bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 127: CYP4A11 overexpression increases aggressiveness in glioblastoma and breast cancer
Authors: Borin Thaiz F. , Ali Sehar , Angara Kartik , Rashid Mohammad , Myers Stephanie , Chawla Divya , Ara Roxan , Lebedyeva Iryna , Achyut Bhagelu R. , Arbab Ali S. 
Published: August 2019

Abstract
Metastatic breast cancer (BC) and glioblastoma (GBM) are two highly invasive forms of cancer that contribute greatly to patient mortality. Due to the complex mechanisms underlying cancer growth and metastasis, novel therapeutic targets must be found to increase patient survival. One such target is the cytochrome P450 4 (CYP4) metabolic pathway leading to the production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE is a lipid signaling molecule that promotes invasion, growth, and neovascularization in tumors by inducing the proliferation and migration of both, the endothelial cells and the tumor cells, therefore promoting BC and GBM tumor survival. N-hydroxy-N’-(4-butyl-2 methyl phenyl) formamidine (HET0016) is a selective inhibitor of 20-HETE synthesis and thus impairs tumor growth and neovascularization. In this study, we investigate the functional and phenotypic changes in BC (MDAMB231 and MCF7) and GBM (U251 and U87) cells overexpressing CYP4A11, a human CYP4 enzyme, with and without HET0016 treatment. Cells that overexpressed CYP4A11 were produced using lentivirus infection and confirmed via western blot. Tumor cell aggressiveness was assessed in vitro using migration and proliferation assays and in vivo by ascertaining the Ki67 levels and incidence of lung metastases foci. Tumor growth with and without CYP4A11 overexpression was followed for 21 days in vivo in athymic nude mice for all groups of cells and the acquisition of stem cell and angiogenic phenotypes by the tumor cells were determined by flow cytometry. The results demonstrated that cells overexpressing CYP4A11 showed protein levels 3-6 times higher than the non-modified cells. CYP4A11-overexpressing MDAMB231 and U87 cells demonstrated increased proliferation capacity, motility and significantly increased tumor growth. Interestingly, MCF7 and U251 cells overexpressing CYP4A11 did not show significant alterations in tumor growth compared to non-modified cells. Additionally, all cells treated with HET0016 showed decreased migration after 24 hours. U87 tumors showed increased stem cell and angiogenic phenotypes compared to non-modified U87 tumors. In conclusion, overexpression of CYP4A11 in Triple Negative BC and U87 GBM cells increased tumor aggressiveness proving that this pathway is an important target for therapeutic inhibition to control tumor growth and invasion.
Citation Format: Thaiz F. Borin, Sehar Ali, Kartik Angara, Mohammad Rashid, Stephanie Myers, Divya Chawla, Roxan Ara, Iryna Lebedyeva, Bhagelu R. Achyut, Ali S. Arbab. CYP4A11 overexpression increases aggressiveness in glioblastoma and breast cancer [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 127.
Abstract 1270: Human P-glycoprotein-mediated drug transport: Two aromatic residues in the drug-binding pocket are critical for function
Authors: Murakami Megumi , Chufan Eduardo E. , Lusvarghi Sabrina , Ambudkar Suresh V. 
Published: August 2019

Abstract
P-glycoprotein (P-gp) is an efflux pump that transports cytotoxic agents, thereby affecting the pharmacokinetics of many drugs and conferring resistance to chemotherapeutic agents in many cancers. P-gp utilizes energy from ATP hydrolysis for the efflux of a number of amphipathic natural products or small molecule anticancer drugs. However, the nature and number of translocation pathways for the transport of substrate-drugs by P-gp is not yet known. Previously we showed that substitution of certain aromatic residues in the drug-binding pocket switched the modulation of ATPase activity from inhibition to stimulation. Molecular modeling studies led to identification of two T-shaped structural motifs formed by F728/Y310 and F978/Y953. In this study, we demonstrate that substitution of all four residues of the T-shaped structural motifs with alanine (Y310A/F728A/Y953A/F978A) results in complete loss of transport of ten fluorescent substrates. Furthermore, alanine substitution of one or two of these residues revealed that when F728 and F978 are both substituted, this has the greatest impact on the binding and/or translocation of drug-substrates. ATPase assays and in silico analyses were performed to gain insight into interactions of these residues with substrates and modulators. These results indicate that the F728 and F978 residues together are critical to maintaining the conformation of the drug-binding pocket for binding and translocation of substrates by P-gp.
Citation Format: Megumi Murakami, Eduardo E. Chufan, Sabrina Lusvarghi, Suresh V. Ambudkar. Human P-glycoprotein-mediated drug transport: Two aromatic residues in the drug-binding pocket are critical for function [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 1270.
Abstract 1273: Molecular dynamics prediction of the mechanism of acquired resistance to EGFR inhibitors in EGFR-mutant lung cancer
Authors: Lee Youngjoo , Choi Yu-Ra 
Published: August 2019

Abstract
Background Acquired drug resistance is the most challenging problem in treating nonsmall cell lung cancer (NSCLC) patients with EGFR tyrosine kinase inhibitor (TKI). We evaluated whether resistance cell subclones significantly increased shortly after treatment with EGFR-TKIs could determine the final resistance phenotype for EGFR-TKIs in the tumor with EGFR mutations.
Methods We generated 2 EGFR-mutant lung cancer cell lines (PC9GR and HCC827GR) resistant to gefitinib and evaluated the resistance mechanisms in each cell line. In parent cell lines (PC9 and HCC827) the amounts of EGFR T790M mutation and C-MET and VIMENTIN mRNA expression were measured before and after 48 hours treatment with gefitinib or paclitaxel. Using a cell line derived directly from tumors of treatment-naïve NSCLC patient with EGFR mutation, the above tests were repeated. We prospectively collected the bloods from 4 NSCLC patients with EGFR mutations at baseline and eight weeks after EGFR-TKI treatment and measured the level of T790M mutation in circulating tumor DNAs (ctDNA) from their bloods by colourimetric assay.
Results EGFR T790M mutation was detected in PC9GR cells whereas C-MET amplification in HCC827GR cells. The proportion of EGFR T790M mutation significantly increased in the PC9 cells treated with gefitinib whereas not in the same cells treated with paclitaxel or not in the HCC827 treated with gefitinib or paclitaxel. The mRNA expression of C-MET was significantly increased in the HCC827 treated with gefitinib. The VIMENTIN mRNA expression was not changed in both cell lines. When we treated the patient-derived cells with gefitnib, the frequency of T790M significantly increased whereas C-MET mRNA expression decreased and VIMENTIN mRNA expression was not changed. In the corresponding resistance tumor tissue, only T790M mutation was detected without C-MET amplification and VIMENTIN overexpression. Two cases whose T790M mutation level in their ctDNAs increased at 8 weeks by more than 50% revealed T790M mutation in their final resistance tumor tissue. But, in other cases without an early surge of T790M mutation in their ctDNAs, T790M mutation was not detected in posttreatment biopsy sample.
Conclusions Early-on-treatment quantitative change of resistance-related gene alterations may predict the final mechanism of resistance to EGFR-TKI.
Citation Format: Youngjoo Lee, Yu-Ra Choi. Molecular dynamics prediction of the mechanism of acquired resistance to EGFR inhibitors in EGFR-mutant lung cancer [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 1273.
Abstract 1281: T790M gatekeeper mutation emerges via de novo at the early stages of erlotinib treament in PC9 non-small cell lung cancer cells
Authors: Kim Sujin , Park Angela KJ , Cho Jeonghee 
Published: August 2019

Abstract
The emergence of the T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) gene is an important mechanism that can lead to the acquired resistance to EGFR-targeted tyrosine kinase inhibitors used in a subset of non-small cell lung cancer (NSCLC) patients harboring activating mutations. Here we investigated the paths leading to the acquisition of the T790M mutation by establishing an erlotinib resistant PC9 cell model harboring ectopically introduced EGFR cDNA. We detect the emergence of T790M mutation within the EGFR cDNA in a subset of erlotinib resistant PC9 cell models through Sanger sequencing and droplet digital PCR-based methods, confirming that T790M mutation can emerge via de novo events following treatment with erlotinib. In addition, we show that the de novo T790M bearing erlotinib resistant PC9 cells are sensitive to the 3rd generation EGFR-targeted drug, WZ4002. Furthermore, GFP-based competition cell proliferation assays reveal that PC9 cells ectopically expressing EGFR mutant become more dominantly resistant to erlotinib than parental PC9 cells by acquiring T790M mutation. Taken together, we believe that our findings expand upon the previous notion of evolutionary paths of T790M development, providing an important clue to designing a therapeutic strategy to overcome drug resistance.
Citation Format: Sujin Kim, Angela KJ Park, Jeonghee Cho. T790M gatekeeper mutation emerges via de novo at the early stages of erlotinib treament in PC9 non-small cell lung 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 1281.
Abstract 129: Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-alpha and MMP-9
Authors: Lee Seungeun , Lee Eunhye , Ko EunYi , Ham Mina , Lee Hye Min , Kim Eun-Sook , Koh Minsoo , Lim Hyun Kyung , Jung Joohee , Park So Yeon , Moon Aree 
Published: August 2019

Abstract
Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that promote invasion and metastasis of cancer cells. In this study, we investigated the effect of TAMs on phenotypic conversion of non-neoplastic MCF10A human breast epithelial cells using an indirect co-culture system. Co-culture with TAMs induced epithelial-to-mesenchymal transition, invasive phenotype, and MMP-9 upregulation in MCF10A cells. Comparative proteomic analysis revealed that endoplasmic reticulum oxidoreductase (ERO)1-alpha was increased in MCF10A cells co-cultured with TAMs compared to that in mono-cultured cells. ERO1-alpha was crucial for TAMs-induced invasive phenotype and MMP-9 upregulation involving transcription factors c-fos and c-Jun. Cytokine array analysis showed that levels of interleukin (IL)-6, C-X-C motif ligand (CXCL)1, C-C motif ligand (CCL)2, growth-regulated protein (GRO), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in conditioned media of co-cultured cells. Among these cytokines increased in conditioned media of co-cultured cells, CCL2 was secreted from TAMs, leading to induction of ERO1-alpha, MMP-9 upregulation, and invasiveness in MCF10A cells. Our findings elucidated a molecular mechanism underlying the aggressive phenotypic change of non-neoplastic breast cells by co-culture with TAMs, providing useful information for prevention or treatment of recurrent breast cancer
Note: This abstract was not presented at the meeting.
Citation Format: Seungeun Lee, Eunhye Lee, EunYi Ko, Mina Ham, Hye Min Lee, Eun-Sook Kim, Minsoo Koh, Hyun Kyung Lim, Joohee Jung, So Yeon Park, Aree Moon. Tumor-associated macrophages secrete CCL2 and induce the invasive phenotype of human breast epithelial cells through upregulation of ERO1-alpha and MMP-9 [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 129.
Abstract 1290: Development of anti inflammatory agents targeting TonEBP for treatment of chronic inflammatory diseases
Authors: YE Byeongjin , Kwon Hyug Moo , Choi Soo Youn , Lee Jun Ho , Kang Hyun Je , Park Cheol-Min 
Published: August 2019

Abstract
Tonicity-responsive enhancer binding protein (TonEBP), also known as nuclear factor of activated T cells 5 (NFAT5), belongs to the Rel family of transcriptional factors which include NF-κB and NFAT. TonEBP is a key regulator in chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, diabetic nephropathy and hepatocellular carcinoma. TonEBP is a rate-limiting component of “pro-inflammatory enhanceosome” in which TonEBP provides a physical tether between activated transcription factors NF-κB and AP-1 to p300 and RNA polymerase II. Assembled in response to inflammatory signals, the pro-inflammatory enhanceosome drives the transcription of TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2. We discovered a class of compounds (CXs) targeting TonEBP. CXs blocked the assembly of the pro-inflammatory enhancesome and potently suppressed the inflammation-induced expression of TNF-α, IL-1β, IL-6, MCP-1, iNOS, and COX-2. Orally administered CXs exhibited remarkable therapeutic activities in mouse models of inflammatory arthritis. Using an alkynyl derivative of a CX and click reaction, we found that CX was covalently attached to TonEBP by alkylation but not to other components of the enhanceosome. Cells harboring a site-directed mutant TonEBP molecule whose amino acid residues for the alkylation were removed exhibited a markedly reduced sensitivity to CXs. These data demonstrate that CXs are a new class of anti-inflammatory agents with a novel mode of action.
Citation Format: Byeongjin YE, Hyug Moo Kwon, Soo Youn Choi, Jun Ho Lee, Hyun Je Kang, Cheol-Min Park. Development of anti inflammatory agents targeting TonEBP for treatment of chronic inflammatory diseases [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 1290.
Abstract 1291: Notch2 inhibition as a therapeutic intervention in osteosarcoma
Authors: Kannan Sankaranarayanan , Livingston John A. , Roth Michael , Benjamin Jonathan , Wang Yifei , Zhang Zhongting , Zhang Wendong , Wu Chia-Chin , Beird Hannah , Futreal Andrew , Gorlick Richard 
Published: August 2019

Abstract
Notch signaling pathway is a mediator of cell differentiation and is critical for normal bone development. Four functional Notch ligands DLL1 and DLL4, and JAG1 and JAG2 showed various levels of affinity for Notch1-4 receptors. Dose dependent Notch signaling activation or blocking is attributed to anchored or soluble form of Notch ligands binding. Interestingly, Notch pathway is shown to play a dual role, either oncogenic or tumor suppressive, depending on signal dose and tissue-context. To understand Notch signaling activities in osteosarcoma (OS), we first studied the cell surface levels of Notch receptor expression in OS cell lines and patient derived xenograft (pdx) models. Cytometry based screening of NOTCH1-4 receptors showed NOTCH2 as a predominant surface expressed protein in most of the samples. Interestingly, the canonical Notch target genes HES1 and DTX1 were higher (~5-fold) in OS cells compared to mesenchymal cells (MSC). Subsequently, we evaluated selected Notch pathway gene expression in 48 patients with recurrent/metastatic OS by RNAseq analysis. High expression of Notch pathway-related genes was seen in a subset of patients. NOTCH2 expression was comparable between primary and metastatic OS specimens, highest as compared to other Notch receptors and was significantly higher than normal tissue. Thus we aimed to elucidate soluble Notch ligands mediated blocking of Notch signaling using immunoglobulin-G bound DLL-1, -3, and -4 and JAG-1, and -2 in in vitro studies using OS cells. Soluble DLL1-Fc treatment increased OS cell death as compared to the other Notch ligands as well as control-Fc cells. Addition of soluble DLL1 resulted in the decreased expression of Notch downstream genes such as HES1, DTX1 and HEY1. Taken together, these findings identify soluble DLL1 as a potent Notch pathway inhibitor in OS in vitro and support further exploration of NOTCH2 as a potential therapeutic target in OS.
Citation Format: Sankaranarayanan Kannan, John A. Livingston, Michael Roth, Jonathan Benjamin, Yifei Wang, Zhongting Zhang, Wendong Zhang, Chia-Chin Wu, Hannah Beird, Andrew Futreal, Richard Gorlick. Notch2 inhibition as a therapeutic intervention in osteosarcoma [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 1291.
Abstract 1295: First-in-field small molecule inhibitors targeting BRN2 as a therapeutic strategy for small cell prostate cancer
Authors: Thaper Daksh , Munuganti Ravi , Nouruzi Shaghayegh , Kumar Sahil , Kim Soojin , Sivak Olena , Aguda Adeleke , Ganguli Dwaipayan , Vahid Sepideh , Puca Loredana , Beltran Himisha , Zoubeidi Amina 
Published: August 2019

Abstract
Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges and patients generally die within two years. In particular, a subset of patients who relapse following ARPI therapy exhibit lineage switching whereby tumours shed their dependence on AR signaling and emerge with neuroendocrine features. These tumours, termed treatment induced neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapy which carries a short-lived response at the cost of significant toxicity. Therefore, targeted therapies for this deadly disease are desperately needed. Thus, the need to develop targeted treatments for this devastating disease is of paramount importance. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of NEPC and aggressive tumor growth, both in vitro and in vivo, suggesting targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC.
Methods: Study the effects of BRN2 inhibition using siRNA, small molecule inhibitors and CRISPR K/O models.
Results: Inhibition of BRN2 by siRNA and by CRISPR/Cas9 knockout drastically reduced cell proliferation in 42DENZR (NEPC) cell lines. This data was re-capitulated in human NEPC NCI-H660 cells. Loss of BRN2 initiated drastic epigenetic changes in NEPC cell lines as well as in G1 arrest through up-regulation of CDKN1A/1B. This was confirmed using our first in field BRN2 inhibitors. Targeting BRN2 also lead to downregulation several known targets in NEPC like EZH2, AURKA, SOX2 and Peg10. Treatment with BRN2i reduced recruitment of BRN2 to the chromatin by approximately 93% within 16 hours. Moreover, these BRN2 inhibitors displayed adequate pharmacokinetic properties and reduced NEPC proliferation in vivo.
Conclusion: No therapies exist for highly lethal NEPC. Hence, the described work aims to verify BRN2, a central driver of NEPC, and lay the pre-clinical foundation for the integration of targeted therapies into the treatment landscape to improve survival and quality of life for patients suffering from deadly form of prostate cancer.
Citation Format: Daksh Thaper, Ravi Munuganti, Shaghayegh Nouruzi, Sahil Kumar, Soojin Kim, Olena Sivak, Adeleke Aguda, Dwaipayan Ganguli, Sepideh Vahid, Loredana Puca, Himisha Beltran, Amina Zoubeidi. First-in-field small molecule inhibitors targeting BRN2 as a therapeutic strategy for small cell prostate cancer [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 1295.
Abstract 1296: Arylsulfonamide KCN1 suppresses primary and metastatic growth of uveal melanoma through anti-angiogenic and anti-invasion mechanisms
Authors: Kaluz Stefan , Zhang Qing , Yang Hua , Osuka Satoru , Mun Jiyoung , Devi Narra S. , Goodman Mark , Grossniklaus Hans E. , Meir Erwin G. Van 
Published: August 2019

Abstract
Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults with a survival time less than 1 year for patients that develop metastases (about 50%). HIF-1 plays a critical role in UM adaptation to the hypoxic microenvironment, treatment failure, and metastasis. In this study, we evaluated biodistribution and anti-cancer efficacy of arylsulfonamide KCN1, a lead compound in a novel class of small-molecule inhibitors of the hypoxia-inducible factor (HIF-1) pathway in UM models. PET with 11C-labeled KCN1 showed that KCN1 preferentially localizes to the eye and liver, the organ where UM preferentially metastasizes. In survival studies, UM cells were injected into the suprachoroidal space of the right murine eye using a transscleral technique and the eye was enucleated 7-9 days post-inoculation. Starting on Day 1, KCN1 or vehicle only (cremophor EL/ethanol 1:1, diluted with sterile PBS 1:5) were administered daily i.p., 5 x week, until animals reached the endpoint. Main organs were collected and evaluated for metastatic load. We found that KCN1 potently inhibited the growth of primary eye tumors, VEGF expression, angiogenesis in the primary tumor, the number and size of hepatic metastases, and extended mice survival. KCN1 inhibited invasion of UM cells in in vitromodels, such as scratch-wound and Boyden chamber migration assays. To identify possible mediators of hypoxia-HIF-induced metastatic processes inhibited by KCN1 in UM, we tested a series of 20 candidates by qRT-PCR. Among the most consistently HIF-induced/KCN1-inhibited genes were prolyl-4-hydroxylases P4HA1 and 2 that modulate physical properties of the tumor microenvironment by post-translationally modifying collagen. Expression of P4HA1 and 2 is significantly higher in UM patients with metastatic disease and high level of expression correlates with poor prognosis. In summary, our studies suggest KCN1 exerts anti UM activity by inhibiting the primary tumor growth, reducing vascular density in the primary tumor, and the number and size of the hepatic metastases; KCN1 has therefore therapeutic potential for treatment of UM and further clinical development.
Citation Format: Stefan Kaluz, Qing Zhang, Hua Yang, Satoru Osuka, Jiyoung Mun, Narra S. Devi, Mark Goodman, Hans E. Grossniklaus, Erwin G. Van Meir. Arylsulfonamide KCN1 suppresses primary and metastatic growth of uveal melanoma through anti-angiogenic and anti-invasion mechanisms [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 1296.