bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3853: AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization
Authors: Lai Shenshen , Xu Qin , Yan Jun , Zhang Hong , Zhang Zaihui 
Published: August 2018

Abstract
Polarization of tumor-associated macrophages (TAMs) to classic pro-inflammatory M1 or alternatively activated M2 types plays an important role in establishing tumor microenvironment and determining therapeutic responses. It has become increasingly clear that M2 macrophages contribute to tumor progression by producing anti-inflammatory cytokines and suppressing anti-tumor immunity. AXL receptor tyrosine kinase has recently emerged as a dual therapeutic target in oncology, due to its function in tumor growth, survival and metastasis, as well as immunosuppressive activity. AXL and its ligand Gas6 are both involved in attenuating anti-tumor immune response through modulation of TAM polarization. Thus, targeting the AXL signaling pathway is expected to promote a pro-inflammatory tumor microenvironment, in addition to direct inhibition of tumor growth. SLC-391, a selective small molecule inhibitor for AXL, displays high potency against numerous cancer cell lines through inhibition of AXL/PI3K/AKT-dependent cell proliferation and survival in vitro. Additionally, this compound was also found to alter the cytokine profile expressed in THP1-derived M2 macrophages, including upregulating pro-inflammatory CXCL10 and downregulating anti-inflammatory IL-10. Noticeably, the expression level of AXL was significantly upregulated in THP1-derived macrophages in presence of tumor cell-conditioned medium, which indicated the involvement of AXL in M2 polarization, and therefore strengthening the notion of AXL as a dual therapeutic target. In a co-culture system consisting of THP1-derived macrophages and A549 non-small cell lung cancer cells, SLC-391 targeted AXL activity in both cell types for overall tumor cell suppression through direct and macrophage-mediated inhibition. This observation is supported by inhibition of tumor growth and the increased ratio of M1/M2-polarized TAMs from mice treated with SLC-391 in a CT-26 murine colon carcinoma syngeneic model, considering CT26 cells are not sensitive to SLC-391 in cell-based proliferation assay. In summary, in addition to direct inhibition of tumor cells, SLC-391 also appears to promote anti-tumor immunity through modulation of M2 to M1 transition.
Citation Format: Shenshen Lai, Qin Xu, Jun Yan, Hong Zhang, Zaihui Zhang. AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization [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 3853.
Abstract 3854: Antizyme inhibitor editing modulates nuclear localization but not antizyme binding: Implications for prostate cancer
Authors: Rice James M. , Ghalali Aram , Wang Liangzhe , Kusztos Amanda , Jernigan Finith , Wu Chin Lee , Zetter Bruce , Rogers Michael S. 
Published: August 2018

Abstract
The endogenous antizyme inhibitor (AZIN) binds to, and is a key regulator of, the cell cycle suppressor antizyme. Antizyme itself is a key regulator of ornithine decarboxylase (ODC), the rate-limiting enzyme in the polyamine synthesis. We have measured the expression and localization of AZIN in 202 prostate cancer specimens, along with 26 adjacent benign samples, and found that nuclear localization of AZIN is dramatically associated with worse outcome. Upregulation and nuclear localization of AZIN have been observed in several cancers, as has editing of the AZIN1 mRNA. Other have hypothesized that the RNA- edited AZIN (edAZIN) may have an increased affinity to antizyme and that could explain the association of edAZIN to the various cancers. We have studied the mechanism behind the nuclear localization of AZIN and found the single base pair substitution caused by RNA editing is sufficient to result in nuclear localization of the protein in all cell types tested. To determine if the nuclear localization might result from increased antizyme-edAZIN affinity, we developed fluorescent protein FRET sensor for protein-protein interaction using Clover-AZIN and antizyme-mRuby2 fusion proteins. Unexpectedly, we found that the editing event decreases edAZIN affinity for antizyme, notwithstanding increased interaction in vivo. Thus, the data indicate that the change in protein localization to the nucleus may be more important to oncogenic function than the actual degree of binding to antizyme. Other functional differences between edAZIN and AZIN might be explained by altered kinetics of binding, by the contribution of an additional adapter protein that modulates the intracellular antizyme:AZIN complex, or by competition for AZIN binding by other partners whose interaction is affected by the editing event. Therefore, we plan to identify AZIN and edAZIN interacting proteins by using proteomic analysis and later study the interaction between AZIN or edAZIN with their binding partners in more detail. Furthermore, our validated FRET assays can be used to identify antagonists of AZIN-antizyme binding (no antagonists are currently known). Given the important role of AZIN in tumor growth, discovery of small-molecule inhibitors of AZIN should lead to antitumor therapies.
Citation Format: James M. Rice, Aram Ghalali, Liangzhe Wang, Amanda Kusztos, Finith Jernigan, Chin Lee Wu, Bruce Zetter, Michael S. Rogers. Antizyme inhibitor editing modulates nuclear localization but not antizyme binding: Implications for prostate 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 3854.
Abstract 3907: Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects
Authors: Fichtner Michael , Bozkurt Emir , McAllister Katherine , McCann Christopher , Longley Daniel , Prehn Jochen H. 
Published: August 2018

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Despite recent advances, the treatment success differs strongly between colorectal cancer patients and new treatment options are urgently needed. Since most tumors avoid apoptosis by a dysregulation of Inhibitor of apoptosis proteins (IAPs), IAP inhibitors such as the SMAC mimetic birinapant are promising new drugs for the treatment of CRC. However, it is currently not possible to stratify for patients who might benefit from adjuvant therapy and those who need new treatments. In 2015, an international consortium unified six independent subtyping approaches and defined 4 distinct, so-called consensus molecular subtypes (CMS). The CMSs are the current gold standard for CRC subtyping and have some prognostic values. Nevertheless, whether the CMS classification can be used to estimate the treatment success is currently under investigation. This study aimed to evaluate the efficacy of treatments with the chemotherapeutics oxaliplatin and 5-fluoruracil (5-FU), TNFalpha, the SMAC-mimetic birinapant and a combination of these drugs. We selected 10 cell lines, representing the four CMSs, and treated them for 24h and 48h with the respective drugs. At both time points, we assessed the cell death by staining with Annexin V/PI followed by flow cytometric analysis of the cells. We were able to show that birinapant has very strong synergistic effects if used in combination with either oxaliplatin/5-FU or TNFalpha, but does not induce apoptosis alone. Importantly, the efficacy of the various co-treatments differed between the cell lines. These differences can, to some extent, be linked to the corresponding CMS of the cells. Cells belonging to the CMS1 subtype showed strong synergistic effects of birinapant and oxaliplatin/5-FU. In contrast, birinapant and TNFalpha co-treatments showed synergistic effects in CMS2 cells, but not in CMS1 cells. Cells belonging to the CMS3 subtype, however, showed a mixed but generally weak response to the co-treatments. Our results highlight birinapant as a promising drug for the treatment of CRC. Our data also suggest that CMSs not only have prognostic values but may also be used as patient stratification tools.
Citation Format: Michael Fichtner, Emir Bozkurt, Katherine McAllister, Christopher McCann, Daniel Longley, Jochen H. Prehn. Birinapant co-treatments of colon cancer cell lines show consensus molecular subtype-specific synergistic effects [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 3907.
Abstract 3914: ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers
Authors: Hamblett Kevin J. , Hammond Phil W. , Barnscher Stuart D. , Fung Vincent K. , Davies Rupert H. , Wickman Grant R. , Hernandez Andrea , Ding Tong , Galey Adam S. , Winters Geoffrey C. , Rich Jamie R. , Babcook John S. 
Published: August 2018

Abstract
Therapies targeting HER2 have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Unfortunately, many patients recur following HER2-targeted treatments and new therapies are needed. Multiple antibody-drug conjugate (ADC) technologies are being explored in this setting, some of which utilize the anti-HER2 antibody trastuzumab. Here we present the preclinical characterization of a new anti-HER2 biparatopic ADC, ZW49, which is generated from the conjugation of a novel N-acyl sulfonamide auristatin payload to the inter-chain disulfide bond cysteines of the bispecific anti-HER2 IgG1 antibody ZW25, via a protease cleavable linker. A series of in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. In cellular binding assays, it was confirmed that the payload conjugation to ZW25 did not affect the antibody's binding to HER2-expressing cells. ZW49 displayed potent in vitro cytotoxicity in multiple cancer cell lines expressing HER2 and was efficacious in multiple patient-derived xenograft (PDX) models. In mice bearing the HBCx-13b HER2 3+ PDX, two doses of ZW49 administered two weeks apart generated tumor regressions. Furthermore, preliminary results from PDX models with lower levels of HER2 expression treated with ZW49 also generated regressions. In nonhuman primates ZW49 administered intravenously every two weeks for three doses was well tolerated. Based on these findings, we are proceeding with further development of ZW49 as a therapeutic candidate in HER2-expressing cancers.
Citation Format: Kevin J. Hamblett, Phil W. Hammond, Stuart D. Barnscher, Vincent K. Fung, Rupert H. Davies, Grant R. Wickman, Andrea Hernandez, Tong Ding, Adam S. Galey, Geoffrey C. Winters, Jamie R. Rich, John S. Babcook. ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers [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 3914.
Abstract 393: Dynamic networks of transcriptome, DNA methylome, and DNA hydroxymethylome during T-cell lineage commitment
Authors: Yoon Byoung-Ha 
Published: August 2018

Abstract
Immunotherapy is a treatment that uses a part of a personal immune system to overcome diseases such as cancer. T cell therapy has been used in a variety of cancer types, including lymphoma, melanoma and colon cancer. There are several strategies used to take advantage of cell-mediated anti-tumor properties of T cells. Cellular immune responses to prevent tumors are typically caused by CD4 and CD8 T cells. The stepwise development of T cells from a multipotent precursor is guided by diverse mechanisms including interactions of lineage specific transcription factors and epigenetic changes and acquires lineage-specific trait. However, in this T-cell development process, a greater understanding of the regulation of genes involved in immunotherapy is needed.
To elucidate the transcriptional networks and epigenetic mechanisms underlying T-cell therapy and T cell lineage commitment, we investigated genome-wide changes in gene expression, DNA methylation and hydroxymethylation among five successive populations of T cell development (DN3, DN4, DP, CD4+, and CD8+) using RNA-seq, MBD-seq and hMeDIP-seq, respectively. And investigated interactive networks of transcription factors, chromatin modifiers, and DNA methylation. We found stage specific differentially methylated regions and some of them occurred near the specific differentially expressed genes related to immune cells or cancer immunotherapy such as Cd4, Ccr9 and Pdcd1. Dynamic changes of DNA methylation and hydroxymethylation is associated with the recruitment of the stage specific transcription factors.
This study may provide a frame work for understanding the complexity of T cell lineage commitment and immunotherapy-related genes were regulated during T-cell differentiation.
Citation Format: Byoung-Ha Yoon. Dynamic networks of transcriptome, DNA methylome, and DNA hydroxymethylome during T-cell lineage commitment [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 393.
Abstract 3941: Heparan sulfate, a new target for platinum in metastatic TNBC
Authors: Katner Samantha J. , Hampton James D. , Peterson Erica J. , Katsuta Eriko , Sayyad Megan R. , Takabe Kazuaki , Koblinski Jennifer , Farrell Nicholas P. 
Published: August 2018

Abstract
Heparan sulfate (HS) are linear polysaccharides conjugated to proteins, heparan sulfate proteoglycans (HSPGs), located on the cell surface and extracellular matrix. The HS chains display varying degrees of sulfation. These sulfate clusters mediate the interaction of polynuclear platinum complexes (PPCs) with HSPG through a “sulfate clamp.” Such PPC-HS interactions can be conceptualized as “polyarginine” mimics. Strong HS-PPC binding protects the oligosaccharide against sulfate loss through metalloshielding. The biological consequences of PPCs metalloshielding HS will in principle affect HS interactions with relevant enzymes and proteins such as heparanase and growth factors, similar in concept to inhibition of DNA-protein binding through modification of DNA structure and conformation. HSPGs, associated growth factors, and heparanase promote tumor progression by facilitating invasion, angiogenesis, and metastasis. High heparanase expression correlates with increased metastatic potential and poor clinical prognosis. PPC-HS interactions inhibit cleavage of a model pentasaccharide by heparanase and further modulated bFGF binding to HS, and bFGF-induced migration and signaling in colon cancer cells. The end-point of functional modulation of HS interactions is inhibition of angiogenesis and metastasis. We report proof-of-principle of strong in vivo anti-metastatic activity of PPCs in triple negative breast cancer (TNBC) models. Further, we examine the anti-metastatic and anti-angiogenic effects of PPC-HS metalloshielding in these in vivo models through multiple growth factor signaling pathways (bFGF, HB-EGF, VEGF), and heparanase activity in breast cancer and endothelial cells. PPCs represent a novel class of intrinsically dual-function agents combining platinum cytotoxicity through DNA targeting with anti-angiogenic effects through glycan targeting.
Chicago 14-17 April 2018
Citation Format: Samantha J. Katner, James D. Hampton, Erica J. Peterson, Eriko Katsuta, Megan R. Sayyad, Kazuaki Takabe, Jennifer Koblinski, Nicholas P. Farrell. Heparan sulfate, a new target for platinum in metastatic TNBC [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 3941.
Abstract 3942: The fraction of garlic protein(s) affect HCC via regulation of angiogenesis
Authors: Chatterjee Nabanita , Das Subhadip , Pal Prajnamoy , Saha Krishna Das 
Published: August 2018

Abstract
Cancers are leading cause of human mortality. Most of deaths are due cancer because of its high resistance to the chemotherapeutic drugs. Thus, there is an ongoing demand for generation of new potent and more effective therapies for cancer treatment. Hepatocellular carcinoma (HCC), is the most leading cause of cancer-related death in all over the world (seems to more than 80% of death cases in USA). It is frequently linked with continuous hepatocytes death, inflammatory cell infiltration, and compensatory liver regeneration with higher angiogenic rate. Considering the different signaling process during this tumorigenesis with the involvement of new ‘lead' identification of various sources, desire to be less toxic and higher bioavailability. The use of natural or its active metabolic component(s) has begun to emerge as a potential innovative approach in medicinal research to deliver bioactive entities. Thus, garlic has already proven as the therapeutic implication on immune system and cancer due to presence of sulfur compound. But the role of active protein fraction present in fresh garlic is still not revealed yet. In our study, we are isolated an active garlic protein from fresh garlic aqueous extract with molecular weight about 40-45kD. This Garlic protein (GP) having non-cytotoxic to human/murine normal cells, could induce apoptosis in human HepG2 cells, as characterized by phosphatydylserine serine exposure, DNA fragmentation, alteration with loss of mitochondrial membrane potential and cytochrome C release, activation of series of caspases, other physiochemical changes lead to induce cancer cell death. This study also focused that the GP effectively suppressed DEN induced liver inflammation and hyperplasia in murine also decline in lipid peroxidation and changes in enzymic antioxidants and biochemical parameter with improvement of their survival rate. It reduced the elevated level of cytokines and growth factors in hepatocytes from liver fibrosis bearing mice. Thus, finding indicated that, GP may induce apoptosis and in hyper proliferating cancer cells via altering cytokines-chemokines level with tumor growth regulation in carcinogen exposed rodent system. Future direction, we are proposing to execute the experiments on p53-/- and cMyc-/- deficient mice to find out the role of GP in these circumstances.
Citation Format: Nabanita Chatterjee, Subhadip Das, Prajnamoy Pal, Krishna Das Saha. The fraction of garlic protein(s) affect HCC via regulation of angiogenesis [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 3942.
Abstract 3944: Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck cancer
Authors: Kuo Ching-Chuan , Chang Jang-Yang , Hsieh Hsing-Pang , Kung Hsing-Jien , Chang Hsih-Huei , Huang Chih-Hsiang , Kuo Cheng-Chin , Ke Yi-Yu 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC), the most common malignant neoplasm arising in the mucosa of the upper aerodigestive tract, remains a significant cause of morbidity worldwide. With respect to the cancer treatment, HNSCC has a moderately good survival rate, however, the disease often recurs, leading to a poor prognostic disease course and tends to fail in treatment. The metabolic properties of cancer cells diverge significantly from those of normal cells. Emerging evidence suggests these metabolic alterations are also linked to therapeutic resistance in cancer treatment. EGFR targeted agents currently approved or under investigation for HNSCC. We recently identified a novel EGFR tyrosine kinase inhibitor (EGFR-TKI), BPR3K007S0, and found that this compound significantly inhibited EGFR phosphorylation in EGFR-overexpressing HNSCC cells in vitro and in vivo than that of gefitinib. BPR3K007S0 significantly suppressed the expression of a wide range of metabolic genes, including metabolic-related transcription factors, glycolysis, TCA cycle, and pentose phosphate pathway genes. Collectively, we also found that BPR3K007S0 significantly decreased glycolytic and mitochondria respiratory capacity. Pharmacological and genetic manipulation demonstrated that c-Myc/hexokinase 2 axis was one of downstream effector in response to EGFR inhibition. Furthermore, we found that EGFR-TKIs were able to suppress succinate dehydrogenase A leading to reduce fumarate, an oncometabolite generates from Kreb cycle, and contributed to EGFR-TKIs mediated antitumor effect. Taken together, these results revealed that blockage of EGFR signaling repurposes tumor metabolism through suppression of hexokinase 2 and succinate dehydrogenase A, in glycolysis and Kreb cycle, respectively, and demonstrated added benefits to treatment of HNSCCs.
Citation Format: Ching-Chuan Kuo, Jang-Yang Chang, Hsing-Pang Hsieh, Hsing-Jien Kung, Hsih-Huei Chang, Chih-Hsiang Huang, Cheng-Chin Kuo, Yi-Yu Ke. Blockage of EGFR signaling repurposes tumor metabolism through suppression of glycolysis and Kreb cycle in head and neck 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 3944.