bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A008: Establishment of novel gastric cancer PDX models and cell lines for developing new therapeutics
Authors: Kuwata Takeshi , Yanagihara Kazuyoshi 
Published: August 2018

Abstract
It is essential to have appropriate preclinical models for developing new drugs for gastric cancer (GC). Cell lines have been the most commonly used model for this purpose. However, the numbers of gastric cancer cell lines established and available for this purpose are limited and not enough to deal with variety of gastric cancer molecular subtypes such as recently proposed by The Cancer Genome Atlas (TCGA). In addition, patient-derived xenograft (PDX) models have been considered more appropriate models for evaluating the efficacy of new drugs in vivo. For contributing to develop new drugs as well as to seek more effective biomarkers, we have been conducting an intramural project, called DEF study, for establishing new GC PDXs as well as new GC cell lines. So far, 30 multi-passage-competent new PDXs have been successfully established from surgically removed gastric cancer tissues or ascites. Twenty-two (22) new GC cell lines have also been established from PDX tissue (16 lines) or directly from ascites (6 lines). All GC PDXs have been examined by immunohistochemistry for HER2, EGFR, and Met expressions, and we identified 5 cases overexpressing HER2 (corresponding to Score3+) and 1 case overexpressing both EGFR and MET. Comprehensive gene mutation analysis has been performed in 21 PDX tissues, and repetitive mutations (SNV/Indel) have been observed in ERBB2, ERBB3, BRAF, APC, ARID1A, and p53. Copy number alternations have also been identified; examples include KRAS and ERBB2 for amplification and PTEN and CDKN2A for deletion.
Citation Format: Takeshi Kuwata, Kazuyoshi Yanagihara. Establishment of novel gastric cancer PDX models and cell lines for developing new therapeutics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A008.
Abstract A017: Optimization of a cachexia animal model for efficacy evaluation of candidates
Authors: Bae Jiyeong , Cho Ig Jun , Shin Jung Hyu , Yuh Hyung Soo , Moon Hyung Ho , Lee Hye Lim , Jo Yeong Nang , Park Yeon Ju , Choi Woo Sung , Hyun Byung Hwa 
Published: August 2018

Abstract
Cachexia-anorexia syndrome, which is called cancer cachexia, is a common and important indicator of cancer and occurs in 30% to 80% of cancer patients. Cancer cachexia is characterized by a severe progressive body wasting, accompanied by loss of adipose tissue and skeletal muscle mass. The presence of cachexia is associated with a worsened prognosis and contributes to up to 20% of cancer deaths. In most cases, cancer cachexia patients clinically show anorexia caused through a complex system of hormones and neuropeptides. To investigate efficacy in development of new medicine, an optimized animal model is essentially required. Although several cancer cachexia animal models have been established, we focused on developing a better animal model particularly for efficacy evaluation with advanced bioimaging evaluation methods. First of all, we confirmed that an appropriate mouse strain is CDF1 in comparison with DBA1 and Balb/c after xenografting of Colon26. As the second step, we checked cell numbers with pattern of tumor growth. In human clinics, cure of cancer cachexia is usually performed with surgical removal of tumor. To make the animal model similar to clinical circumstances, we tested recovery time and pattern after removal of tumor. With optimized mouse model we tested efficacy of anticancer drug Megace 200 mg/kg as a positive control. In addition, we applied advanced bioimaging equipment such as MRI and CT to visualize actual tumor and fat with body composition. We expect that optimized animal model of cancer cachexia will prepare the way for more accurate efficacy test in preclinical state to go to a clinical trial.
Citation Format: Jiyeong Bae, Ig Jun Cho, Jung Hyu Shin, Hyung Soo Yuh, Hyung Ho Moon, Hye Lim Lee, Yeong Nang Jo, Yeon Ju Park, Woo Sung Choi, Byung Hwa Hyun. Optimization of a cachexia animal model for efficacy evaluation of candidates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A017.
Abstract A039: FGF/PTX3 crosstalk in bladder cancer: novel prognostic and therapeutic implications
Authors: Matarazzo Sara , Maccarinelli Federica , Ghedini Gaia Cristina , Melocchi Laura , Bugatti Mattia , Vermi William , Presta Marco , Ronca Roberto 
Published: August 2018

Abstract
Bladder cancer is one of the most common cancers in the world. Although most of urothelial carcinomas (UCs) are low-grade papillary tumors, their propensity to recur and to progress to become invasive with a poor survival rate represents a major challenge. Different members of the Fibroblast growth factor (FGF) family are expressed by human bladder cancer cells, and aberrant expression of FGF receptors (FGFRs) is a typical feature of bladder cancer compared to normal urothelium. High expression levels of FGFR1 are associated with poor survival and FGFR3 is frequently dysregulated in UC. Thus, the FGF/FGFR system may represent a promising therapeutic target in invasive and noninvasive bladder cancer.
Long-pentraxin 3 (PTX3) acts as a natural FGF trap by binding FGFs and hampering their biologic activity in various tumor models. Preliminary observations have shown that low-grade UCs express PTX3 while high-grade/invasive UCs lose PTX3 expression. Accordingly, bladder cancer cell lines share an overall presence of FGFRs and FGFs but express different levels of PTX3 in vitro and in vivo. Of note, high-grade/invasive cells express very low or undetectable levels of PTX3, whereas low-grade, papilloma-like cells express high levels of PTX3. Indeed, invasive bladder cancer cell xenografts grow faster in nude mice and express much lower levels of PTX3 than low grade-derived lesions, thus confirming an inverse correlation between UC grade and PTX3 expression. This hypothesis is reinforced by a preliminary case study performed on a small cohort of biopsies from UC patients confirming that the presence of PTX3 is a common feature of low-grade samples while PTX3 is poorly expressed or absent in aggressive/invasive cases. These data point to PTX3 as a natural FGF trap that could play a role in modulating bladder cancer progression and invasiveness and indicate that inhibition of the FGF/FGFR system by natural and synthetic FGF traps may represent a promising target for the therapy of UCs.
Citation Format: Sara Matarazzo, Federica Maccarinelli, Gaia Cristina Ghedini, Laura Melocchi, Mattia Bugatti, William Vermi, Marco Presta, Roberto Ronca. FGF/PTX3 crosstalk in bladder cancer: novel prognostic and therapeutic implications [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A039.
Abstract A064: MiR-2861 behaves as a LCSCs biomarker and regulates the HDAC5-ERK system genes
Authors: Zhu Yimin , Zhao Mengya 
Published: August 2018

Abstract
Cancer stem cells (CSCs) are responsible for cancer initiation, recurrence, and drug resistance. Discovery of novel biomarkers for CSCs may be helpful for early diagnosis and prognosis. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSCs differentiation model was established through introducing serum into the culture medium of H460 spheres. MiR-2861 expression was significantly higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861. The role of HDAC5 in the regulation of differentiation of LCSCs was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSCs differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy.
Citation Format: Yimin Zhu, Mengya Zhao. MiR-2861 behaves as a LCSCs biomarker and regulates the HDAC5-ERK system genes [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A064.
Abstract A073: Gemcitabine cotreatment enhances the therapeutic effect of prexasertib in HNSCC cells that are less sensitive to Chk1 inhibition single-agent therapy
Authors: Gadhikar Mayur A. , Myers Jeffrey N. 
Published: August 2018

Abstract
Prexasertib, a highly potent Chk1 inhibitor, has shown remarkable single-agent activity (IC50 &lt; 5 nmol/L) in a subset of head and neck cancer (HNSCC) cells that are genomically predisposed to replication stress. Nevertheless, a broader application of this therapeutic strategy in HNSCC is hindered because many HNSCC cells lack innate susceptibility to replication stress and exhibit much higher IC50 values for prexasertib. Here we report that gemcitabine cotreatment markedly augments the therapeutic efficacy of prexasertib in HNSCC cells that are recalcitrant/less sensitive to Chk1 inhibition monotherapy. Mechanistic investigations revealed perturbation in the S phase progression and induction of replication stress markers that associated with decreased colony survival upon gemcitabine and prexasertib combination treatment. These results indicate that therapeutic utility of prexasertib could be further expanded in HNSCC through a combination treatment with gemcitabine.
Citation Format: Mayur A. Gadhikar, Jeffrey N. Myers. Gemcitabine cotreatment enhances the therapeutic effect of prexasertib in HNSCC cells that are less sensitive to Chk1 inhibition single-agent therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A073.
Abstract A122: Anti-Helicobacter pylori activity of a novel derivative of intervenolin
Authors: Kawada Manabu , Ohishi Tomokazu , Abe Hikaru , Hayashi Chigusa , Sakashita Chiharu , Ohba Shun-ichi , Inoue Hiroyuki , Igarashi Masayuki , Watanabe Takumi , Shibasaki Masakatsu 
Published: August 2018

Abstract
Helicobacter pylori (H. pylori) infection plays a critical role in pathogenesis of gastric ulcer and gastric cancer. Thus, the eradication of H. pylori could prevent the onset of these diseases. At present the standard therapy against H. pylori infection is a combination therapy of a proton pump inhibitor and two antibiotics such as clarithromycin and amoxicillin. However, there exist H. pylori strains that show resistance against these antibiotics. Furthermore, adverse effect of these antibiotics against intestinal bacteria is unavoidable. We previously discovered a novel compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2. Intervenolin is a very unique compound having both antitumor and anti-H. pylori activities. To create a potent anti-H. pylori compound, we synthesized various derivatives of intervenolin. Among them we identified compounds that show selective anti-H. pylori activity in vitro without effect on other bacteria including intestinal bacteria. Oral monotherapy of the derivative exerts a significant eradicative effect against H. pylori-infected mice more than the standard combination therapy. Taken together, we have successfully created a potent new anti-H. pylori compound.
Citation Format: Manabu Kawada, Tomokazu Ohishi, Hikaru Abe, Chigusa Hayashi, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue, Masayuki Igarashi, Takumi Watanabe, Masakatsu Shibasaki. Anti-Helicobacter pylori activity of a novel derivative of intervenolin [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A122.
Abstract A125: Fragment-based approach to develop small-molecule STAT3 transcription factor inhibitors
Authors: Nahar Kazi S. , Jamshidi Shirin , Thurston David E. , Rahman Khondaker Miraz 
Published: August 2018

Abstract
Oncogenic transcription factors are an increasingly important target for anticancer therapies, as inhibition could allow the “reprogramming” of tumor cells, leading to apoptosis or differentiation from the malignant phenotype. STAT3 induces the transcription of genes that control differentiation, inflammation, proliferation, and tumor cell invasion, and its overexpression has been implicated in many different tumor types. Although tumor cells are often dependent upon activation of STAT3, nontumor cells are fairly tolerant of loss of its function, most likely reflecting redundancies in normal signal transduction. Thus, STAT3 inhibitors have high therapeutic potential. A combination of advanced in silico design and pharmacophore-based approaches has been used to design a series of novel inhibitors capable of disrupting STAT3 dimerization by interacting with the hexapeptide pocket of the STAT3 SH2 domain of the protein. The medicinal chemistry optimized mature ligand library members showed a notable improvement in STAT3-dimerization inhibition potency, with activities ranging from 33% to 59% inhibition. The optimized compounds had submicromolar to low micromolar cytotoxicity in STAT3-dependent cell lines with good selectivity ratios between these cells and nontumor cells (e.g., WI38 and A4). A number of the most active compounds (e.g., 6.6, 6.10, and 6.13) were selected for molecular dynamics simulation studies, and for an evaluation of their ability to downregulate STAT3-dependent genes in the STAT3-dependent cell line MDA MB 231. In these experiments, they were found to be able to downregulate the STAT3-dependent genes survivin, cyclin D1, fascin, and BCL-2 in comparison to the housekeeping gene GAPDH. The most active compound, 6.6, was also evaluated in a preliminary in vivo efficacy study in immune-compromised mice bearing MDA MB 231 tumors, and was found to have significant in vivo antitumor properties. Although further work is required to confirm the proposed mechanism of action, efforts are now focused on identifying the most suitable candidate molecule to take forward to the clinic.
Citation Format: Kazi S. Nahar, Shirin Jamshidi, David E. Thurston, Khondaker Miraz Rahman. Fragment-based approach to develop small-molecule STAT3 transcription factor inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A125.
Abstract A135: IFIT1 and 3 modulate the drug sensitivity in human oral squamous cell carcinoma cells
Authors: Pidugu Vijaya Kumar , Wu Mei-Maan , Liu Chung-Ji , Lee Te-Chang 
Published: August 2018

Abstract
Interferon-induced protein with tetratricopeptide repeats (IFITs) family, well-known interferons stimulated genes, have multiple tetratricopeptide repeats with helix-turn-helix structural motifs that mediate a variety of protein-protein interactions. There are four IFIT genes that have been identified: IFIT1, IFIT2, IFIT3, and IFIT5 in humans. We have previously shown that IFIT2 inhibits oral squamous cell carcinoma (OSCC) metastasis. Alternatively, our recent studies revealed the involvement of IFIT1 and IFIT3 in the progression of OSCC. The study on IFIT5 was far from adequate. The failure of chemotherapy or targeted therapy was often associated with the intrinsic or acquired drug resistance. In the present study, we are investigating the role of IFIT1 and IFIT3 genes on drug resistance in OSCC cells. Our results showed that ectopic expression of IFIT1 and IFIT3 proteins in OSCC cells significantly increased the resistance to cisplatin, whereas they became highly susceptible to gefitinib, a tyrosine kinase inhibitor. Consistently, silencing of IFIT1 and IFIT3 by shRNA enhanced the sensitivity to cisplatin but resulted in increased resistance to gefitinib. We further demonstrated that enhanced expression of IFIT1 and IFIT3 significantly increased the levels of activated forms of AKT (p-AKT) and EGFR (p-EGFR), suggesting that AKT and EGFR signaling could be activated by IFIT1 and IFIT3. Our present results indicate that IFIT1 and IFIT3 may serve as a marker for precisely choosing right therapeutic agents for the treatment of patients with OSCC.
Citation Format: Vijaya Kumar Pidugu, Mei-Maan Wu, Chung-Ji Liu, Te-Chang Lee. IFIT1 and 3 modulate the drug sensitivity in human oral squamous cell carcinoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A135.
Abstract A149: A chemical screening and machine learning approach to de-convolve kinase addictions in TNBC
Authors: Gautam Prson , Al-Ali Hassan , Wennerberg Krister 
Published: August 2018

Abstract
Protein kinases are major regulators of cellular signalling and known drivers of cancer and other diseases. In the last two decades, kinase inhibitors have gained much attention as cancer therapeutic agents. In this study, we combined drug vulnerability data of 19 breast cancer cell lines with kinase activity data, and employed machine learning and information theory to de-convolve cell line specific kinase addictions. The study was mainly focused on triple-negative breast cancers (TNBC), which still lack targeted therapy. With this approach, we identified several novel TNBC cell line selective kinase addictions (e.g., FGFR2 for MFM-223) and, as added validation, detected previously established kinase sensitivities (e.g., BRAF in DU4475, ERBB2 in luminal cell lines SK-BR-3 and BT-474, along with generic addiction towards cell cycle and apoptosis regulators like PLK1 and PI3K). A major benefit of this approach is that it can identify readily druggable targets while avoiding false positives and undruggable candidates from loss-of-function analyses. Comparison of kinase inhibitor vulnerabilities with loss-of-function data showed significant discordance, highlighting the need for cautious evaluation of loss-of-function data for drug target identification. Our study underscores the heterogeneity of drug response in TNBC and provides a platform for rapidly identifying vulnerabilities and guiding targeted therapy regimens.
Citation Format: Prson Gautam, Hassan Al-Ali, Krister Wennerberg. A chemical screening and machine learning approach to de-convolve kinase addictions in TNBC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A149.
Abstract A152: Emerging indications for kinase-targeted therapies: screening for new targets
Authors: Li Rick , Lai Shenshen , Mah Allan , Zhang Hong , Yan Jun , Marotta Anthony , Zhang Zaihui 
Published: August 2018

Abstract
Protein kinases play key roles in normal physiologic functions. Aberration of individual protein kinases and the pathways that these enzymes govern are centrally involved in the pathogenesis of a number of diseases including cancer, neurologic disorders, metabolic diseases, and autoimmune conditions. Targeting these enzymes using small-molecule approaches has been proven to be highly relevant in terms of treating cancer and, more recently, autoimmune conditions like rheumatoid arthritis. Evaluating the specificities of these compounds across the kinome and relating these effects with clinical manifestations may provide important insights into how these compounds can be used to treat other diseases. In this study, we evaluated the specificity of four compounds–saracatinib, vandetanib, crizotinib, and cabozantinib–across a panel of 48 kinases representing 7 major groups and other kinases. They were assessed at 1 and 10 µM using the “gold standard” radiometric assay. A 50% reduction in kinase activity at the single point concentration at 1 μM was deemed to be of relevance in this study as that would signify an IC50 of less than 1 µM. The study demonstrated that all four compounds inhibited greater than 30% of the kinases within this 48-kinase panel, albeit different kinase targets. Interestingly, none of the selected kinases within AGC, CAMK, and CGMC subgroups was inhibited more than 50% at 1 μM. Furthermore, all 4 inhibitors exhibited greatest potency against their intended kinase targets, mainly receptor and cytoplasmic tyrosine kinases, RTKs, and CTKs, respectively. Specifically, saracatanib inhibited PDGFR, KIT, EGFR, and BTK; vandetanib inhibited FGFR2 and KDR, an RTK that interacts with the ligand VEGF; crizotinib inhibited insulin receptor (InsR); and cabozantinb had effect on DDR2, FLT1, FLT3, KDR, MET, and TRKA. In conclusion, we have demonstrated the power of using unbiased protein kinase panels to uncover novel biochemical interactions with potential therapeutic values. Of the four inhibitors tested above, we have found several new targets for each, including an interaction between crizotinib and insulin receptor, an RTK involved in metabolic homeostasis. This opens up possible implications for crizotinib in regulating metabolic homeostasis.
Citation Format: Rick Li, Shenshen Lai, Allan Mah, Hong Zhang, Jun Yan, Anthony Marotta, Zaihui Zhang. Emerging indications for kinase-targeted therapies: screening for new targets [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A152.
Abstract A181: Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments
Authors: Cho Sung-Yup 
Published: August 2018

Abstract
Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBL are largely unknown because of limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during engraftment of gastric cancer adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using the ROCK inhibitor, fasudil, decreased tumor growth markedly in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.
Citation Format: Sung-Yup Cho. Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A181.