bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3120: Application of a lectin as a drug carrier for glycan-targeting cancer therapy
Authors: Oda Tatsuya , Shimomura Osamu , Tateno Hiroaki , Hirabayashi Jun , Noguchi Masayuki , Chiba Shigeru , Asashima Makoto , Ohkohchi Nobuhiro 
Published: July 2017

Abstract
Various cancers such as pancreatic ductal adenocarcinoma (PDAC) remain intractable despite recent advances in tumour-targeting antibody drugs. Although the outermost coating of every cell type is predominantly composed of cell-specific glycans, antibody strategies have hit walls of technical difficulties in intentional glycan targeting, and medico-economic burden. Lectins, proteins with glycan-binding potential, could be used as an alternative scaffold; however, the prejudice that all lectins mediate harmful haemagglutination limited its use only in experimental and diagnostic applications. Here, we show the successful in vivo application of a lectin as a drug carrier for cancer therapy. We have employed rBC2LC-N lectin since this has already shown a specific affinity between PDAC cell-surface glycans. When a lectin-drug conjugate (LecD) was developed by fusion with a bacterial exotoxin, the 50% inhibitory concentration (1.04 pg/ml=0.0195 pM) was 1000 times lower than that of conventional immunotoxins (on the order of ng/ml). In addition, we have revealed that rBC2LC-N lectin was safely administrable to mice without haemagglutination. Administration of this LecD in a PDAC mouse model of subcutaneous nodules and peritoneal dissemination, generated prominent therapeutic effects. The utilization of lectins as an in vivo drug-carrier targeting cancer glycan shows realistic potential when paired with advanced lectin engineering technologies, and their applications could be expanded by coupling with small molecule and/or nanoparticle drugs.
Citation Format: Tatsuya Oda, Osamu Shimomura, Hiroaki Tateno, Jun Hirabayashi, Masayuki Noguchi, Shigeru Chiba, Makoto Asashima, Nobuhiro Ohkohchi. Application of a lectin as a drug carrier for glycan-targeting cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3120. doi:10.1158/1538-7445.AM2017-3120
Abstract 3128: TRPM7 regulates glioma cell proliferation and migration through different function domains
Authors: Liu Mingli 
Published: July 2017

Abstract
Background: Transient Receptor Potential Melastatin-related 7 (TRPM7) is a non-selective cation channel fused with a functional kinase domain. TRPM7 channel expression is aberrant in numerous cancers. We have previously reported that suppression of TRPM7 inhibits the proliferation, migration, and invasion of malignant human glioma cells using A172 glioma cell line and brain tissue of human glioma [CNS Neuroscience & Therapeutics 2015,21(3):252-61]. We further found that TRPM7 channels regulate glioma stem cell growth/proliferation through STAT3 and Notch signaling pathways [Cellular Signaling, 2014; 26: 2773-2781]. Since TRPM7 is a bifunctional protein with channel and α-kinase domain, we next investigated whether the changes in glioma cancer cell proliferation and migration might be caused through channel domain-mediated and/or kinase domain mediated TRPM7 activation.
Methods: 1) A172 cells expressing wild-type human TRPM7 (wtTRPM7) or constructs in which the α-kinase domain was deleted (Δkinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. 2) The effects of TRPM7 on glioma cell proliferation and invasion were determined using MTT assay and transwell invasion assay by TRPM7 expression using wtTRPM7, Δkinase, and K1648R, respectively.
Results: 1) Treatment of A172 cells with Δkinase and K1648R significantly increased TRPM7 expression demonstrated by Western blot assay. 2) The cell invasion was significantly reduced when treated with Δkinase and K1648R which indicate that TRPM7 kinase activity is required for changes in cell migration and invasion. 3) The cell proliferation was not significantly changed when treated with Δkinase and K1648R which indicate that TRPM7 channel rather than kinase activity is required in cell growth of A172 cells.
Conclusion: TRPM7 regulates glioma cell proliferation and migration/invasion through different function domains. The channel activity of TRPM7 is required for the cell growth while the kinase domain is required for the cell migration/invasion. The finding is important for designing and developing drugs targeting TRPM7 in human malignancies.
Note: This abstract was not presented at the meeting.
Citation Format: Mingli Liu. TRPM7 regulates glioma cell proliferation and migration through different function domains [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2017-3128
Abstract 3141: Combined cetuximab and pemetrexed therapy enhances cytotoxicity against crizotinib-resistant non-small cell lung cancer cells by downregulating thymidylate synthase
Authors: Kim Hwang-Phill , Han Sae-Won , Song Sang-Hyun , Kim Tae-You 
Published: July 2017

Abstract
Although non-small cell lung cancer (NSCLC) cells with anaplastic lymphoma kinase (ALK)-rearranged initially show a dramatic response to crizotinib, these cells eventually develop resistance to crizotinib. This resistance is caused by secondary mutations and copy number gain in the ALK gene. However, other resistance mechanisms through activation of the bypass tracts have yet to be clearly elucidated. To investigate the mechanisms of acquired resistance to ALK fusion-directed treatment in NSCLC, we generated crizotinib-resistant NSCLC cell lines in vitro through chronic exposure of an ALK fusion NSCLC line (SNU2292) to crizotinib. Interestingly, the resultant SNU2292-CR cells maintained activation of epidermal growth factor receptor (EGFR) and expressed increased levels of transforming growth factor alpha (TGF-α), an EGFR ligand. Additionally, we found that thymidylate synthase (TS) was overexpressed in SNU2292-CR cells compared with the parental cells. We showed reduction of TS enhanced synergistic inhibition of cell proliferation when cetuximab, an EGFR inhibitor, was combined with pemetrexed, a TS inhibitor. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against crizotinib-resistant cells by downregulating TS expression. Taken together, these results support a potential role of activation of the bypass tracts in acquired resistance to ALK-directed treatment in ALK-rearranged NSCLC, and provide insights into strategies for preventing and/or overcoming this resistance in patients
Citation Format: Hwang-Phill Kim, Sae-Won Han, Sang-Hyun Song, Tae-You Kim. Combined cetuximab and pemetrexed therapy enhances cytotoxicity against crizotinib-resistant non-small cell lung cancer cells by downregulating thymidylate synthase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3141. doi:10.1158/1538-7445.AM2017-3141
Abstract 3145: Mechanisms of resistance to FGFR-targeted therapy in bladder cancer
Authors: Pettitt Geoffrey A. , McPherson Helen R. , Hurst Carolyn D. , Burns Julie E. , Alder Olivia A. , Dunning Matthew C. , Knowles Margaret A. 
Published: July 2017

Abstract
Fibroblast growth factor receptor 3 (FGFR3) overexpression, point mutations or gene fusions are found in ~80% of non muscle-invasive and ~15% of muscle-invasive bladder cancer. FGFR inhibitors have entered clinical trials in advanced bladder cancer however, as with other targeted therapies, intrinsic and acquired resistance are expected to limit treatment efficacy. We have used an in vitro model to explore possible mechanisms of resistance.
The urothelial cancer cell line RT112 expresses an FGFR3-TACC3 fusion protein and is sensitive to FGFR inhibition. Isogenic resistant cell lines, termed R1, R2 and R3, were derived by long-term culture of RT112 in the presence of the FGFR inhibitor PD173074. Compared to parental RT112, R1 and R2 show reduced proliferation and have a more mesenchymal morphology, decreased expression of FGFR3 and increased expression of N-cadherin. R3 has a faster growth rate, more epithelial morphology and lower N-cadherin expression than R1 and R2.
The changes in morphology and gene expression between parental and resistant derivatives R1 and R2 were reversed when the resistant cells were cultured without PD173074 for 4 passages. Despite this, the cells retained their resistance when re-exposed to PD173074.
Exome sequencing, RNA microarray analysis and phospho-receptor tyrosine kinase array data on the parental cells and resistant derivatives and will be presented. Our data suggests that diverse mechanisms of resistance occur following prolonged FGFR inhibition.
Citation Format: Geoffrey A. Pettitt, Helen R. McPherson, Carolyn D. Hurst, Julie E. Burns, Olivia A. Alder, Matthew C. Dunning, Margaret A. Knowles. Mechanisms of resistance to FGFR-targeted therapy in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3145. doi:10.1158/1538-7445.AM2017-3145
Abstract 3169: SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer cells
Authors: Bae Song Yi , Kim Donghwa , Park Hyen Joo , Byun Woong Sub , Hong Ji-Young , Lee Hye-Jung , Lee Sang Kook 
Published: July 2017

Abstract
Non-small cell lung cancer (NSCLC) is a major type of lung cancer which accounts for approximately 80-85% of all lung cancers. The targeted therapies have significantly improved the survival of advanced NSCLC patients, but the failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is now considered a major problem. SerpinB2 is a component of the urokinase plasminogen activator (uPA) system and has been recognized as a biomarker for the progression and metastasis of lung cancer. We found that SerpinB2 is down-regulated in gefitinib-resistant (H292-Gef) cells compared to gefitinib-sensitive (H292) cells. The low SerpinB2 levels in H292-Gef cells were also associated with an enhancement in invasiveness and increase in the length of invadopodia-like structures in the cells. The effect on invasiveness and gefitinib sensitivity was confirmed by knockdown and overexpression of SerpinB2. In addition, an antitumor agent yuanhuadine (YD) was used to test the possibility to overcome the resistance through the up-regulation of SerpinB2. YD effectively elevated SerpinB2 levels and suppressed invasive properties in H292-Gef cells. Collectively, these findings demonstrate the prospective role of SerpinB2 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment.
Acknowledgement
This study was funded by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A02062012).
Citation Format: Song Yi Bae, Donghwa Kim, Hyen Joo Park, Woong Sub Byun, Ji-Young Hong, Hye-Jung Lee, Sang Kook Lee. SerpinB2 enhances invadopodia-like structure protrusions and is down-regulated in acquired gefitinib-resistant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3169. doi:10.1158/1538-7445.AM2017-3169
Abstract 3173: AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple-negative breast cancer patients
Authors: Kabraji Sheheryar , Sole Xavier , Huang Ying , Bango Clyde , Bowden Michaela , Bardia Aditya , Sgroi Dennis , Loda Massimo , Ramaswamy Sridhar 
Published: July 2017

Abstract
The mechanisms that allow triple negative breast cancer tumors to survive neoadjuvant chemotherapy are incompletely understood. Evidence suggests that proliferative heterogeneity may contribute to primary chemotherapy resistance in patients with triple negative breast cancer. AKT1low quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy resistant subpopulation initially identified in experimental cancer models. Here, we identify QCCs in primary and metastatic human breast tumors using automated, quantitative, immunofluorescence microscopy coupled with computational and statistical analysis. We show that QCCs exist as non-random and heterogeneously distributed clusters within primary tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors as well as nodal and distant metastases in patients with triple negative breast cancer. Together, these data qualify QCCs as a non-genetic mechanism of chemotherapy resistance in triple negative breast cancer patients that warrants further study.
Citation Format: Sheheryar Kabraji, Xavier Sole, Ying Huang, Clyde Bango, Michaela Bowden, Aditya Bardia, Dennis Sgroi, Massimo Loda, Sridhar Ramaswamy. AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple-negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3173. doi:10.1158/1538-7445.AM2017-3173
Abstract 3176: Inhibition of HER2/β-catenin signaling by penfluridol overcomes resistance to paclitaxel in breast cancer
Authors: Gupta Nehal , Gupta Parul , Srivastava Sanjay 
Published: July 2017

Abstract
Paclitaxel is a first line treatment option for patients with metastatic breast cancer. However, inherited or acquired resistance is a limiting factor for therapy with paclitaxel. The mechanism of paclitaxel resistance remains obscured and hinders the development of therapeutic strategies. HER2 is an oncogene overexpressed in about 30% of breast cancer patients and plays role in drug resistance leading to poor prognosis. To identify more clinically relevant mechanism of paclitaxel resistance, we developed resistance to paclitaxel in MCF-7 and 4T1 breast cancer cell lines. The continuous exposure to paclitaxel for several months resulted in &gt;1000 fold resistance in MCF-7 cells and &gt;100 fold resistance in 4T1 cells. Western blot analysis showed enhanced expression of HER2, β-catenin and downstream molecules such as TCF/LEF, c-Myc, Cyclin D in these resistant cells. We have recently demonstrated that penfluridol, an anti-psychotic drug, suppresses the growth of triple negative metastatic breast cancer cells (Ranjan and Srivastava, Cancer Res 2016; 76(4): 877-890), giving us the rationale to evaluate whether penfluridol inhibits HER2 and β-catenin signaling. Our current results showed that penfluridol treatment not only suppressed HER2 but also inhibited β-catenin expression. We also observed down regulation of LEF-1/TCF, Cyclin D1 and c-Myc expression with penfluridol treatment in paclitaxel sensitive as well as resistant cells resulting in reduced survival of cells. Our results further showed that penfluridol treatment synergistically enhanced the growth suppressive effects of paclitaxel in MCF-7 and 4T1 paclitaxel resistant cells. Treatment of paclitaxel resistant 4T1 cells with 1.5μM of penfluridol in combination with 50nM of paclitaxel resulted in 65% of cell growth suppression whereas either treatment alone was not cytotoxic at all. We also observed an enhanced down regulation of proteins involved in paclitaxel resistance such as HER2, β-catenin, c-Myc and Cyclin D1 as well as increase in apoptotic markers such as Cl-PARP and Cl-Caspase3 when paclitaxel treatment was combined with penfluridol in resistant cells. Taken together, our results provided a novel insight into the mechanism of resistance to paclitaxel and also opened new avenues for application of penfluridol in cancer therapeutics. Further detailed mechanistic and in vivo studies are in progress. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH).
Citation Format: Nehal Gupta, Parul Gupta, Sanjay Srivastava. Inhibition of HER2/β-catenin signaling by penfluridol overcomes resistance to paclitaxel in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3176. doi:10.1158/1538-7445.AM2017-3176
Abstract 3177: KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model
Authors: Lee Kyung-Hwa , Ahn Eun-Jung , Jung Shin , Lee Jae-Hyuk , Kim Kyung-Keun , Moon Kyung-Sub 
Published: July 2017

Abstract
Background: Recently, a new research spotlighted the role of KITENIN (KAI1 COOH-terminal interacting tetraspanin) on glioma invasiveness and progression, associated with the up-regulation of EMT (epithelial-mesenchymal transition) and cancer stemness markers. In this study, furthermore, it is investigated whether KITENIN leads to resistance against TMZ through enhancement of cancer stemness factors using mouse glioma model.
Materials and Methods: TMZ-resistant T98G cell line (T98G/TR) was developed. EMT and cancer stemness markers and KITENIN expression were assessed by Western blotting and qRT-PCR. With KITENIN modulated U251 (knockdown) and GL261 (overexpression) cells, cell viability and apoptotic cell death factors after TMZ treatment were evaluated. Biological role of KITENIN on TMZ-resistance was investigated using magnetic resonance imaging (MRI) and immunofluorescence analysis for tumor sections of orthotopic glioma model. Using human glioma samples and primary cells, the mechanistic link between KITENIN and cancer stemness factors was confirmed.
Results: T98G/TR cells showed increased expression of the KITENIN and EMT and cancer stemness factors. Also, In vitro assays revealed that KITENIN knockdown inhibited cell viability against TMZ treatment, whereas KITENIN overexpression promoted their viability, via apoptotic cell death pathway. In orthotopic glioma models, mice implanted with KITENIN-overexpressed cells showed resistance to TMZ on MRI and histopathological examination. The expression of KITENIN/ALDH1 or KITENIN/CD44 were co-localized and significantly higher in tumor sections of mouse transplanted with KITENIN-overexpressed cells than in tumor sections of mouse transplanted with control cells. Genetic down-regulation of KITENIN for KITENIN-overexpressed cell line and primary glioma cells led decreased expression of ALDH1 and CD44. In human glioma samples, high expression of KITENIN was closely related with high expression of ALDH1.
Conclusion: KITENIN affects TMZ-resistance in malignant gliomas through induction of ALDH1 and CD44. Therefore, it could be suggested that KITENIN is therapeutic target to overcome TMZ-resistance of malignant gliomas.
Citation Format: Kyung-Hwa Lee, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Kyung-Sub Moon. KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3177. doi:10.1158/1538-7445.AM2017-3177
Abstract 318: Identification of FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex
Authors: Furukawa Yoichi , Zhu Chi , Ohsugi Tomoyuki , Terakado Yumi , Noguchi Rei , Ikenoue Tsuneo , Yamaguchi Kiyoshi 
Published: July 2017

Abstract
Deregulated Wnt signaling is one of the earliest steps in colorectal tumorigenesis. The impairment results most frequently from APC mutations, which leads to the accumulation of β-catenin and subsequent activation of TCF7L2. Although previous studies have identified a number of target genes of the activated β-catenin/TCF7L2 transcriptional complex such as cMYC and CCND1, the comprehensive effect of the activation on tumorigenesis remains to be elucidated. To understand the precise molecular mechanisms underlying colorectal cancer, we searched for novel genes regulated by the complex in colorectal tumors. We performed expression profile analysis of HCT116 and SW480 colon cancer cells treated with β-catenin siRNAs, and combined these data with public microarray data of LS174 cells treated with a dominant-negative form of TCF7L2. As a result, we identified a total of 134 genes that were regulated by both β-catenin and TCF7L2. Subsequent ChIP-sequence with TCF7L2 antibody selected 11 genes from the 134 genes as candidates of direct target genes. In this study, we focused on FERM domain-containing protein 5 (FRMD5) among the 11 candidates. Quantitative PCR confirmed that its expression was reduced by β-catenin siRNA in HCT116 and SW480 cells. ChIP-quantitative PCR analysis with ant-TCF7L2 antibody also corroborated the interaction of TCF7L2 with a region (hg19; chr15:44,449,680-44,450,487) within intron 1 of FRMD5. Reporter assay with plasmids containing this region revealed that the reporter activity was down-regulated by the knockdown of β-catenin. These data suggested that FRMD5 is a direct target of β-catenin/TCF7L2 complex, and that the region is involved in the transcriptional activation through an interaction with the complex. Consistently, its expression was elevated in colorectal tumors compared to normal colonic mucosa in public microarray data. To uncover the role of FRMD5 in colorectal carcinogenesis, we analyzed expression profile of HCT116 cells treated with FRMD5 siRNA, and combined the data with profile with β-catenin siRNA. Gene set analysis with 53 commonly up-regulated and 36 commonly down-regulated genes by both FRMD5 and β-catenin disclosed that the gene sets of DNA replication, cell cycle, and extracellular matrix (ECM) were altered by FRMD5. These data may be useful for the future studies of colorectal carcinogenesis.
Citation Format: Yoichi Furukawa, Chi Zhu, Tomoyuki Ohsugi, Yumi Terakado, Rei Noguchi, Tsuneo Ikenoue, Kiyoshi Yamaguchi. Identification of FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 318. doi:10.1158/1538-7445.AM2017-318