tbuckley/cabot-search huggingface dataset:
Abstract 3075: Analysis of microRNA profiles involved in the resistance to trifluridine
Authors: Kenta Tsunekuni, Jun Koseki, Masamitsu Konno, Ayumu Asai, Norihiro Nishida, Hugh Colvin, Koichi Kawamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2017)

Abstract Background: Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil, which was approved for the treatment of patients with metastatic colorectal cancer refractory to standard chemotherapies. A comprehensive analysis of miRNA profiles was performed in cell lines resistant to FTD established by ourselves, in order to explore the underlying mechanisms of resistance to the drug. Method: We established subline resistance to FTD through continuous administration and increasing dose of the drug for 5 months using the colorectal cancer cell line DLD-1. Total RNA was extracted at intervals whilst establishing FTD resistant sublines, and miRNA expression was analyzed by microarray. The expression of miRNA that was significantly downregulated in the FTD resistant subline was knocked down to test its involvement in resistance to FTD. Cell viability was evaluated by crystal violet cytotoxicity test. Results: The established FTD-resistant sublines showed more than 22-fold higher resistance to FTD and no cross-resistance to 5-FU. miRNA and mRNA clustered in the genome locus located in chromosome 9, 9p22.32 were downregulated in the FTD-resistant cell line, one of which was the miRNA let-7d-5p, which is one of the let-7 family and is known to target oncogenes and several key components of the cell cycle and cell proliferation. Anti-let-7d-5p treated DLD-1 was less sensitive to FTD than compared to control. The IC50 values of FTD were 16.8 µM and 7.6 µM for the anti-let-7d-5p treated cells and control respectively. On the other hand, overexpression of let-7d-5p in DLD-1 using let-7d-5p mimic increased the sensitivity to FTD compared to control. The IC50 values of FTD were 3.7 µM and 13.9 µM in the let-7d-5p overexpression cells and control respectively. 5FU sensitivity was only altered slightly in anti- let-7d-5p treated or let-7d-5p mimic treated cells. These data suggest that let-7d-5p is more relevant to sensitivity for FTD than that of 5FU. Conclusion: Let-7d-5p expression level influenced FTD sensitivity more effectively than 5FU. It suggests that the let-7d-5p is a potential predictive marker for trifluridine/tipiracil treatment in the clinical setting. Citation Format: Kenta Tsunekuni, Jun Koseki, Masamitsu Konno, Ayumu Asai, Norihiro Nishida, Hugh Colvin, Koichi Kawamoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Analysis of microRNA profiles involved in the resistance to trifluridine [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 3075. doi:10.1158/1538-7445.AM2017-3075
Abstract 5386: Does chemotherapeutics contribute to DNMT1 expression level in colorectal cancer cells
Authors: NURAY VAROL, SUNA ARIKAN TERZİ, ZAFER SOYLEMEZ, HANDAN YILDIZ, MUJGAN OZDEMİR, MUSTAFA SOLAK
Journal: Cancer Research (2017)

Abstract Epigenetic modifications, particularly DNA methylation in selected gene promoters is a pivotal role in the development of colorectal cancer. DNA methylation is considered as one of the most important epigenetic mechanisms and it is catalyzed by DNA methyltransferases (DNMTs). DNMT1 abundance has been frequently seen in colorectal cancers but the reasons are not well understood. We investigated to the effect of chemotherapeutics used in treatment of colorectal cancer on expression of DNMT1 and this effect is achieved over which signalling pathway. In this study, GSK3β; IWP2 for β-catenin) and chemotherapeutics (oxaliplatin, fluorouracil, irinotecan) were detected by WST1. DNMT1 expression level was determinated by real-time PCR; and protein levels of GSK3β, pGSK3β(Ser9), Akt1, pAkt1(Ser473), β-catenin, pβ-catenin(Ser675) and DNMT1 by western blot. Our results indicated taht Akt1 increased the protein level of DNMT1 expression with coordinate transcriptional change via β-catenin pathway. Fluorouracil and irinotecan decreased DNMT1 expression at both transcriptional and translational levels but not oxaliplatin. Oxaliplatin increased DNMT1 expression at mRNA and protein levels. This effect is achieved by specific phosphorylation of β-catenin protein. The results revealed that use of some chemotherapeutic, particularly oxaliplatin, with spesific inhibitors (such as β-catenin inhibitor) in combination led to a reduced DNMT1 expression. Our findings may offer a new approach for determining the molecular effects of β-catenin signal pathway on DNMT1. This may allow us to identify new molecular targets for the treatment of colorectal cancers. However, the results revealed that some chemotherapeutics may contribute the aberration of DNA methylation. Citation Format: NURAY VAROL, SUNA ARIKAN TERZİ, ZAFER SOYLEMEZ, HANDAN YILDIZ, MUJGAN OZDEMİR, MUSTAFA SOLAK. Does chemotherapeutics contribute to DNMT1 expression level in colorectal 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 5386. doi:10.1158/1538-7445.AM2017-5386
Abstract 4000: Establishing the natural history of the immunosuppressive myeloid microenvironment in an inducible model of lung adenocarcinoma
Authors: Mouna Lagraoui, Clifton L. Dalgard, Gauthaman Sukumar, Celeste Huaman, Thomas Summers, Corey A. Carter, Brian C. Schaefer
Journal: Cancer Research (2017)

Abstract Tumorigenesis is accompanied by broad changes to the surrounding tissue microenvironment in a tumor- and patient-specific manner. Phenotype shifts in tissue-resident immune cells promote cancer progression by establishing a proliferative inflammatory environment, activating angiogenesis, stimulating tumor cell invasion and suppressing anti-tumor immunity. While the former mechanisms are well appreciated and often targeted by current cancer therapeutics, the nature of the mechanisms controlling establishment of the local immunosuppressive state that contribute to a failure of anti-tumor immunity are less clearly defined. Blockade of tumor antigen-specific T cell killing is clearly a major contributor to the failure to control tumorigenesis. However, evidence suggests that phenotypic shifts in innate immune cell populations also contribute to the failure of anti-tumor immunity. We hypothesize that the emergence of early lung adenocarcinomas is accompanied by a shift in myeloid phenotypes, rapidly establishing a microenvironment favorable to tumor growth, survival and vascularization, and hostile to cell-mediated anti-tumor immune responses. Through the utilization of a Cre-inducible mouse model of p53-null, Kras-G12D+ lung adenocarcinoma, we have begun to define the natural history of the myeloid component of the tumor microenvironment, from tumor initiation to a point equivalent to human stage I adenocarcinoma. Histological, flow cytometry and real-time PCR approaches collectively demonstrate that tumor-associated myeloid phenotypes emerge at a very early stage of disease. These data are consistent with our hypothesis that the myeloid component of the tumor microenvironment plays a crucial role in establishing an immunosuppressive state during early tumorigenesis. Implications of these findings for current and emerging immunotherapies will be discussed. Citation Format: Mouna Lagraoui, Clifton L. Dalgard, Gauthaman Sukumar, Celeste Huaman, Thomas Summers, Corey A. Carter, Brian C. Schaefer. Establishing the natural history of the immunosuppressive myeloid microenvironment in an inducible model of lung adenocarcinoma [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 4000. doi:10.1158/1538-7445.AM2017-4000
Abstract 3921: Detection of circulating tumor cells in osteosarcoma: A validation study using a translational model
Authors: Marilia Takada, Ya-Ting Yang, Hunter Piegols, Paulo Vilar Saavedra, Cha-Mei Tang, Pete Amstutz, Vilma Yuzbasiyan-Gurkan
Journal: Cancer Research (2017)

Abstract Osteosarcoma (OS) is the most common primary bone cancer in humans, and most frequently seen in pediatric patients. Metastasis to distant organs via hematogenous route is the leading cause of mortality in OS. Current methods to detect metastasis and to monitor response to treatment largely depend on imaging systems with low sensitivity to micrometastases. The value of circulating tumor cells (CTCs) as prognostic marker has been demonstrated in several types of malignancies, including cancer of breast, prostate and colorectal. The objective of this study was to establish a protocol to quantify CTC in patients with OS, as a biomarker for the presence of micrometastases and early detection of tumor relapse. We used dogs with spontaneous OS as a unique translational model. OS occurs in dogs with a 15-fold higher incidence than in humans. Our experimental method consisted of the isolation of CTCs using the microfiltration system CellSieve™, and further enumeration of tumor cells by immunostaining. Normal blood cells were spiked with cultured OS cells and processed using the CellSieve™ system where the CTCs are captured on a microfilter and then incubated with an antibody mixture consisting of fluorescent dye-conjugated antibodies against Osteocalcin, Vimentin, and CD45R. We demonstrated that osteosarcoma tumor cells could be recovered from the blood and characterized by 4-channel immunofluorescence assay as Osteocalcin+ / Vimentin+ / DAPI + and CD45R-, where CD45 serves as a differential marker of normal blood cells. In addition, we were able to demonstrate that the system has a 98% yield of recovery of spiked tumor cells. When this protocol was applied to 7.5 ml of blood sample from a naïve large breed dog diagnosed with OS, we were able to detect one CTC with the predicted staining pattern. Ongoing studies evaluating CTC throughout the clinical course of dogs with OS will determine the value for prognosis as well as for evaluating response to therapy. In conclusion, the CellSieve™ microfiltration platform applied with a set of 4 immunofluorescent antibodies is an effective method for detection of CTCs in canine OS. Citation Format: Marilia Takada, Ya-Ting Yang, Hunter Piegols, Paulo Vilar Saavedra, Cha-Mei Tang, Pete Amstutz, Vilma Yuzbasiyan-Gurkan. Detection of circulating tumor cells in osteosarcoma: A validation study using a translational 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 3921. doi:10.1158/1538-7445.AM2017-3921
Abstract 3304: Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane
Authors: Yoon Jin Lee, David M. Lee, Hae Nam, Sang Lee
Journal: Cancer Research (2017)

Abstract Drug resistance to current chemotherapy regimens has been considered a cell survival adaptive response in malignant mesothelioma cells. Therefore, new strategies to enhance the apoptotic signal and overcome resistance to chemotherapeutics are necessary to improve treatment outcomes for this deadly disease. Here, the effect of sulforaphane, an isothiocyanate compound derived from glucoraphanin present in cruciferous vegetables, on enhancing anticancer role of cisplatin was investigated in malignant mesothelioma cells. At concentrations showing little toxicity in normal human mesothelial MeT-5A cells, the combined treatment with both compounds exhibited synergistic growth-inhibiting and apoptosis-promoting effects, as demonstrated in a series of pro-apoptotic events including reactive oxygen species (ROS) accumulation, loss of mitochondrial membrane potential, up-regulation of p53, increased Bax/Bcl-2 ratio, activation of caspase-3, and the occurrence of a sub-G0/G1 peak with an increase in the cells with pyknotic and fragmented nuclei, Annexin V-PE(+), and G2/M phase transition delay in the cell cycle. The levels of phosphorylation of both Akt and mTOR were decreased by the combined treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein LC3-II and the accumulation of acidic vesicular organelles. Furthermore, scavenging of ROS by antioxidant N-acetylcysteine inhibited both the apoptosis and autophagy, while the inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment of sulforaphane and cisplatin, indicating the cytoprotective role of autophagy counteracts apoptosis of malignant mesothelioma cells. Considering the pro-oxidant-based combinational approach, our data provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma. Citation Format: Yoon Jin Lee, David M. Lee, Hae Nam, Sang Lee. Inhibition of autophagy enhances mitochondria-mediated apoptosis in malignant mesothelioma cells by cisplatin and sulforaphane [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 3304. doi:10.1158/1538-7445.AM2017-3304
Abstract 2118: The food additive agent potassium bromate prevents growth and aggressive phenotypes by targeting multiple molecular signatures in breast cancer cells
Authors: Priyanka Ghosh, Gargi Maity, Snigdha Banerjee, Sushanta Banerjee
Journal: Cancer Research (2017)

Abstract Potassium bromate (KBrO3) is by-product of ozone that has found multifunctional purpose in modern society. It is used as disinfectant in drinking water, a bleaching agent to improve flour, a component of cold-wave hair lotion and an ingredient in the production of fish paste and fermented beverages. Potassium bromide has also been used in America for bread-baking as a safe food additive since 1914. Despite the commercial value of this chemical, some studies suggest that KBrO3 could be a carcinogen. During the bread-baking process, Potassium bromate is normally converted into a stable and inert compound, potassium bromide (KBr). However, due to incomplete reduction, the residual KBrO3 remains in the bread, which eventually acts as a potential carcinogen to humans. Interestingly, our studies, in breast cancer cells, found contrasting results. We found that KBrO3 delays growth of ER-α positive luminal type breast cancer cells and triple-negative breast cancer cells (TNBC) via inducing apoptosis in a dose-dependent manner. KBrO3-induced apoptosis is mediated via targeting BCL-2/Bax and Caspase-3 signaling pathway. Moreover, aggressive phenotypes such as migration, invasion and sphere-forming ability of breast cancer cells are significantly impaired by KBrO3-treatment via targeting multiple molecular signatures in breast cancer cells. The growth inhibition effect of KBrO3 is also documented in a tumor xenograft model. Collectively, our findings provide a rationale for the basic and pre-clinical evaluation of the role of KBrO3 in breast cancer progression and therapy. Citation Format: Priyanka Ghosh, Gargi Maity, Snigdha Banerjee, Sushanta Banerjee. The food additive agent potassium bromate prevents growth and aggressive phenotypes by targeting multiple molecular signatures in breast 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 2118. doi:10.1158/1538-7445.AM2017-2118
Abstract 2576: Benzyl isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes
Authors: Arumugam Nagalingam, Bei Xie, Panjamurthy Kuppusamy, Nethaji Muniraj, Peter Langford, Balázs Győrffy, Neeraj Saxena, Dipali Sharma
Journal: Cancer Research (2017)

Abstract Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active. Furthermore, BITC-induced p53 and p73 axes converge on tumor-suppressor LKB1 which is transcriptionally upregulated by p53 and p73 in p53-wild-type and p53-mutant cells respectively; and in a feed-forward mechanism, LKB1 tethers with p53 and p73 to get recruited to p53-responsive promoters. Analyses of BITC-treated xenografts using LKB1-null cells corroborate in vitro mechanistic findings and establish LKB1 as the key node whereby BITC potentiates as well as rescues p53-pathway in p53-wild-type as well as p53-mutant cells. These data provide first in vitro and in vivo evidence of the integral role of previously unrecognized crosstalk between BITC, p53/LKB1 and p73/LKB1 axes in breast tumor growth-inhibition. Citation Format: Arumugam Nagalingam, Bei Xie, Panjamurthy Kuppusamy, Nethaji Muniraj, Peter Langford, Balázs Győrffy, Neeraj Saxena, Dipali Sharma. Benzyl isothiocyanate potentiates p53 signaling and antitumor effects against breast cancer through activation of p53-LKB1 and p73-LKB1 axes [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 2576. doi:10.1158/1538-7445.AM2017-2576
Abstract 3635: Improved T Cell activation bioassays to advance the development of bispecific antibodies and engineered T cell immunotherapies
Authors: Richard L. Somberg, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Jey Cheng
Journal: Cancer Research (2017)

Abstract T cells play a central role in cell-mediated immunity and can mediate long-term, antigen-specific, effector and memory responses. In recent years, a variety of immunotherapy strategies aimed at inducing, strengthening or engineering T cell responses have emerged as promising approaches for the treatment of diseases such as cancer and autoimmunity. Current methods used to measure TCR-mediated T cell proliferation and cytokine production rely on primary PBMCs as a source of T cells, which must be stimulated via co-culture with APCs or anti-TCR/CD3 antibodies. These assays are laborious and highly variable due to their reliance on donor primary cells, complex assay protocols and unqualified assay reagents. As a result, these assays are difficult to establish in quality-controlled drug development settings. To overcome this barrier, we developed two reporter-based bioluminescent T cell activation bioassays that can be used for the development of bispecific antibodies and engineered T cell immunotherapies. The assays consist of Jurkat T cells genetically engineered to express luciferase downstream of either NFAT or IL-2 response elements. The T cell activation bioassays reflect the mechanisms of action of biologics designed to induce TCR and/or CD28-mediated T cell activation, as demonstrated using anti-CD3 and/or anti-CD28 antibodies as well as blinatumomab, a bispecific antibody that simultaneously binds CD3 expressed on T cells and CD19 expressed on malignant B cells. The bioassays are pre-qualified according to ICH guidelines and show assay specificity, precision, accuracy and linearity required for routine use in potency and stability studies. Finally, our data illustrate the use of reporter-based T cell activation bioassays for characterizing and measuring the activity of engineered chimeric antigen receptor T cells. Citation Format: Richard L. Somberg, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Jey Cheng. Improved T Cell activation bioassays to advance the development of bispecific antibodies and engineered T cell immunotherapies [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 3635. doi:10.1158/1538-7445.AM2017-3635
Spatiotemporally Controlled Release of Rho‐Inhibiting C3 Toxin from a Protein–DNA Hybrid Hydrogel for Targeted Inhibition of Osteoclast Formation and Activity
Authors: Jasmina Gačanin, Anna Kovtun, Stephan Fischer, Victoria Schwager, Johanna Quambusch, Seah Ling Kuan, Weina Liu, Felix Boldt, Chuang Li, Zhongqiang Yang, Dongsheng Liu, Yuzhou Wu, Tanja Weil, Holger Barth, Anita Ignatius
Journal: Advanced Healthcare Materials (2017)

Abstract In osteoporosis, bone structure can be improved by the introduction of therapeutic molecules inhibiting bone resorption by osteoclasts. Here, biocompatible hydrogels represent an excellent option for the delivery of pharmacologically active molecules to the bone tissue because of their biodegradability, injectability, and manifold functionalization capacity. The present study reports the preparation of a multifunctional hybrid hydrogel from chemically modified human serum albumin and rationally designed DNA building blocks. The hybrid hydrogel combines advantageous characteristics, including rapid gelation through DNA hybridization under physiological conditions and a self‐healing and injectable nature with the possibility of specific loading and spatiotemporally controlled release of active proteins, making it an advanced biomaterial for the local treatment of bone diseases, for example, osteoporosis. The hydrogels are loaded with a recombinant Rho‐inhibiting C3 toxin, C2IN‐C3lim‐G205C. This toxin selectively targets osteoclasts and inhibits Rho‐signaling and, thereby, actin‐dependent processes in these cells. Application of C2IN‐C3lim‐G205C toxin‐loaded hydrogels effectively reduces osteoclast formation and resorption activity in vitro, as demonstrated by tartrate‐resistant acid phosphatase staining and the pit resorption assay. Simultaneously, osteoblast activity, viability, and proliferation are unaffected, thus making C2IN‐C3lim‐G205C toxin‐loaded hybrid hydrogels an attractive pharmacological system for spatial and selective modulation of osteoclast functions to reduce bone resorption.