bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 85: Oleic acid promotes head and neck squamous cell carcinoma anoikis resistance and metastasis via ANGPTL4/fibronectin pathway
Authors: Shen Chih-Jie , Chan Shih-Hung , Lee Chung-Ta , Huang Wan-Chen , Tsai Jhih-Peng , Chang Kwang-Yu , Chang Wen-Chang , Chen Ben-Kuen 
Published: August 2018

Abstract
Obese patients have higher levels of free fatty acids (FFAs) in their plasma and a higher risk of cancer than their non-obese counterparts. However, the mechanisms involved in the regulation of cancer metastasis by FFAs remain unclear. In this study, we found that oleic acid (OA) induced angiopoietin-like 4 (ANGPTL4) protein expression and secretion and conferred anoikis resistance to head and neck squamous cell carcinomas (HNSCCs). The autocrine production of OA-induced ANGPTL4 further promoted HNSCC migration and invasion. In addition, the expression of peroxisome proliferator-activated receptor (PPAR) was essential for the OA-induced ANGPTL4 expression and invasion. The levels of OA-induced epithelial-mesenchymal transition markers, such as vimentin, MMP-9, and fibronectin and its downstream effectors Rac1/Cdc42, were significantly reduced in ANGPTL4-depleted cells. Knocking down fibronectin not only inhibited the expression of MMP-9 but also repressed OA- and recombinant ANGPTL4-induced HNSCC invasion. On the other hand, ANGPTL4 siRNA inhibited OA-induced MMP-9 expression, which was reversed in fibronectin-overexpressing cells. Furthermore, the depletion of ANGPTL4 impeded the OA-primed metastatic seeding of tumor cells in the lungs. These results demonstrate that OA enhances HNSCC metastasis through the ANGPTL4/fibronectin/Rac1/Cdc42 and ANGPTL4/fibronectin/MMP-9 signaling axes. The inhibition of ANGPTL4 could be a potential strategy for the treatment of FFA-mediated HNSCC metastasis.
Citation Format: Chih-Jie Shen, Shih-Hung Chan, Chung-Ta Lee, Wan-Chen Huang, Jhih-Peng Tsai, Kwang-Yu Chang, Wen-Chang Chang, Ben-Kuen Chen. Oleic acid promotes head and neck squamous cell carcinoma anoikis resistance and metastasis via ANGPTL4/fibronectin 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 85.
Abstract 858: Enzalutamide versus abiraterone as a radiosensitizer in hormone-sensitive prostate cancer cells
Authors: Ghashghaei Maryam , Muanza Thierry , Alaoui-Jamali Moulay , Paliouras Miltiadis , Niazi Mohammad Tamim 
Published: August 2018

Abstract
Prostate cancer treatment is based on the estimated risk of recurrence in the U.S. Combined androgen deprivation therapy (ADT) with radiation therapy (XRT) is the standard of care for high-risk localized PCa. However, a large percentage of tumors are resistance to ADT due to continued AR signaling. Abiraterone (ABI), an androgen synthesis inhibitor, and Enzalutamide (ENZA), a potent AR antagonist, are new treatment options for metastatic castration resistance prostate cancer (mCRPC) patients. The aim of this study is to compare the efficacy of ENZA or ABI as a radiosensitizer in XRT therapy on PCa cells.
Methods: The effect of ENZA or ABI alone or in combination with XRT was assessed on hormone-sensitive (LNCaP, PC3-AR-T877A) and insensitive (PC3, PC3-AR V7) PCa cells using cell viability (MTT) and also clonogenic assays in different scheduling regimens: A- drug 24 h before XRT, B-drug 2h before XRT, or C- XRT followed by 24h later drug.
Results: We first determined the effect of ENZA or ABI on MTT assays in androgen-dependent (AD) and androgen-independent (AI) PCa cell lines. The results of MTT assay showed that ENZA inhibited the growth of the four different cell lines, LNCaP, PC3-T877A, PC3 and PC3 AR-V7 with IC50 values of 20, 22, 50, and 45μmol/L, respectively, after 24 hours of treatment. The same effect was observed on ABI treated cell lines. Radiosensitivity was not significantly increased in AD and AI PCa cell lines by ABI (DEF=1.00, in all cases) while there was a supra-additive dose enhancement factor (DEF= 1.75±0.08) for hormone-sensitive cells treated with ENZA (Table 1).
Conclusion: Our data indicates that ENZA acts as a much stronger radiosensitizer compared to ABI through different probable mechanisms of radiosensitivity.
Table 1. Dose Enhancement Factors calculations by scheduling ProtocolABCENZAABIENZAABIENZAABIADLNCaP1.35±0.021.05±0.011.75±0.081.001.30±0.051.00PC3-AR T877A1.30±0.031.001.65±0.011.001.35±0.061.05±0.02AIPC31.001.001.001.001.001.00PC3-AR V71.001.001.001.001.001.00
Citation Format: Maryam Ghashghaei, Thierry Muanza, Moulay Alaoui-Jamali, Miltiadis Paliouras, Mohammad Tamim Niazi. Enzalutamide versus abiraterone as a radiosensitizer in hormone-sensitive prostate cancer 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 858.
Abstract 863: Targeted α-therapy for treatment of metastatic melanoma
Authors: Nedrow Jessie , McCarty Greg , Cortez Angel , Roy Sanchita , Sgouros George 
Published: August 2018

Abstract
Background Very late antigen 4 (VLA-4; also called integrin α4β1) is overexpressed in melanoma tumors with an active role in tumor growth, angiogenesis, and metastasis. This makes VLA-4 an ideal antigenic target for targeted alpha therapy. The expression of VLA-4 on primary melanomas in human correlates with the development of metastasis and has been associated with high risk of metastasis and tumor progression. Furthermore, up-regulation of VLA-4 in melanoma is associated with a more aggressive, metastatic phenotype. Here in we evaluated an 225Ac-anti-VLA-4 conjugate as well as its 111In-labeled companion imaging agent for targeted radiotherapy in an aggressive mouse melanoma model. Methods An anti-VLA-4 antibody was conjugated to DOTA for 225Ac-labeling and DTPA for 111In-labeling. The resulting agents, 225Ac- or 111In-labeled anti-VLA-4 were evaluated in vitro, including binding affinity, internalization, and clonogenic assays. Furthermore, the therapeutic efficacy of 225Ac-anti-VLA-4 will be evaluated in multiple metastatic animal models of melanoma. Results 111In-DTPA-anti-VLA-4 demonstrated high affinity for VLA-4 in B16F10 cells, having a Kd of 0.18 ± 0.05 nM and approximately 46% was internalized at 6 hours. For delivery of an α-emitting radionuclide to VLA-4 positive tumor cells, the DOTA conjugate was labeled with 225Ac with specific activity of 3.5 MBq/nmol and &gt;95% radiochemical purity, and demonstrated selective uptake in VLA-4 positive B16F10 cells. Clonogenic assays demonstrated a decrease in the surviving fraction of B16F10 cells treated with 225Ac-DOTA-anti-VLA-4 compared to controls. Therapeutic efficacy studies are currently underway. Conclusion 111In- and 225Ac-labeled anti-VLA-4 antibody conjugates are capable of selectively delivering radionuclides for SPECT imaging and targeted alpha therapy to melanoma tumor cells that overexpresses VLA-4. The agents presented here have the potential to identify and treat patients who have metastatic melanoma.
Citation Format: Jessie Nedrow, Greg McCarty, Angel Cortez, Sanchita Roy, George Sgouros. Targeted α-therapy for treatment of metastatic melanoma [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 863.
Abstract 870: Effects of epigenetic modifier inhibitors on AML cell sensitivity to differentiation therapy
Authors: Heimdal Kalsi K. , Hernandez Edjay Ralph A. , Super Heidi J. Gill 
Published: August 2018

Abstract
Human acute myeloid leukemia (AML), the most common type of acute leukemia, has approximately eight subtypes, many of which have poor prognosis. Most of these subtypes are associated with specific, recurrent chromosome translocations. These translocations result in fusion genes, which encode oncoproteins that block differentiation and promote proliferation of immature cells. The Myeloid Lymphoid Leukemia gene (MLL) is frequently involved in these translocations, and is considered a driver of the AML. Differentiation promoting drugs, such as all-trans-retinoic acid (ATRA) are an attractive alternative to cytotoxic chemotherapy, but few types of AML, other than acute promyelocytic leukemia (APL), respond to ATRA. We hypothesize that specific genes must be activated or inhibited in AML for drugs like ATRA to induce differentiation, and that gene activation or inhibition may be the result of specific epigenetic modification. We also hypothesize that AML with different genetic alterations may respond differently to specific epigenetic inhibitors. Our initial studies have focused on one AML cell line, MV4;11, with alterations in the MLL gene, and one non-MLL related AML cell line, U937. MV4;11 and U937 were treated with specific epigenetic modifiers, including tranylcypromine (TCP), an inhibitor of histone demethylase KMD1A/LSD1, and CI-994, a general histone deacetylase inhibitor. Evidence for differentiation was noted in a variety of assays, including reduced cell proliferation as measured directly and by MTT assay, upregulation of myeloid-specific cell surface markers such as CD11b as measured by fluorescence-activated cell sorting (FACS), and myeloid-related nuclear morphological changes noted with cytospin analysis of cells. Both CI-994 and TCP seemed to sensitize U937 cells to differentiate when treated with ATRA as measured by all indicators of differentiation. MV4;11 cells were sensitized to differentiation by CI-994 with or without ATRA, although there was no indication of CD11b upregulation. However, MV4;11 was not sensitized by TCP to differentiate with ATRA. These experiments suggest epigenetic inhibitors may increase sensitivity to differentiation therapy, but that the response may still be dependent on the specific genetic alteration driving the AML. Our studies suggest that in MLL-driven leukemia, the MLL fusion oncoprotein may override genetic manipulation resulting from treatment with epigenetic inhibitors, preventing differentiation by ATRA.
Citation Format: Kalsi K. Heimdal, Edjay Ralph A. Hernandez, Heidi J. Gill Super. Effects of epigenetic modifier inhibitors on AML cell sensitivity to differentiation therapy [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 870.
Abstract 887: The effect of anticancer chemotherapeutics on immune microenvironment of lung adenocarcinoma with EGFR mutation in vivomicroenvironment of lung adenocarcinoma with EGFR mutation in vivo
Authors: Suh Young-Ah , Mun Hyemin , Lee Sun-Hye , Jo Se-Young , Oh Ju-Hee , Lee Chu-Hee 
Published: August 2018

Abstract
Lung cancer is the leading cause of cancer related deaths worldwide. Molecular targeting therapy is an attractive treatment for lung cancer, although it eventually develops resistance in most cases. In this report, we tested taxan antitumor effect on lung adenocarcinomas in vitro and in vivo. It could inhibit cell growth of many NSCLC cells tested, exhibiting reduced expression of c-MET and STAT3. The nascent effect of taxan on lung tumor cells were also proved on patient-derived primary lung tumor cells and patient-derived xenograft model that highly expresses c-MET. The antitumor effect of this chemotherapeutics was also observed on T790M mutant cells. Interestingly, the antitumor effect of taxan was synergistic in combination of c-Met inhibitor on lung tumor cells as well as patient-derived primary lung tumor cells. However, single treatment of taxan was sufficient for halting tumor growth in vivo, as no combinational effect of c-Met inhibitor was obvious. Not only c-Met inhibitor but also taxan reduced phosphorylated c-MET and STAT3, although cytokines on downstream of c-MET and STAT3 were explosively increased in vitro setting resulting in high expression of chemokines/cytokines. Importantly, the effect was not true in in vivo setting, in which the expressions of chemokines/cytokines as well as phosphorylated c-MET and STAT3 were influenced with this agent. These results suggest that taxane is one of the comparative adjuvant for lung tumors exhibiting targeted drug resistance, especially for enhanced signaling of MET-STAT-immuno-microenvironment.
Citation Format: Young-Ah Suh, Hyemin Mun, Sun-Hye Lee, Se-Young Jo, Ju-Hee Oh, Chu-Hee Lee. The effect of anticancer chemotherapeutics on immune microenvironment of lung adenocarcinoma with EGFR mutation in vivomicroenvironment of lung adenocarcinoma with EGFR mutation in vivo [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 887.
Abstract 888: A novel assay for the evaluation of ADCC in 3D-culture
Authors: Irigoyen Macarena , Alms Andrea , Ejiri Yoko , Ayano Satoru , Castillo Gonzalo 
Published: August 2018

Abstract
In the last few years, one of the most innovative areas of cancer research has been immuno-oncology where significant advancements have been seen, particularly, in the use of monoclonal antibodies to treat cancers. The regulation of immune-mediated killing by monoclonal antibodies is an important mechanism of action, like in the case of trastuzumab, a humanized monoclonal antibody used in the treatment of HER-2 positive breast cancers. Binding of the humanized antibody to the receptor induces antibody-dependent cellular cytotoxicity (ADCC). Assays that monitor this activity are historically difficult to execute suffering from low sensitivity and reproducibility. Furthermore, experiments are typically done in suspension of cells grown as monolayers; often, showing limited clinical translatability when studying solid tumor models. Unencumbered by the limitations of 2D assays, the tumor microenvironment of 3D-cultures includes cell-cell interactions and formations of metabolic gradients, which are vital to understanding drug efficacy and resistance. To study the ADCC triggered by trastuzumab in 3D-cellular models, we developed a novel method to evaluate cellular toxicity in spheroids. In this study, we demonstrated the quantification, with specificity and precision, of the ADCC activity elicited by trastuzumab in 3D-culture. The high HER2-expressing BT474 cell line (target cells) was pre-labeled and formed into spheroids utilizing Kuraray's 384-well Elplasia's microplates. PBMCs (effector cells) isolated from healthy donors were added in the presence or absence of the antibody, trastuzumab, and incubated overnight. Cytotoxicity of the tumor-derived cells was evaluated by counting stained dead cells using a cell imager. In parallel, a 2D-platform for ADCC assay was run and the pharmacology of trastuzumab was characterized. BT474 cells grown as spheroids show an IC50 of 0.09 µg/mL, when the study was done in 2D-culture an IC50 of 0.028 µg/mL was obtained. The ability to evaluate ADCC in both 2D- and 3D- may help the development of more translatable models in the clinic.
Citation Format: Macarena Irigoyen, Andrea Alms, Yoko Ejiri, Satoru Ayano, Gonzalo Castillo. A novel assay for the evaluation of ADCC in 3D-culture [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 888.
Abstract 890: Calmodulin governs nuclear entry of fusion PAX3/FOXO1 oncoprotein, a target in alveolar rhabdomyosarcoma
Authors: Darvishi Emad , Thomas Cheryl Lynn , Gryder Berkley Eric , Shern John Frederick , Khan Javed , Woldemichael Girma M 
Published: August 2018

Abstract
Reciprocal chromosomal translocations resulting in the fusion of the DNA binding domain of the transcription factor PAX3 and the transactivational domain of FOXO1 underlie most cases of alveolar rhabdomyosarcoma (aRMS). Testing of compound MTPF63 against a panel of sarcoma cell lines showed that it had an inhibitory effect on proliferation of PAX3-FOXO1 translocation-positive cells. Further evaluation of its activity in Rh4 cells transduced with a PAX3-FOXO1 luciferase reporter showed that it attenuated reporter activity. Additional confirmation for the compound's inhibitory impact on PAX3-FOXO1 activity was obtained by detecting significant attenuation in the levels of Alk1 and MyoD1 proteins whose expression is driven by PAX3-FOXO1 in aRMS cells. Cell viability assays performed under 2D and 3D culturing conditions demonstrated that MTPF63 inhibits cell growth more effectively in translocation-positive alveolar RMS than in translocation-negative embryonal RMS. A hypothesis for MTPF63's mode of action was generated using the complete pool of barcoded essential heterozygous (~1150 strains) and homozygous (~4800 strains) diploid gene deletion mutants of Saccharomyces cerevisiae to identify gene deletions that confer sensitivity to the compound. Gene ontology enrichment analysis of 255 sensitive mutants whose growth rates were significantly inhibited in the presence of the compound compared to control, not only revealed calmodulin as main target of the compound but also illustrated the compound's interference with calmodulin-dependent nuclear protein import pathway, suggesting that it might impact PAX3-FOXO1 nuclear localization. Immunostaining of nuclear-localized PAX3-FOXO1 oncoprotein in two aRMS cell lines revealed cytoplasmic localization. Immunoblot analysis of fractionated cytosolic and nuclear protein lysates for PAX3-FOXO1 in MTPF63 treated cells also showed increased amounts in the cytosolic fractions. Transient overexpression of calmodulin was shown to partially rescue the inhibitory effect of the compound on PAX3-FOXO1-driven luciferase expression in RH4 reporter cells. Taken together, the data demonstrate the involvement of calmodulin in the nuclear import of PAX3-FOXO1 and introduce calmodulin antagonists as potential therapeutics against translocation-positive childhood alveolar rhabdomyosarcoma.
Citation Format: Emad Darvishi, Cheryl Lynn Thomas, Berkley Eric Gryder, John Frederick Shern, Javed Khan, Girma M Woldemichael. Calmodulin governs nuclear entry of fusion PAX3/FOXO1 oncoprotein, a target in alveolar rhabdomyosarcoma [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 890.
Abstract 896: Adjutant therapeutic strategy for sorafenib-resistant hepatocellular carcinoma
Authors: Peng Syue-Wei , Lin Yi-Heng , Teng Ming-Hao , Lai Hung-Cheng , Chang Te-Sheng , Huang Yen-Hua 
Published: August 2018

Abstract
Purpose: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the leading cause of cancer mortality worldwide. To date, Sorafenib remains the standard of care for advanced HCCs not amenable to curative therapies such as surgery or local ablation. Unfortunately, clinical efficacy of Sorafenib remains marginal as most HCC patients receiving Sorafenib treatment develop Sorafenib resistance. The recently approved regorafenib is the only rescue therapy for patients who fail Sorafenib treatment. However, the effect of regorafenib is also far from satisfactory. Therefore, new strategies to overcome sorefenib resistance are critically warranted. Recently, one FDA-approved drug, here we tentatively named as “FA”, was shown to suppress different cancer malignancy by various mechanisms including inhibiting the development of drug resistance in cancer. These findings provide a rationale for combination treatment of this FA drug with Sorafenib in Sorafenib-resistant HCC. Results: Two Sorafenib-resistant HCC cell lines of Hep3B and HepG2215 were established. The Sorafenib resistance characteristics of the HCC cells were further verified by western blotting assay detecting protein tyrosine phosphorylation. We also demonstarted the resistant HCC cells expressed stemness-related genes and showed high ability of cell migration and metastasis. Combination use of FA drug and Sorafenib significantly suppressed the cell viability as well as the stemness-related properties of Sorafenib-resistant HCC cells, including stemness-related gene/protein expression, secondary sphere formation, and the cell migration. Conclusion: Combination use of FA drug and Sorafenib would be a potential therapeutic strategy for Sorafenib-resistant HCC treatment.
Citation Format: Syue-Wei Peng, Yi-Heng Lin, Ming-Hao Teng, Hung-Cheng Lai, Te-Sheng Chang, Yen-Hua Huang. Adjutant therapeutic strategy for sorafenib-resistant hepatocellular carcinoma [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 896.
Abstract 899: Phosphorylated mTOR by signaling through EphB3 confers resistance to a selective FGFR inhibitor in SNU-16 gastric cancer cells
Authors: Lee Suk-young , Na YooJin , Jung YoonA , Kim JungLim , Oh Sang Cheul , Lee Dae-Hee 
Published: August 2018

Abstract
Because about 10% of gastric cancers show amplification of FGFR2, inhibition of FGFR2 activation has been regarded as one of therapeutic targets. AZD4547, a selective inhibitor of the FGFR1-3 tyrosine kinases, was developed to inhibit FGFR signaling; however, its efficacy is limited by emergency of the acquired resistance. We tried to clarify a resistance mechanism against the FGFR inhibitor. The cell line resistant against AZD4547 was established using SNU-16 (SNU16R), an FGFR2-amplified gastric cancer cell line, by culturing with increasing concentration of AZD4547. The expression levels of FGFR or phosphorylated FGFR (pFGFR), EphB3 and downstream signaling molecules, proteins involved in epithelial-mesenchymal transition (EMT) and apoptosis, were determined by Western blot. Cell viability was measured with EZ-Cytox kit reagent (DoGen, Seoul, Korea). Relative level of tyrosine phosphorylation of receptor tyrosine kinases (RTKs) was evaluated with Proteome ProfilerTM array by human phosphor-RTK kit (R&D Systems). Apoptosis was determined by Annexin V-FITC apoptosis detection kit (BioBud, Seoul, Korea). Cell cycle assay was performed using Beckman Coulter flow cytometer and WinMDI for determination of cell numbers in G1, S, G2/M phases. Here we show the following: 1) establishment of a gastric cancer cell line (SNU16) resistant to AZD4547 (SNU16R); 2) expression of EphB3 receptor in SNU16R and induction of apoptosis and cell cycle arrest as well as inhibition of cell proliferation and suppressed expression of EMT markers under the treatment EphB3 inhibitor in SNU16R; 3) demonstration of mTOR as a downstream signaling cascade molecule of EphB3 by showing increased expression of phosphorylated (p-) mTOR and its downstream molecules in SNU16R and suppressed expression of p-mTOR by the EphB3 inhibitor. Cell cycle arrest, inhibition of cell proliferation and suppressed expression of p-mTOR under treatment with everolimus were also shown. We concluded that phosphorylation of mTOR through activation of EphB3 receptor is one of the mechanisms that confer resistance to AZD 4547, a selective FGFR inhibitor, in gastric cancer cells.
Citation Format: Suk-young Lee, YooJin Na, YoonA Jung, JungLim Kim, Sang Cheul Oh, Dae-Hee Lee. Phosphorylated mTOR by signaling through EphB3 confers resistance to a selective FGFR inhibitor in SNU-16 gastric cancer 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 899.