bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5450: Anticancer effects of picrasidine Q from Angelica keiski on esophageal squamous cell carcinoma by downregulation of FGFR2 signaling pathways
Authors: Liu Xuejiao , Shi Yuanyuan , Song Mengqiu , Zhao Ran , Chen Hanyong , Shim Jung Hyun , Dong Zigang , Lee Mee-Hyun 
Published: August 2018

Abstract
Fibroblast growth factor receptor (FGFR) 2 and its downstream signaling cascades, PI3 K/AKT/mTOR is playing an important role in cell survival and proliferations. In this study, we firstly found that picrasidine Q (PQ), an alkaloid component extracted from Angelica keiskei species, has the capacity of anti-cell transformation and anticancer. After ligand shape similarity approach of PQ, we found that PQ targeted FGFR 2 and verified by FGFR2 kinase assay as well as computational docking model. FGFR2 highly expressed in esophageal cancer tissues and PQ inhibited fibroblast growth factor (FGF)-induced cell transformation. Furthermore, PQ inhibited cell proliferation and induced G1 phase arrest of cell cycle and apoptosis in KYSE30, KYSE410, and KYSE450 esophageal squamous cell carcinoma (ESCC) cells. It was confirmed by detecting of biological markers such as cyclinD1, cyclinD3 and cyclinB1 for cell cycle or cleaved caspase-7, caspase-3, and PARP for apoptosis. PQ targeting of FGFR2 kinase activities suppressed downstream target proteins including phosphorylation of AKT and mTOR but not MEK/ERK signaling pathways. Taken together, our results are the first to identify that PQ might be a chemopreventive and chemotherapeutic agent by direct targeting FGFR2 and inhibiting cell proliferation of ESCC cells.
Citation Format: Xuejiao Liu, Yuanyuan Shi, Mengqiu Song, Ran Zhao, Hanyong Chen, Jung Hyun Shim, Zigang Dong, Mee-Hyun Lee. Anticancer effects of picrasidine Q from Angelica keiski on esophageal squamous cell carcinoma by downregulation of FGFR2 signaling pathways [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 5450.
Abstract 5463: Free fatty acids augment radiation-induced cytotoxicity in cervical cancer cells via mTOR/Akt//PPARg/p53-mediated pathway
Authors: Muhammad Naoshad , Rashmi Ramachandran , Ruiz Fiona , Zahner Michael C. , Schwarz Julie K. 
Published: August 2018

Abstract
Purposes of the study: Our clinical results show that obese patients with cervical cancer who are treated with definitive chemoradiation have favorable outcomes, and this effect is independent of diabetes or metformin use. PI3K/AKT pathway signaling is decreased in cervical tumors from obese hosts, even in the context of genomic mutations that would otherwise activate PI3K signaling, such as PTEN deletion. The objective of the present study is to determine whether other factors related to obesity, such as circulating free fatty acids, influence radiation responses in vitro.
Experimental procedures: Radiation sensitivity experiments were performed in cervical cancer cells with and without PI3K pathway mutations (CaSki (mutant), ME180 (mutant), SiHa (WT). To determine whether combination treatment of free fatty acids (palmitic, oleic and linoleic) plus radiation increases cytotoxicity in cervical cells, we performed cell viability assay, long term colony formation assays (CFA) and morphological examination by vertical microscope. To determine whether the addition of free fatty acids to radiation influences cell survival signaling, a series of Western blots were performed.
Summary: We observed that combination treatment of free fatty acids and radiation significantly increased cytotoxicity in all the cervical cancer cell lines tested. Mechanistic investigations revealed that free fatty acids induced potentiation of radiation-induced cytotoxicity through downregulation of p-mTOR, p-Akt and PTEN. Furthermore, we observed that this combination regimen upregulates the expression PPARγ and p53.
Conclusions: Free fatty acids potentiated the effect of radiation in PI3K-activated cervical cancer cell lines through mTOR/Akt//PPARg/p53 mediated pathway. Future studies will characterize the mechanism of free fatty acid potentiation of radiation-induced tumor cell death in detail, including the potential contribution of lipid peroxidation and alterations in glucose metabolism.
Citation Format: Naoshad Muhammad, Ramachandran Rashmi, Fiona Ruiz, Michael C. Zahner, Julie K. Schwarz. Free fatty acids augment radiation-induced cytotoxicity in cervical cancer cells via mTOR/Akt//PPARg/p53-mediated pathway [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 5463.
Abstract 5566: LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies
Authors: Hu Xiao , Liu Xikui , Li Hongxiu , Weems Garry , Zawidzka Elizabeth , Gao Yilin , Wilkins H. Jeffrey , Carter Laura 
Published: August 2018

Abstract
The retinoic acid-related orphan receptor γt (RORγt) is a nuclear receptor transcription factor that acts as an immune cell master control switch driving the generation and function of Th17 (helper) and Tc17 (cytotoxic) T cells. Preclinical data show that synthetic RORγ agonists modulate immune cell gene expression to both increase immune activity and decrease immunosuppressive mechanisms in the tumor microenvironment. Because RORγ agonists impact multiple antitumor mechanisms, these compounds have the potential to combine with other agents to enhance tumor immunity. In addition to preclinical data supporting a biologic rationale, bioinformatic and machine learning approaches based on the RORγ pathway were undertaken to prioritize possible clinical combinations. This work highlighted other immuno-oncology agents as well as targeted therapies and more conventional treatments. Preclinical, syngeneic mouse cancer models were used to test some of the hypotheses. Based on the finding that RORγ agonists decrease PD-1 expression and that anti-CTLA4 induces ICOS, which stabilizes RORγ expression, anti-PD1 or anti-CTLA4 agents were combined with the RORγ agonist LYC-54143 in 12 syngeneic murine models. Compared with individual agents, combination treatments elicited superior tumor growth inhibition in 6 of the models (Table). RORγ agonist treatment was also able to augment antitumor activity of doxorubicin. In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule RORγ agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer.
Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine modelAnti-PD1 aloneAnti-CTLA4 aloneRORγ agonist aloneRORγ agonist + anti-PD1RORγ agonist + anti-CTLA4H22 (Liver)30-50%&gt;50%*10-30%&gt;50%*&gt;50%*Pan02 (Pancreas)&lt;10%10-30%&lt;10%10-30%*10-30%*CT26 (Colon)10-30%&lt;10%&lt;10%&lt;10%30-50%B16F10 (Melanoma)10-30%10%10-30%10-30%30-50%A230 (Lymphoma)&lt;10%&lt;10%10-30%30-50%10%Renca (Renal)&lt;10%10-30%30-50%*30-50%*30-50%*P&lt;.05 vs vehicle.
Citation Format: Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter. LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies [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 5566.
Abstract 5700: IDO1 high expression is associated with a poor prognosis in patients with esophageal cancer
Authors: Kiyozumi Yuki 
Published: August 2018

Abstract
[Background] Esophageal cancer is the sixth most common cause of death from cancer worldwide. Although the development of multidisciplinary treatment for esophageal cancer, the prognosis of those patients remains poor. Recently, immunotherapy is expected as innovative therapy for several types of cancer. Indoleamine 2, 3- Dioxygenase (IDO1) is an enzyme responsible for the oxidation of tryptophan into kynurenine and implicated in immune modulation through its ability to limit T cell function and engage mechanisms of immune tolerance. IDO1 is focused as one of the immune subversion strategy and the therapy of targeting IDO1 is in clinical development for many types of cancer. IDO1 activation induces the downregulation of activating natural killer (NK) cell receptors on NK cells and inhibition of cytotoxic T cells by promotion of cell cycle arrest and apoptosis. However, the significance of IDO1 expression in esophageal cancer remains still unknown. The aim of this study is to examine the relationship between IDO1 expression and tumoral immune status, and its prognostic impact in esophageal cancer.
[Methods] IDO1 expression, cluster of differentiation (CD8) expression as a marker of cytotoxic T cells, forkhead Box P3 (FOXP3) as a maker of regulatory T cells were evaluated by immunostaining in 305 clinical samples of curative resected esophageal cancer.
[Result] In 305 clinical samples, high IDO1 high expression (n=71) was significantly associated with poor prognosis in overall survival(OS)(p=0.0034). In uni-and multivariate analysis, IDO1 high expression was an independent prognostic factor for OS. In those patients, CD8 low expression was also associated with poor prognosis in OS (p = 0.025). Furthermore, double immunostaning with IDO1 and CD8 revealed that CD8 expression levels was inverse correlated with IDO1 expression levels in those patients. In combination analysis of IDO1 and CD8 expression, IDO1 high expression and CD8 low expression group experienced worse overall survival (p=0.0024). Conversely, IDO1 low expression and CD8 high expression group was shown the best overall survival. In addition, IDO1 high expression group is correlate with the high counts of FOXP3 positive cells (p = 0.02).
[Conclusion] IDO1 expression was associated with an unfavorable clinical outcomes by induced immune tolerance and the classification of IDO1 and CD8 expression levels might serve as a predictive biomarker in esophageal cancer. The correlation between IDO1 and FOXP3 expression suggested that IDO1 involved in immune tolerance in esophageal cancer. These findings indicate that IDO1 would be a regulator of, and candidate therapeutic target in esophageal cancer.
Citation Format: Yuki Kiyozumi. IDO1 high expression is associated with a poor prognosis in patients with esophageal 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 5700.
Abstract 681: Targeting diacylglycerol kinases for immuno-oncology
Authors: Hsu Ku-Lung ,   Hsu Lab at the University of Virginia
Published: August 2018

Abstract
Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through phosphorylation of the ubiquitous secondary messenger diacylglycerol. Emerging clinical evidence supports DGK-alpha (DGKA) as a promising target for cancer immunotherapy because of its critical role in regulating lipid signaling necessary for proper T cell activation. Methods for direct evaluation of DGK activity in native biologic systems are lacking and needed to develop chemical probes for studying isoform-specific functions. Here, I will discuss efforts from my group to utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to map previously undefined ATP- and small molecule-binding sites of representative members from all subtypes of the DGK family. We use our chemical proteomics strategy to discover an unusual binding mode for DGKA inhibitors, including interactions at a novel binding site remote from the ATP binding pocket. I will also describe our efforts towards discovery of new lead inhibitors for future development of highly potent and selective DGKA inhibitors. Collectively, our studies illustrate the power of chemical proteomics to site-specifically profile protein-small molecule interactions and reveal key ligand binding sites for selective inactivation of the DGK family of lipid kinases.
Citation Format: Ku-Lung Hsu, Hsu Lab at the University of Virginia. Targeting diacylglycerol kinases for immuno-oncology [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 681.
Abstract 79: Stromal regulation of prostate cancer cell proliferation by mevalonate pathway enzymes HMGCS1 and HMGCR
Authors: Ashida Shingo , Kawada Chiaki , Inoue Keiji 
Published: August 2018

Abstract
It has been suggested that the tumor microenvironment plays an important role in tumor progression, acquisition of androgen independence, and distant metastasis in prostate cancer (PC). However, little is known about the transcriptional basis of cellular interactions in the human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we investigated the interaction of PC, epithelial, and stromal cells by analyzing genome-wide gene expression profiles. Our hypothesis is that PC cells could induce stromal cells to differentiate into so-called cancer-associated fibroblasts (CAFs), which might contribute to cancer invasion and metastasis. We identified the up-regulated genes in normal human prostate stromal cells (PrSC) co-cultured with human PC cells (LNCaP), which included the mevalonate pathway enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Knockdown of endogenous HMGCS1 or HMGCR in PC cells by shRNA resulted in a significant reduction of PC cell viability. Importantly, exogenous overexpression of HMGCS1 or HMGCR in either PC cells or prostate stromal cells stimulated PC cell growth, suggesting a possible autocrine/paracrine regulation. Immunohistochemical analysis confirmed that HMGCS1 and HMGCR were overexpressed in PC stroma, especially in the early stage of PC. These results provide clues to the molecular mechanisms underlying PC invasion and metastasis, and suggest that HMGCS1 and HMGCR in PC, as well as in PC stroma, might serve as molecular targets for the treatment of PC.
Citation Format: Shingo Ashida, Chiaki Kawada, Keiji Inoue. Stromal regulation of prostate cancer cell proliferation by mevalonate pathway enzymes HMGCS1 and HMGCR [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 79.
Abstract 886: Metformin effect on multidrug resistant leukemia cells: metalloproteinases 2 and 9
Authors: Oliveira Ligia P. , Perea Camila , Baldi Caroline , Prata Rodrigo F. , Renó Débora L. , Lima Luana P. , Curvello Rodrigo , Souza Ana Carolina S. 
Published: August 2018

Abstract
Besides the progress in studies of cancer, the rates of morbidity and mortality due to this disease still considerably elevated. Chronic myeloid leukemia (CML) is a hematological neoplasm, therefore chemotherapy is the main therapeutic approach used, however most patients develop resistance to chemotherapy. Several factors contribute to this scenario, among them the lack of selective treatment, the emergence of tumor cells resistant to the wide variety of cytotoxic agents during treatment and the formation of metastases, which accounts for the majority of cancer deaths. Therefore, application of new drugs in antitumor therapies has been constantly studied. Studies have shown that metformin, an oral euglycemic used in the treatment of type II diabetes, has potential use in the treatment of cancer, potentializing the effects of standard chemotherapy used in treatment. In this work the effects of metformin on the metastatic capacity of K562 (non-resistant leukemic cell), Lucena and FEPS (leukemic cells resistant to multiple drugs) were evaluated through the study of MMP2 and MMP9 metalloproteinases, enzymes essential for the metastatic process. Thus, the present project aimed to evaluate the gene expression and enzymatic activity of MMP2 and MMP9 metalloproteinases in CML cells, before and after treatment with metformin, seeking to verify the effects of metformin on the expression and activity of these enzymes. Gene expression was evaluated using quantitative PCR and the quantification of enzymatic activity was performed by the substrate degradation using the zymography method. The results showed that metformin has the potential to modulate the expression and activity of the studied metalloproteinases.
Citation Format: Ligia P. Oliveira, Camila Perea, Caroline Baldi, Rodrigo F. Prata, Débora L. Renó, Luana P. Lima, Rodrigo Curvello, Ana Carolina S. Souza. Metformin effect on multidrug resistant leukemia cells: metalloproteinases 2 and 9 [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 886.
Abstract 889: Metformin treatment inhibits proliferation and induces apoptosis in medulloblastoma cells
Authors: Payne Kristen C. , Hunter Abigail , Bowman W Paul , Murray Jeffrey C. , Basha Riyaz , Sankpal Umesh T. 
Published: August 2018

Abstract
Medulloblastoma is the most common malignant brain tumor in children that typically requires a patient specific combination of surgical resection, chemotherapy, and radiation. Up to 80% of medulloblastoma patients respond to treatment and survive long-term. However, survivors often suffer from severe long term sequelae secondary to treatment that affects their neurocognitive and growth potential. Therefore, there is an urgency to develop less toxic, more focused treatment strategies that target specific pathways or molecules involved in medulloblastoma development and progression. Metformin is a widely used non-toxic anti-diabetic drug that has mild, generally well-tolerated side effects. Studies have shown that it can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear and varies depending on the type of cancer. There are reports that metformin can target the specificity protein 1 (Sp1) transcription factor. Sp1 regulates the expression of a variety of proteins involved in regulation of cancer cell proliferation including survivin, an Inhibitor of Apoptosis Protein family member. Expression of survivin is increased in medulloblastoma cells and often correlates with poor prognosis. We studied the anti-cancer activity of metformin on medulloblastoma using DAOY and D283 cells. Metformin treatment resulted in a dose and time dependent reduction in cell proliferation in both cell lines. This growth inhibition was accompanied by the induction of apoptosis as determined by annexin-V staining, PARP cleavage, and activation of caspase3/7. Metformin also induced cell cycle arrest in G0/G1 phase. Western blot analysis using extracts from cells treated with metformin revealed that the anti-proliferative and apoptotic effects of metformin in medulloblastoma were accompanied by a reduction in the expression of survivin protein. Overexpression of survivin is reported to be associated with chemo- and radio-resistance. This study suggests the use of metformin as a novel anticancer agent in combination with standard therapy for the treatment of medulloblastoma.
Citation Format: Kristen C. Payne, Abigail Hunter, W Paul Bowman, Jeffrey C. Murray, Riyaz Basha, Umesh T. Sankpal. Metformin treatment inhibits proliferation and induces apoptosis in medulloblastoma cells [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 889.
Abstract 95: Heparan sulfate and glypican-1 mediate renal carcinoma metastasis
Authors: Qazi Henry , Moran Heriberto , Cancel Limary M. , Mayer Mariya , Roberge Sylvie , Huang Peigen , Munn Lance L. , Tarbell John M. 
Published: August 2018

Abstract
The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive renal carcinoma cells (SN12L1) with high metastatic potential have enhanced invasion rates compared to low metastatic (SN12C) cells in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) and hyaluronic acid (HA) in the glycocalyx play an important role in this flow mediated mechanotransduction and upregulation of invasive and metastatic potential. In our recent study, SN12L1 cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chambers with defined interstitial flow, we showed that flow-enhanced invasion is suppressed in HS deficient cells. We also examined two prominent HSPGs on renal carcinoma cells, glypican-1 and syndecan-1, and one prominent HA receptor, CD44. We observed higher glypican-1 levels in flow dependent SN12L1 cells when compared to SN12C cells. Caki-1 (highly metastatic) cells did not display flow-dependent invasion in vitro and did not display elevated glypican-1 compared to low metastatic Caki-2 cells. However, we did observe significantly increased HS, HA, syndecan-1 and CD44 in Caki-1 compared to Caki-2 cells suggesting an alternative mechanism for reported higher metastatic rates in these cells. All of our data are consistent with the hypothesis that glypican-1 is the core protein responsible for flow sensing in metastatic cancer cells. This is also consistent with observations in endothelial cells. To assess the ability of tumor cells to metastasize in vivo, parental or HS knockdown SN12L1 cells expressing fluorescent reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from knockdown cells compared to control cells with intact HS. The reduction was even greater (98%) in lungs where most of the metastases from the control cells were observed. The ability of these knockdown cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx and glypican-1 in tumor progression.
Citation Format: Henry Qazi, Heriberto Moran, Limary M. Cancel, Mariya Mayer, Sylvie Roberge, Peigen Huang, Lance L. Munn, John M. Tarbell. Heparan sulfate and glypican-1 mediate renal carcinoma metastasis [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 95.