bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 203: Pseudosemiglabrin inhibits tumor angiogenesis and tumor growth of human colon cancer in xenograft mouse models by downregulating endothelial functions, Notch and VEGF pathways
Authors: Hassan Loiy E. Ahmed , Seeni Azman , Majid Amin M. Abdul 
Published: August 2019

Abstract
Many antineoplasic agents were identified from natural product. One such agent is (-)-pseudosemiglabrin extracted from aerial parts of Tephrosia apollinea, while significant progress has been made in understanding the antineoplasic and anti-inflammatory of prenylated flavone (-)-pseudosemiglabrin (SSG), little is known about its antiangiogenic and antitumor in vivo. Using rat aortic ring assay and zebrafish model, SSG dramatically suppressed angiogenesis in vitro, ex vivo and in vivo models, SSG profoundly inhibited the outgrowth of new vessels from explants rat aortic ring, moreover it impaired human endothelial cells (HUVEC) migration and formation of capillary-like structure in vitro in none toxic doses. In this study we hypothesize that SSG can hampered tumor angiogenesis and tumor growth of colorectal cancer in ectopically and orthotopically implanted in nude mice, oral administration of SSG (25- 100mg/kg) significantly inhibited colon tumors growth in nude mice. Histological and Immunohistochemistry analysis further revealed that the stained blood vessels and expression of CD31 in xenograft were remarkably decreased in tumors excised from animals treated with SSG. Mechanistically the compound inhibits tumor angiogenesis by downregulation of Notch downstream (NCID); also SSG was found to inhibit VEGF secretion from human cancer cells as well as endothelial cells. In conclusion, the results demonstrated an original role of (-)-pseudosemiglabrin in inhibiting tumor angiogenesis and tumor growth via inhibition Notch and VEGF pathways. This study also validates the central role of Notch in tumor angiogenesis and suggests that (-)-pseudosemiglabrin could be a potential therapeutic candidate for cancer and other angiogenesis related diseases.
Note: This abstract was not presented at the meeting.
Citation Format: Loiy E. Ahmed Hassan, Azman Seeni, Amin M. Abdul Majid. Pseudosemiglabrin inhibits tumor angiogenesis and tumor growth of human colon cancer in xenograft mouse models by downregulating endothelial functions, Notch and VEGF pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 203.
Abstract 2030: Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma
Authors: Lee Dagyoeng , Woo Jongsu , Bae Cheong A , Ham In-Hye , Oh Hye Jung , Son Sang-Yong , Han Sang-Uk , Kim Tae-Min , Yoon Jung Hwan , Park Won Sang , Hur Hoon 
Published: August 2019

Abstract
Cancer-associated fibroblasts (CAF) are a major component of tumor stroma and their effect on the progression of gastric carcinoma (GC) has recently been demonstrated. However, agents targeting the interaction between CAF and GC cells have not been applied in a clinical setting. The aim of this study was to investigate the effect of an AXL inhibitor on CAF-induced GC progression. We examined growth arrest specific factor 6 (GAS6) expression and phosphorylation of AXL in various cell lines, including GC cells and non-cancerous cells, by qPCR, western blot, and immunocytochemistry. We investigated the role of CAF-derived GAS6 on the migration and proliferation of GC cells using migration and cell survival assays. The effect of the AXL inhibitor, Bemcentinib, on the CAF-induced aggressive phenotype of GC cells was also investigated. Finally, we performed immunohistochemistry to measure the phosphorylation of AXL in a tissue microarray composed of 175 GC tissues, and evaluated its correlation with the prognosis of GC patients. qPCR and western blot analysis showed that GAS6 expression was higher in CAF relative to other cells. We found that CAF increased the phosphorylation of AXL (P-AXL), differentiation into a mesenchymal-like phenotype, and cell survival in GC cell lines. When the expression of AXL was inhibited in GC cells, the effect of CAF was reduced. In addition, Bemcentinib, a small molecule inhibitor of AXL, suppressed the effects of CAF on GC cell lines. In GC tissues, P-AXL positively correlated with the expression of vimentin (P &lt; 0.001) and high levels of P-AXL were significantly associated with poor overall survival (P = 0.022).These findings suggest that CAF is a major source of GAS6 in the GC microenvironment and actively promotes an aggressive phenotype in GC cells through AXL activation. We conclude that an AXL inhibitor may be a novel agent for GC treatment.
Citation Format: Dagyoeng Lee, Jongsu Woo, Cheong A Bae, In-Hye Ham, Hye Jung Oh, Sang-Yong Son, Sang-Uk Han, Tae-Min Kim, Jung Hwan Yoon, Won Sang Park, Hoon Hur. Inhibiting the GAS6/AXL axis suppresses tumor progression by blocking the interaction between cancer-associated fibroblasts and cancer cells in gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2030.
Abstract 2033: Bidirectional paracrine IL-33-TGF-beta signaling underlies a tumor-promoting stem cell niche
Authors: Oshimori Naoki , Oshimori Sachiko , Elhance Ajit , Leitenberger Justin , Kumar Sushil 
Published: August 2019

Abstract
Malignant tumor progression and aggressive tumor recurrence after treatment are driven by subsets of cancer stem cells (CSCs), but targeting CSCs remains a major challenge due to their plasticity. CSCs in squamous cell carcinoma reside at the tumor-stromal interface, a paramount tumor microenvironment (TME) for interactive crosstalk between cancer cells and various other cells via soluble mediators, and tumor-infiltrating immune cells are pivotal regulators of tumor progression. However, the molecular link between tumor-associated immune-inflammatory responses and the regulation of CSCs are largely unknown. To define a framework of the CSC niche, we have been focusing on crosstalk between TGF-beta-activated CSCs and their neighboring immune cells. By transcriptomic analysis, we identify interleukin-33 (IL-33) as the most upregulated cytokine in TGF-beta-activated CSCs. We find that IL-33 is secreted in response to the activation of antioxidant responses, and IL-33 mobilizes a subset of tumor-promoting macrophages that express the IL-33 receptor in the adjacent stroma. Tumor-specific IL33 knockdown in vivo dampens both invasive carcinogenesis and paracrine TGF-beta signaling in tumor cells, indicating that IL-33 has a crucial role in the formation of TGF-beta-rich tumor-promoting TME by affecting tumor-infiltrating bone marrow-derived monocytes. Together, these findings on a bidirectional paracrine signaling axis provide novel insights into mechanisms of the formation a CSC privilege niche, which may hold great potential to drastically improve the therapeutic efficacy of current and future cancer treatments.
Note: This abstract was not presented at the meeting.
Citation Format: Naoki Oshimori, Sachiko Oshimori, Ajit Elhance, Justin Leitenberger, Sushil Kumar. Bidirectional paracrine IL-33-TGF-beta signaling underlies a tumor-promoting stem cell niche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2033.
Abstract 2047: Identification of endometrial cancer specific immuno-therapeutic targets by comprehensive In Silico analysis
Authors: Ikeda Yuji 
Published: August 2019

Abstract
Background; Immune-therapeutic targets specific to endometrial cancer has been unclarified. In term of HLA allele type, about 60% and 40% of Japanese has HLA-A*24 and -A*02,respectively. Development of new immune-therapeutics taking account of these types is required. We herein aimed to identify immune-therapeutic targets specific to endometrial cancer and commonly available for Japanese patients using in Silico analysis, which can search comprehensively peptides binding to HLA molecule in an allele-specific manner. Methods; mRNA sequencing data obtained from 582 samples of endometrial cancer and 53 control samples from 31 normal organs were extracted from cancer genome atlas (TCGA) database and Genotype-Tissue Expression project, respectively. After filtering of protein coding genes, 8 to 12 peptides with high binding affinity to HLA-A*24 and -A*02 alleles were identified by an artificial neural network soft trained for peptide-MHC class I binding. Results; Based on mRNA sequencing data, we identified 71 genes that are expressed in endometrial cancer but not in control organs. Of them, top ten genes with high mRNA levels in the cancer are selected. Analysis of binding affinity revealed that 21 and 146 peptides derived-from ten genes of interest showed high binding affinity to HLA-A*24 and -A*02, respectively. Especially, one target gene showed the highest expression levels in endometrial cancer, and possessed 15 and 58 candidate peptides in HLA-A*24 and -A*02, respectively. Conclusion; By comprehensive analysis using mRNA data, we identified reliable candidates target of immune-therapeutics for HLA-A*02 and -A*24 patient with endometrial cancer.
Citation Format: Yuji Ikeda. Identification of endometrial cancer specific immuno-therapeutic targets by comprehensive In Silico analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2047.
Abstract 2050: Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo
Authors: Rotolo Jim A. , Ramirez Rick , Koester Mark , Leong Siok , Ghamsari Lila , Merutka Gene , Kappel Barry J. 
Published: August 2019

Abstract
Anti-apoptotic B cell lymphoma 2 (Bcl-2) family proteins are frequently overexpressed across a variety of tumors, resulting in tumor cell survival and resistance to therapy. Inhibition of the expression or activity of these survival factors is an attractive approach for cancer therapy. Activating transcription factor 5 (ATF5) regulates gene transcription of anti-apoptotic Bcl-2 family proteins in neural progenitor cells and a wide range of human cancer cells. Here, we describe ST101, a rationally designed, synthetic, D-amino acid, cell penetrating peptide therapeutic designed to disrupt the protein-protein interactions driving ATF5-regulated gene transcription. Exposure of HL60 promyelocytic leukemia cells and MCF7 breast adenocarcinoma cells to low micromolar concentration of ST101 resulted in a decrease in MCL-1, BCL-2 and BIRC5 (Survivin) mRNA expression at 4 and 24 hrs post exposure. Further, exposure to ST101 resulted in a dose-dependent loss of viability across a panel of human cancer cells, including MCF7, HL60, U251 glioblastoma, A375 melanoma, DU145 prostate cancer, and A549 lung adenocarcinoma, characterized by an increase in annexin V and PI staining by flow cytometry peaking 48 hrs post exposure, resulting in a median half maximal effective concentration (EC50) value of 4.0 micromolar. In contrast, normal human peripheral blood mononuclear cells and bone marrow mononuclear cells were resistant to ST101-mediated cell death, with &gt;80 micromolar EC50 values. In mouse xenograft experiments, 25mg/kg ST101 administered three times per week for three weeks resulted in significant tumor regression in MCF7 and U251 subcutaneous tumors as well as tumor growth delay in HL60 subcutaneous tumors. Tumor growth remained significantly inhibited weeks after the last treatment in the MCF7 and U251 models. In summary, ST101 selectively kills cancer cell lines by decreasing BCL-2 family gene expression, resulting in significant reductions in tumor growth in mouse models. Taken together, these data validate ST101 as a potent peptide therapeutic candidate for a variety of solid tumor and hematologic malignancies.
Citation Format: Jim A. Rotolo, Rick Ramirez, Mark Koester, Siok Leong, Lila Ghamsari, Gene Merutka, Barry J. Kappel. Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2050.
Abstract 2053: Targeting GRK2 increases chemotherapy-induced apoptosis in medulloblastoma
Authors: Pathania Anup S. , Ren Xiuhai , Mahdi Min , Shackleford Gregory M. , Erdreich-Epstein Anat 
Published: August 2019

Abstract
Background: G protein receptor kinase-2 (GRK2; ADRBK1) belongs to the family of G protein-coupled receptor (GPCR) kinases (GRKs). GRK2 phosphorylates GPCR and non-GPCR targets including cell surface receptors, cytoskeletal and mitochondrial proteins and transcription factors. It also functions in embryonic development, heart function, metabolism, and some cancer models. Here we hypothesized that targeting GRK2 will sensitizes cancer cells to therapy. We tested this in medulloblastoma, the most common malignant brain tumor in children.
Methods: siRNA transfections, shRNA viral infections, SDS-PAGE, western blotting, flow cytometry. Cells: UW228 and DAOY medulloblastoma.
Results: We found that GRK2 inhibition promotes anti-tumor effects of chemotherapeutic drugs cisplatin and etoposide in UW228 and DAOY medulloblastoma cell lines. GRK2 silencing increased apoptosis induced by cisplatin and etoposide and GRK2 overexpression decreased apoptosis induced by these drugs in UW228 and DAOY. Time dependent studies revealed that GRK2 overexpression delayed cisplatin- and etoposide-induced apoptosis measured by the induction of Annexin V positive population and by PARP-1 cleavage. GRK2 mutants, GRK2 K220R (kinase deficient mutant) and GRK2 S670A (cannot be phosphorylated) were similar to wildtype GRK2 in delaying the cisplatin and etoposide induced apoptosis. GRK2 knockdown antagonized serum induced AKT and ERK phosphorylation in both lines whereas GRK2 overexpression promoted phosphorylation, suggesting that GRK2 is important in medulloblastoma survival pathways.
Conclusions: These results demonstrate that targeting GRK2 enhances cisplatin- and etoposide-induced apoptosis in medulloblastoma cell lines and suggests that GRK2 inhibitors may enhance responsiveness of medulloblastoma to chemotherapy.
Citation Format: Anup S. Pathania, Xiuhai Ren, Min Mahdi, Gregory M. Shackleford, Anat Erdreich-Epstein. Targeting GRK2 increases chemotherapy-induced apoptosis in medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2053.
Abstract 2054: A novel Bcl-2/Bcl-XL inhibitor APG-1252-12A as a potential therapeutic strategy for gastric carcinoma
Authors: Yan Xianglei , Yi Hanjie , Luo Qiuyun , Yuan Luping , Zhou Suna , Pan Wentao , Zhang Lin , Qiu Miaozhen , Yang Dajun 
Published: August 2019

Abstract
Background: Gastric cancer (GC) is the fourth most common type of malignant tumor and is the second leading cause of cancer-related mortality. Surgery and chemotherapy play important role in the treatment of GC, however the overall survival of gastric cancer patients is not promising. APG-1252-12A specifically binding to Bcl-2 and Bcl-xl has shown efficacy in some solid tumor. We intend to investigate the anticancer effect and combination enhancement of Fluorouracil (5-FU) in gastric cancer.
Materials and methods: Human gastric cancer cell lines (AGS, NCI-N87, SGC7901, BGC823, MKN45 and NUGC3) were treated with different concentrations and time of APG-1252-12A. CCK-8, survival assays, flow cytometry and western blot were used to assess cell survival, cell cycle progression and apoptosis. In vivo, xenograft mouse models (NCI-N87) were established to analyze the anticancer effect and combination enhancement of 5-FU.
Results: In vitro, APG-1252-12A inhibited proliferation of gastric cancer cell lines, without cell-cycle arrest. Meanwhile, APG-1252-12A increased protein expression of apoptosis signal pathway. The combination of APG-1252-12A and 5-FU resulted in the accumulation of apoptosis protein such as PARP and cleaved caspase3, which indicating an increasing of chemosensitivity. In xenograft mouse models, single therapy with APG-1252-12A obviously suppressed tumor growth, especially in 100mg/kg group. Combination group delayed tumor growth more significantly compared with APG-1252-12A and 5-FU single therapy. By analyzing proliferation marker Ki67 in xenograft tumor specimens, we found that the number of proliferating cells significantly decreased in tumors receiving combination treatment of APG-1252-12A and 5-FU compared with tumors receiving single treatment. The results strongly confirmed the antitumor capacity of APG-1252-12A combined with 5-FU.
Conclusions: The results strongly suggest that Bcl-2 and Bcl-xl inhibitor APG-1252-12A may serve not only as a single therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating gastric cancer through apoptosis signal pathway.
Citation Format: Xianglei Yan, Hanjie Yi, Qiuyun Luo, Luping Yuan, Suna Zhou, Wentao Pan, Lin Zhang, Miaozhen Qiu, Dajun Yang. A novel Bcl-2/Bcl-XL inhibitor APG-1252-12A as a potential therapeutic strategy for gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2054.
Abstract 2057: Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer cells
Authors: Zhang Shengliang , Zhou Lanlan , Ralff Marie D. , El-Deiry Wafik S. 
Published: August 2019

Abstract
Cellular FADD-like IL-1β-converting enzyme-inhibitory protein (c-FLIP) is a master anti-apoptotic regulator in cancer cells. c-FLIP inhibits caspase 8 activation and suppresses cell apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) in malignant cells. Targeting c-FLIP is an attractive strategy for cancer therapy. We previously identified a small-molecule CB001 as a p53-restoring compound and found that CB001 induces cell death with little or no genotoxicity in human colorectal cancer cells. We now show that CB001 downregulates c-FLIP expression in cancer cells at the post-translational level via protein degradation. CB001 treatment induces an increase in caspase 8 activity which correlates with the decrease in c-FLIP at the protein level in mutant p53-expressing cancer cells. Knockdown of caspase 8 rescues cancer cells from CB001-induced apoptosis in mutant p53-expressing cancer cells, suggesting that downregulation of c-FLIP is one of the major mechanisms by which CB001 induces extrinsic cell apoptosis. Furthermore, our studies reveal a synergy between CB001 and TRAIL to induce apoptosis in TRAIL-resistant cancer cells, but not in normal cells at the tested doses. These results taken together suggest that CB001 is a promising lead for drug development with a strong capability to suppress tumor growth through targeting c-FLIP in cancer cells.
Citation Format: Shengliang Zhang, Lanlan Zhou, Marie D. Ralff, Wafik S. El-Deiry. Small molecule CB001 induces extrinsic apoptosis via downregulation of c-FLIP expression in mutant p53-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2057.
Abstract 2062: Evaluating the effect of tumor necrosis on glycolytic flux and cell survival in glioblastoma
Authors: Noch Evan , Yim Isaiah , Cantley Lewis 
Published: August 2019

Abstract
Glioblastoma continues to rank as one of the most lethal primary human tumors. The degree of necrosis in glioblastoma remains one of the most powerful predictors of poor prognosis, but the relationship between necrosis and poor prognosis is not known. It is unclear whether endogenous tumor necrosis is merely an indicator of an aggressive phenotype or whether tumor necrosis itself propagates the aggressive phenotype. Determining the role of necrosis in mediating the malignant potential of glioblastoma therefore represents an important aspect of therapy. We describe a model of patient-derived glioblastoma spheroids expressing a genetically encoded fluorescent NADH/NAD+ biosensor. This biosensor reports glycolytic flux and can be imaged with fluorescent microscopy. We imaged spheroids using multiphoton microscopy and differentiated cells by high versus low NADH/NAD+ levels. FACS analysis of dissociated spheroids followed by RT-PCR analysis demonstrated increased expression of genes known to be upregulated in peri-necrotic regions, including procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), activating transcription factor 5 (ATF5), and protein O-fucosyltransferase 2 (POFUT2). These cells also had increased expression of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF) and jumonji domain-containing protein 6 (JMJD6). We created an intracranial glioblastoma patient-derived xenograft model, with cells expressing this NADH/NAD+ biosensor. When imaging these tumors in vivo, we were able to demonstrate that cells with high NADH/NAD+ levels are more likely to survive within the peri-necrotic environment. These findings indicate that increased glycolytic flux facilitates survival from expanding regions of necrosis. Future experiments will focus on biopsy of cellular populations with high versus low NADH/NAD+ levels within the peri-necrotic niche. We will then perform RNAseq and metabolomics analysis to determine the genetic and metabolic adaptations that facilitate survival within this microenvironment. This model to study cell survival within the peri-necrotic region will improve awareness of necrosis-mediated growth proliferation and may lead to treatments targeted to tumor necrosis that could improve patient prognosis.
Citation Format: Evan Noch, Isaiah Yim, Lewis Cantley. Evaluating the effect of tumor necrosis on glycolytic flux and cell survival in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2062.