bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3195: Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in brainstem glioma
Authors: Choi Seung Ah , Lee Chanhee , Kwak Pil Ae , Wang Kyu-Chang , Phi Ji Hoon , Lee Ji Yeoun , Chong Sangjoon , Kim Seung-Ki 
Published: July 2016

Abstract
Human adipose-derived mesenchymal stem cells expressing secreted form of the tumor necrosis factor-related apoptosis-inducing ligand (hAT-MSC.sTRAIL) have demonstrated therapeutic activity against various tumors. However, sTRAIL resistance remains a challenge in developing anticancer strategies. To solve this problem, many studies have tried to combine drugs to produce synergism or sensitize resistant cancer cells. Histone deacetylase inhibitors (HDACi) have been known to induce expression of TRAIL death receptors 4 and 5 (DR4/DR5). Herein, we evaluated the use of combined therapy of hAT-MSC.sTRAIL with HDAC inhibitor, panobinostat, in enhancing sensitivity to hAT-MSC.sTRAIL mediated apoptosis against the brainstem glioma.
A sTRAIL was introduced into the characterized hAT-MSCs using electroporation. To confirm appropriate treatment concentration of panobinostat to the glioblastoma cells, dose titration was tested using cell viability assay. The therapeutic effect of single or combination treatment against glioblastoma was evaluated using primary cultured glioblastoma cells and cell lines. Orthotopic xenograft brainstem glioma mouse model was established using engineered firefly luciferase expressing tumor cells for bioluminescence in vivo imaging.
Panobinostat induced anti-proliferative effects in dose and time-dependent manner (IC50 range, 0.05-0.2 μM) and effectively enhanced the expression of TRAIL DR4 and DR5, but not decoy receptors. Combined hAT-MSC.sTRAIL and panobinostat significantly decreased the tumor cell growth compared to each alone. Intriguingly, the combination treatment not only induced apoptosis but also autophagy. Using a preclinical brainstem mouse model, we confirmed that the combination of hAT-MSC.sTRAIL and panobinostat was safe and induced regression of tumor volume. Furthermore, the combination therapy prolonged the survival of brainstem glioma-bearing mice.
Our results suggested that combination therapy of panobinostat enhanced the anti-cancer effect of hAT-MSC.sTRAIL and represent potential therapeutic approach to the brainstem glioma.
Citation Format: Seung Ah Choi, Chanhee Lee, Pil Ae Kwak, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Seung-Ki Kim. Synergistic effects of combined treatment with hAT-MSC.sTRAIL and panobinostat in brainstem glioma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3195.
Abstract 3214: A fully human anti-TIM3 antibody with co-stimulatory activity
Authors: Gray J Dixon , Krapf Irina , Zhou Heyue , Kaufmann Gunnar 
Published: July 2016

Abstract
Targeting immune checkpoint molecules has been demonstrated to have significant benefit to patients with cancer. One such molecule is TIM3 whose expression is associated with a phenomenon referred to as T cell exhaustion. While it has been suggested that ligation of TIM3 provides a negative signal to the T cell, there is no obvious inhibitory signaling motif associated with the molecule. We have developed a fully human antibody to TIM3 which demonstrates potent co-stimulatory activity. T cells stimulated with anti-CD3 plus either anti-CD28 or anti-TIM3 show comparable levels of cell activation. Similar to co-stimulation with anti-CD28, the anti-TIM3 antibody promotes expression of CD25, interferon gamma, Tbet and granzyme B, amongst others. Thus, anti-TIM3 co-stimulation promotes T cells with a pro-inflammitory phenotype. With TIM3 being associated with exhausted T cells, co-stimulation with this antibody would be expected to specifically re-activate these exhausted T cells at the tumor site. Moreover, since some NK cells constitutively express TIM3, it would be expected that this antibody would activate these cells as well. Altogether, we have identified a novel anti-TIM3 antibody that is capable of targeting T cells at the tumor site and activating them.
Citation Format: J Dixon Gray, Irina Krapf, Heyue Zhou, Gunnar Kaufmann. A fully human anti-TIM3 antibody with co-stimulatory activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3214.
Abstract 322: Selective inhibition of MYC expression by a small molecule G-quadruplex stabilizer
Authors: Leon Elena C. , Simmons John K. , Calabrese David , DuBois Wendy , Felsenstein Kenneth , Saunders Lindsey B. , Zhang Shuling , Michalowski Aleksandra , Gonzalez Frank , Mock Beverly A. , Schneekloth John S. 
Published: July 2016

Abstract
MYC overexpression or amplification is commonly seen in a wide variety of tumor types, including multiple myeloma. Although MYC appears to be an important driver of the oncogenic phenotype, the helix-loop-helix topology, short half-life, and rapid replenishment of its encoded protein make it a particularly challenging drug target. However, the promoter region of the MYC gene contains a G-quadruplex (G4) DNA secondary structure that can be stabilized to block transcription. Recently, we reported the identification of a compound from a small molecule microarray screen that selectively binds the MYC G4, compared with other oncogenes that also contain G4s, and inhibits MYC mRNA and protein expression, leading to cell cycle arrest in human multiple myeloma cell lines (ACS Chem Biol. 2015). Here we describe the in vitro and in vivo evaluation of a more potent analog that retains the selectivity of the original compound for the MYC G4 sequence. After observing strong growth inhibitory activity of this new compound in a diverse panel of human cancer cell lines, we evaluated its pharmacokinetic and toxicity profiles in mice. Preliminary pharmacokinetic studies showed promising serum bioavailability and exposure properties when administered either intravenously or intraperitoneally. The compound was well tolerated in a month long, dose-escalation toxicity study in mice receiving daily administration of the compound. No adverse effects were observed during the study. In an assessment of short term in vivo activity, MYC expression was inhibited in multiple myeloma xenografts. More long-term studies to evaluate the anti-tumor activity of the compound are currently in progress. Thus, our data provide evidence that small molecule stabilization of the MYC G4 can drive transcriptional silencing of oncogenic MYC expression both in vitro and in vivo.
Citation Format: Elena C. Leon, John K. Simmons, David Calabrese, Wendy DuBois, Kenneth Felsenstein, Lindsey B. Saunders, Shuling Zhang, Aleksandra Michalowski, Frank Gonzalez, Beverly A. Mock, John S. Schneekloth. Selective inhibition of MYC expression by a small molecule G-quadruplex stabilizer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 322.
Abstract 3224: Blocking FSTL1 reprograms cancer-caused abnormal immunity
Authors: Kudo-Saito Chie , Toyoura Masayoshi , Shoya Yuji , Ishida Akiko , Kon Ryoko 
Published: July 2016

Abstract
Purposes:
The close connection between imbalanced immunity and tumor progression has been increasingly recognized, and a number of inhibitors for blocking immune inhibitory checkpoints have been established to improve the anti-tumor immunity in cancer patients. However, clinical responses are limited to a part of the treated patients. We previously identified FSTL1, which is significantly secreted from Snail+ metastatic tumor cells, as a key effector molecule in the cancer-caused immune suppression and dysfunction. FSTL1 generates and expands pluripotent mesenchymal stem cells (MSCs), which are able to generate various immunoregulatory cells and functionally impaired CD8-low T cells, and also to induce de novo tumor dissemination into bone marrow. FSTL1 also directly confers higher invasiveness on tumor cells (EMT induction). To prevent the FSTL1-caused vicious circulation for tumor progression, we attempted to establish anti-FSTL1 blocking mAbs.
Results:
We generated chicken/mouse chimeric anti-FSTL1 mAbs, which specifically recognized human and mouse FSTL1. The anti-FSTL1 mAb significantly suppressed tumor proliferation and invasion, MSC induction in mouse bone marrow cells, and Treg induction in human PBMCs in vitro as compared to the control group. When bone metastatic melanoma models (C57BL/6 mice implanted with snail-transduced B16-F10 melanoma cells both subcutaneously and intravenously) were intraperitoneally injected with the anti-FSTL1 mAb (10 mg/kg) on Day 5 (when tumor metastasis was already observed in bone marrow) and Day 10 after tumor implantation, the FSTL1-caused events were inhibited, and tumor-specific CD8+ T cells with higher CTL activities were generated, resulting in significant suppression of subcutaneous tumor growth and bone metastasis in the treated mice as compared to those of the control mice. At least in the same models, conventional immune checkpoint inhibitors including anti-CTLA4, anti-PD1, and anti-PDL1 mAbs failed to improve the anti-tumor immunity, and rather promoted bone metastasis because of no reduction of regulatory cells, particularly the MSCs in the treated mice.
Conclusions:
These results suggest that blocking FSTL1 reprograms and properly induces anti-tumor immunity by switching the tumor-supportive immune directivity to the active mode against cancer. Our anti-FSTL1 mAb having totally different molecular mechanisms from the conventional ones may be a promising therapeutics as a next generation of “immune checkpoint inhibitors” for radically correcting cancer-manipulated immunity in clinical settings.
Citation Format: Chie Kudo-Saito, Masayoshi Toyoura, Yuji Shoya, Akiko Ishida, Ryoko Kon. Blocking FSTL1 reprograms cancer-caused abnormal immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3224.
Abstract 3228: High salt induces anti-inflammatory MΦ2-like phenotype in peripheral macrophages
Authors: Amara Suneetha , Mehta Toral R. , Whalen Margaret , Tiriveedhi Venkataswarup 
Published: July 2016

Abstract
Macrophages play a critical role in inflammation and antigen-presentation. Abnormal macrophage function has been attributed in autoimmune diseases and cancer progression. Recent evidence suggests that high salt tissue micro-environment causes changes in macrophage activation. In our current report, we studied the role of extracellular sodium chloride (NaCl) on phenotype changes in peripheral circulating monocyte/macrophages collected from healthy donors. High salt (0.2 M NaCl) treatment resulted in a decrease in MΦ1 macrophage phenotype (CD11b+CD14highCD16low) from 77.4±6.2% (0.1 M) to 29.3±5.7% (0.2 M, p&lt;0.05), while there was an increase in MΦ2 macrophage phenotype (CD11b+ CD14lowCD16high) from 17.2±5.9% (0.1 M) to 67.4±9.4% (0.2 M, p&lt;0.05). ELISA-based cytokine analysis demonstrated that high salt treatment induced decreased expression of in the MΦ1 phenotype specific pro-inflammatory cytokine, TNFα (3.3 fold), IL-12 (2.3 fold), CCL-10 (2 fold) and CCL-5 (3.8 fold), but conversely induced an enhanced expression MΦ2 phenotype specific anti-inflammatory cytokine, IL-10, TGFβ, CCL-17 (3.7 fold) and CCR-2 (4.3 fold). Further high salt treatment significantly decreased phagocytic efficiency of macrophages and inducible nitric oxide synthetase expression. Taken together, these data suggest that high salt extracellular environment induces an anti-inflammatory MΦ2 macrophage phenotype with poor phagocytic and potentially reduced antigen presentation capacity commonly found in tumor microenvironment.
Citation Format: Suneetha Amara, Toral R. Mehta, Margaret Whalen, Venkataswarup Tiriveedhi. High salt induces anti-inflammatory MΦ2-like phenotype in peripheral macrophages. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3228.
Abstract 3232: NF-κB regulates suppression of macrophage activity during tumor initiation
Authors: Ratnam Nivedita , Wang David , Guttridge Denis 
Published: July 2016

Abstract
Constitutive activation of NF-κB is characteristic of most cancer cells. However, how NF-κB functions during tumor initiation is not well established. Recent findings from our laboratory showed that one mechanism by which NF-κB functions to promote tumor initiation is by suppressing immune surveillance. Here we investigated how this occurs. Initiating tumors are characterized by a massive infiltration of immune cells, especially macrophages that exhibit anti-tumor activity through the secretion of pro-apoptotic factors like tumor necrosis factor (TNF) and nitric oxide (NO). Using co-culture assays with conditioned media from Ras transformed tumor cells in the presence of NF-κB, we find that the tumor cells are able to protect themselves from the pro-apoptotic activity of the macrophages by secreting a neutralizing factor. RNA sequencing analysis identified this factor as macrophage inhibitory cytokine-1 (MIC-1)/ growth and differentiation factor-15 (GDF-15). Our results show that MIC-1/GDF-15 is a direct transcriptional target of NF-κB. Furthermore, xenografts in SCID mice show delayed tumor initiation in p65+/+ Ras tumor cells that are depleted for MIC-1/GDF-15 compared to wild type p65+/+ Ras tumor cells. Moreover, we find that MIC-1/GDF-15 inactivates macrophages directly by suppressing their ability to produce TNF and NO. This suppression occurs through the inhibition of NF-κB signaling in the macrophages. Interestingly, expression of MIC-1/GDF-15 is increased in patients with pancreatic ductal adenocarcinoma. In the pancreatic cancer cell line, Panc02, we show that knocking down MIC-1/GDF-15 prevents macrophage inhibition thereby increasing their sensitivity to macrophage-mediated killing both in vitro and in vivo. Thus, NF-κB functions during pancreatic cancer initiation to suppress the anti-tumor activity of infiltrating macrophages by regulating the expression of MIC-1/GDF-15.
Citation Format: Nivedita Ratnam, David Wang, Denis Guttridge. NF-κB regulates suppression of macrophage activity during tumor initiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3232.
Abstract 3233: Macrophages orchestrate early dissemination of HER2+ cancer cells
Authors: Linde Nina , Mortha Arthur , Saenger Nicole , Sosa Maria Soledad , Harper Kathryn , Tardio Ethan , Fehm Tanja , Karn Thomas , Merad Miriam , Aguirre-Ghiso Julio A. 
Published: July 2016

Abstract
Metastatic dissemination was proposed to occur only in invasive cancer. However, detection of cancer cells in the bone marrow of patients with pre-invasive breast ductal carcinoma in situ (DCIS) showed that dissemination could, through unknown mechanisms, take place earlier. Late evolved invasive breast cancer cells disseminated by recruiting circulating monocyte-derived tumor associated macrophages (TAMs). We therefore investigated whether macrophages might actively participate in early dissemination. We show that pre-malignant cancer cells in MMTV-HER2 mice produced CCL2 in an NFkB dependent manner and thereby recruited resident mammary tissue macrophages into the duct, months before monocyte-derived TAMs arrived. Intra-epithelial mammary tissue macrophages induced an epithelial-to-mesenchymal transition in early HER2+ cells in a Wnt-dependent manner and thereby drove early dissemination. Consequently, depletion of macrophages from pre-malignant MMTV-HER2 mice significantly reduced early dissemination of pre-malignant cancer cells as measured by reduction in levels of circulating cancer cells and disseminated cancer cells in lungs. Interestingly, macrophage depletion during pre-malignant stages alone was sufficient to reduce the onset of late metastasis in MMTV-HER2 mice, indicating that early disseminating cancer cells contributed to late metastasis formation. In humans DCIS samples we frequently found intra-epithelial macrophages inside of ducts and their presence correlated with reduced E-Cadherin levels. Finally, a first pilot study indicated that those patients whose DCIS lesions contained macrophage +/E-Cadherin low microenvironments frequently had DCCs in the bone marrow. Taken together, we reveal that resident mammary tissue macrophages can promote early dissemination, and unravel a mechanism how early cancer spread might proceed in breast cancer patients and in other cancers where metastasis are diagnosed and the primary tumor is never detected (cancer of unknown primary). We also propose that early DCCs play a long-term causal role in metastasis development when patients are diagnosed in late stages, implying that the heterogeneity of metastases is higher than we might anticipate.
Citation Format: Nina Linde, Arthur Mortha, Nicole Saenger, Maria Soledad Sosa, Kathryn Harper, Ethan Tardio, Tanja Fehm, Thomas Karn, Miriam Merad, Julio A. Aguirre-Ghiso. Macrophages orchestrate early dissemination of HER2+ cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3233.
Abstract 3234: Genetic deletion of macrophage migration inhibitory factor reduces oral carcinogenesis
Authors: Oghumu Steve , Knobloch Thomas , Terrazas Cesar , Varikuti Sanjay , Bollinger Claire , Iwenofu Hans , Weghorst Christopher , Satoskar Abhay 
Published: July 2016

Abstract
Oral cancer kills about 1 person every hour, each day in the United States and is the 6th most prevalent cancer worldwide. The pro-inflammatory cytokine ‘macrophage migration inhibitory factor’ (MIF) has been shown to be expressed in oral cancer patients, yet its precise role in oral carcinogenesis is not clear. In this study, we examined the impact of global Mif deletion on the cellular and molecular process occurring during oral carcinogenesis using a well-established mouse model of oral cancer with the carcinogen 4-nitroquinoline-1-oxide (4NQO). C57BL/6 Wild-type (WT) and Mif knock-out mice were administered with 4NQO in drinking water for 16 weeks, then regular drinking water for 8 weeks. Mif knock-out mice displayed fewer oral tumor incidence and multiplicity, accompanied by a significant reduction in the expression of pro-inflammatory cytokines Il-1β, Tnf-α, chemokines Cxcl1, Cxcl6, Cxcl8 and Ccl3 and other molecular biomarkers of oral carcinogenesis Mmp1 and Ptgs2. Further, recruitment of myeloid-derived tumor promoting immune cells was inhibited in Mif knock-out mice. Our results demonstrate that genetic Mif deletion reduces the incidence and severity of oral carcinogenesis, by inhibiting the expression inflammatory cytokines and infiltration of tumor promoting immune cells. Thus, targeting MIF is a promising strategy for the prevention or therapy of oral cancer.
Citation Format: Steve Oghumu, Thomas Knobloch, Cesar Terrazas, Sanjay Varikuti, Claire Bollinger, Hans Iwenofu, Christopher Weghorst, Abhay Satoskar. Genetic deletion of macrophage migration inhibitory factor reduces oral carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3234.
Abstract 3235: IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligands
Authors: Rao Aparna , Zhang Xiaoran , Deibert Christopher , Sette Paola , Chan Tim , Grandi Paola , Amankulor Nduka 
Published: July 2016

Abstract
Background: Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Gain of function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods: We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza- 2’deoxycytodine (Decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. Results: All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell- mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK-mediated lysis of IDH mutant cells in an NKG2D- dependent manner. Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell- mediated immune surveillance in patients with IDH mutated diffuse gliomas.
Citation Format: Aparna Rao, Xiaoran Zhang, Christopher Deibert, Paola Sette, Tim Chan, Paola Grandi, Nduka Amankulor. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligands. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3235.