAR3/PTX cells, we transplanted OVCAR3 and OVCAR3/PTX onto the back of the NOD-scid IL2Rgammanullmice and found that the OVCAR3/PTX tumor grew less rapidly than paclitaxel-sensitive ovarian cancer cells (OVCAR3). We also found that GLDC is downregulated in OVCAR3/PTX tumor. In vitro study revealed that the inhibitory effect of siGLDC on proliferation was significantly greater in OVCAR3 than in OVCAR3/PTX. We also found that knockdown of GLDC in OVCAR3 cells rendered ovarian cancer cells PTX-resistant. Finally, we determined GLDC expressions in patients with chemosensitive and chemoresistant serous-type ovarian cancer and found that GLDC expression was markedly downregulated in chemoresistant cancer patients. In summary, these results suggest that GLDC is associated with ovarian cancer chemoresistance.
Citation Format: So-Jin Shin, Hyewon Chung, Jin Young Kim, Hyera Kim, Chi-Heum Cho, Eunyoung Ha. Downregulation of glycine decarboxylase renders ovarian cancer cells less proliferative and more chemoresistant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5748.
Abstract 5802: Efficacy of PI3Kβ inhibitor AZD8186 in PTEN-deficient triple-negative breast cancer
Authors: Owusu-Brackett Nicci , Zhao Ming , Akcakanat Argun , Evans Kurt W. , Yuca Erkan , Meric-Bernstam Funda 
Published: August 2018

Abstract
Background: Phosphatase and tensin homologue (PTEN) loss is a frequently disrupted tumor suppressor in cancer. PTEN serves as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. Consequently, loss of PTEN function increases cell proliferation, decreases cell death and contributes to tumor initiation. PTEN loss occurs across a variety of cancer subtypes, and these PTEN deficient tumors are dependent on PI3Kβ activity. As a result, therapeutic approaches that focus on the inhibition of PI3Kβ isoform in PTEN-null cells are of interest. We evaluate the efficacy of PI3Kβ inhibitors focused on triple negative breast cancers with loss of PTEN function. Methods: We studied the effects of p110β inhibitor AZD8186 in a panel of ten TNBC cell lines, which included four PTEN-mutant cell lines. Three of four cell lines were confirmed to have PTEN loss on western blot. In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with chemotherapy. We confirmed the sensitivity of the PTEN-null cell lines to AZD8186 with colony formation assays. Western blot analysis was performed to assess PTEN expression and PI3K pathway activation in MDA-MB-436 and MDA-MB-468 cell lines, and to evaluate effects of AZD8186 on PI3K signaling. Results: Cell lines with PTEN loss were significantly more sensitive to AZD8186 in vitro (p= 0.008). AZD8186 inhibited PI3K signaling. Western blot revealed decreased activation of pAKT, pGSK3β, pPRAS40 and pS6. Activation of other pathways were evaluated with no activation of the MAPK/ERK or MEK pathways appreciated. AZD8186 treatment resulted in increased apoptosis but did not have a significant effect on cell-cycle progression in PTEN-deficient cell lines. AZD8186 was not synergistic with eribulin, paclitaxel or carboplatin; combinations with novel targeted therapies in vitro and in vivo are ongoing. Conclusion: AZD8186 had single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro. Further study is needed to identify rationale combinations and in vivo efficacy.
Citation Format: Nicci Owusu-Brackett, Ming Zhao, Argun Akcakanat, Kurt W. Evans, Erkan Yuca, Funda Meric-Bernstam. Efficacy of PI3Kβ inhibitor AZD8186 in PTEN-deficient triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5802.
Abstract 5816: Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy
Authors: Nagaraju Ganji Purnachandra , El-Rayes Bassel F. 
Published: August 2018

Abstract
Purpose: Important signaling pathways contributing to proliferation, development, metastasis and resistance to chemo-radiotherapy in pancreatic adenocarcinoma (PDAC) includes the PI3K/AKT/HIF-1α/STAT-3 pathway. The molecular chaperone heat shock protein 90 (HSP90) controls the activity, stability, turnover, and trafficking of many molecules involved in these major signaling pathways. Functional inhibition of HSP90 may inhibit these pathways simultaneously. We evaluated the efficacy of HSP90 functional inhibitor ganetespib in combination with chemo-radiotherapy against PDAC in vitro and in vivo.
Methods and Materials: Cell proliferation (Br-dU), colony formation (clonogenic assay), migration (spheroid), and Western blot analyses were carried out in HPAC and PANC-1 PDAC cell lines to determine the effect of ganetespib alone or in combination with 5-FU+ 2Gy XRT. Tumor regression study of PDAC with ganetespib alone and in combination with chemo-radiation was analyzed in xenograft mouse models.
Results: At the clinically achievable dose of 50 nM, ganetespib inhibited PDAC cells proliferation (p&lt;0.001), potentiated 5-FU chemotherapy and 2Gy of ionizing radiation (p&lt;0.001), and decreased the levels of survival molecules such as PI3K, p-AKT, and p-ERK in vitro. Additionally, ganetespib indeed potentiates the effects of chemo-radiation in both cell lines: significant decrease in colony formation as well as decrease in migration. Combinations of ganetespib and chemo-radiation therapy demonstrated synergistic ability in human xenograft mouse models (p&lt;0.001).
Conclusion: Ganetespib potentiates the effects of chemo-radiation in preclinical studies. Evaluating HSP90 inhibitors in PDAC patients is a rational approach in assessing the fatal PDAC.
Citation Format: Ganji Purnachandra Nagaraju, Bassel F. El-Rayes. Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5816.
Abstract 5866: Discovery and profiling of a highly potent and selective ERK5 inhibitor: BAY-885
Authors: Lemos Clara , Nguyen Duy , Wortmann Lars , Bömer Ulf , Holton Simon , Lechner Christian , Prechtl Stefan , Sülzle Detlev , Siegel Franziska , Mumberg Dominik , Bauser Marcus , Hägebarth Andrea 
Published: August 2018

Abstract
ERK5 (Extracellular signal regulated kinase 5, also known as MAPK7, Gene ID: 5598) is a key integrator of cellular signal transduction and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis and cell survival. Several studies have demonstrated that inhibition of ERK5 with siRNA or shRNA decreases proliferation and increases cell death in different tumor models, thereby highlighting the potential of ERK5 as a therapeutic target in cancer. By HTS and subsequent lead identification, we discovered a highly potent and selective ERK5 inhibitor, BAY-885, which was used to investigate the therapeutic potential of ERK5 in tumor cells displaying ERK5 genomic amplifications or with constitutive activation of the ERK5 pathway. BAY-885 inhibited ERK5 enzymatic activity with IC50 = 40 nM and was highly selective vs. 357 kinases (Eurofins panel). Inhibition by BAY-855 was confirmed in a cellular setting using a MEF2 reporter cell line (SN12C-MEF2-luc). The EGF-stimulated MEF2 transcriptional activity was strongly inhibited by BAY-885 (IC50 = 115 nM; IC90 = 691 nM). In contrast, the compound had no effect on a reporter cell line with constitutive luciferase expression (SN12C-CMV-luc, IC50 &gt; 50 µM), thereby ruling out potential effects as a general inhibitor of transcription or translation. Importantly, despite its high potency, BAY-885 failed to inhibit the proliferation of cells with ERK5 genomic amplification (SN12C, SNU-449, MFM-223) or with constitutively active ERK5 signaling (BT-474, SK-BR-3). Altogether, our results demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, thus raising doubts as to the viability of ERK5 as a therapeutic target for anticancer drug development. The availability of potent and selective chemical probes, as the one described here, will contribute to further understanding the biology of ERK5 signaling in cancer.
Citation Format: Clara Lemos, Duy Nguyen, Lars Wortmann, Ulf Bömer, Simon Holton, Christian Lechner, Stefan Prechtl, Detlev Sülzle, Franziska Siegel, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth. Discovery and profiling of a highly potent and selective ERK5 inhibitor: BAY-885 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5866.
Abstract 5869: TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo
Authors: Peng Peng , Yang Xiaoju , Qiang Xiaoyan , Li Lin , Ni Shumao , Sun Xiaofen , Wu Di , Wu Frank 
Published: August 2018

Abstract
The hallmarks of cancer comprise dysregulated cell cycle and mitosis, active angiogenesis, tumor-promoting inflammation, and immune escape as well as other features. Therapeutic targeting one of the hallmarks has shown promising but short-lived efficacy in cancer therapy. Therefore, combination of two or more mechanisms holds great promise of next generation oncology drug development. Aurora kinase A and B are often over expressed in many malignancies and associated with poor prognosis. Several anti-angiogenesis agents have been approved alone or in combination with other oncology drugs. In addition to its role for tumor growth, recent studies illustrate that angiogenesis also plays critical roles in the complexity and dynamic regulation of tumor microenvironment (TME). With the rapid advancement of immune-oncology, several attractive targets involved in tumor-promoting inflammation and immune escape have emerged. We have focused our efforts on the discovery and development of small molecule kinase inhibitors with novel mechanisms to treat cancer. Kinase profiling showed that TT-00420, one of our leading compounds, inhibited Aurora A/B, RTKs involved in angiogenesis, and a few other targets directly involved in tumor-assocated inflammation and immune escape with low nano molar activities. In a screening of human breast cancer cell lines, TT-00420 was highly efficacious against triple negative breast cancer (TNBC) cells while leaving ER+ cells intact, which is completely complimentary to the activity of CDK4/6 inhibitors. This anti-TNBC activity was confirmed in a patient derived xenograft (PDX) TNBC model in vivo, in which TT-00420 was highly active both as first-line and second-line treatment. TT-00420 demonstrated good oral bioavailability and pharmacokinetic properties in mice, rats and dogs. 2-week repeated dose-range finding studies revealed mechanism-related but manageable toxicities of TT-00420 in the 3 species mentioned above. Its dual mechanism involving anti-mitosis and TME modulation will be discussed in this presentation. TT-00420 is now under active development for IND filings both in the US and China.
Citation Format: Peng Peng, Xiaoju Yang, Xiaoyan Qiang, Lin Li, Shumao Ni, Xiaofen Sun, Di Wu, Frank Wu. TT-00420, a dual mechanism kinase inhibitor targeting both mitosis and tumor microenvironment, is highly active against TNBC both in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5869.