tbuckley/cabot-search huggingface dataset:
Abstract 5592: Metformin improves immune function of exhausted peripheral CD8+ T cells derived from cancer patients
Authors: Mototsugu Watanabe, Shingo Eikawa, Kazuhiko Shien, Hiromasa Yamamoto, Tadahiko Shien, Junichi Soh, Hiroyoshi Doihara, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono
Journal: Cancer Research (2017)

Abstract Background: Immunotherapy has been developed and shown a drastic effect on several malignancies. However, in the tumor microenvironment, CD8+ tumor infiltrating lymphocytes (CD8+ TILs) are repeatedly exposed to tumor antigens and lose their anti-tumor activities. We have recently shown that metformin can show anti-tumor effect thorough improving immune function in mouse models. Increased numbers of such multifunctional CD8+ TILs have well correlated with tumor retardation, suggesting an underlying mechanism of metformin in tumor immunity. The objectives of this study are to evaluate the efficacy of metformin on human immune function. Methods: We obtained peripheral blood mononuclear cells (PBMC) from healthy volunteers (HV) and cancer patients (CP) before and after taking metformin orally for about 2 weeks. We cultured the PBMC in a presence of stimulation with phorbol 12-myristate 13-acetate (PMA) / ionomycin in vitro for 6 hours. Expressions of markers for immune-check points (PD-1 and Tim-3) were examined together with accumulated intracellular cytokines, IFN-γ, IL-2 and TNF-α by flow cytometry analysis. Results: We obtained consents for take part in our clinical research from 20 HV and 15 CP (10 breast cancer, 4 metastatic lung cancer and 1 primary lung cancer). CD8+ T cells which expressed both of PD-1 and Tim-3 derived from CP were higher than those of HV (p = 0.041). Increased production of multiple cytokines, IFN-γ, IL-2 and TNF-α was observed in CD8+ T cells of almost all cancer patients by metformin treatment and its increasement was significant (p &amp;lt; 0.01), whereas marginal difference before and after metformin administration was detected in the samples from healthy volunteers so far (p = 0.051). Conclusion: Metformin treatment might be useful in reversion of exhausted CD8+T cells in cancer bearing patients. Citation Format: Mototsugu Watanabe, Shingo Eikawa, Kazuhiko Shien, Hiromasa Yamamoto, Tadahiko Shien, Junichi Soh, Hiroyoshi Doihara, Shinichi Toyooka, Shinichiro Miyoshi, Heiichiro Udono. Metformin improves immune function of exhausted peripheral CD8+ T cells derived from 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 5592. doi:10.1158/1538-7445.AM2017-5592
Abstract 869: Mesenchymal identity of breast cancer promotes brain metastases and therapeutic resistance through MLK4/NFkB signaling Pathway
Authors: Heba Allah M. Alsheikh, Mutsuko Minata, Shinobu Yamaguchi, Ichiro Nakano
Journal: Cancer Research (2017)

Abstract Patients with breast cancer brain metastases (BCBM) suffer from a devastating outcome despite recent progress in a variety of therapeutic modality. Among the four major molecular subtypes, breast cancers that are either human epidermal growth factor receptor (HER) 2- positive or triple-negative breast cancer (TNBC) patients have a higher risk of BCBM compared with the luminal cancer patients. The mechanisms by which the disseminated cancer cells overcome the multistep defense mechanism in the brain, adapt the microenvironment, and subsequently initiate metastasis remain elusive. Recently, we identified a set of genes that contribute to initiate Glioblastoma (GBM) and at least some of them are functionally essential for GBM establishment and the therapy resistance. Mixed lineage kinase 4 (MLK4) is a relatively poorly characterized serine/threonine kinase, which is largely expressed in various cancers including GBM. We recently found a critical role of MLK4 in controlling the mesenchymal identity in GBM stem cells and plays a role in GBM initiation through direct activation of NF-kB signaling. Our preliminary data indicates MLK4 is also highly expressed in patient-derived hormone receptor (HR)-negative breast cancer cells in comparison with the other HR-positive counterparts. For therapeutic development purpose, we performed the structure-based drug design, which has led to identify two small molecule MLK4 inhibitor candidates to test efficacy on a set of patient-derived breast cancer cells in vitro and their xenografted tumors in vivo. Results will be presented in the conference. Citation Format: Heba Allah M. Alsheikh, Mutsuko Minata, Shinobu Yamaguchi, Ichiro Nakano. Mesenchymal identity of breast cancer promotes brain metastases and therapeutic resistance through MLK4/NFkB signaling Pathway [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 869. doi:10.1158/1538-7445.AM2017-869
Abstract 5909: Microfluidic vertical adhesion-suspension co-culture platform for studying cancer stem cell-fibroblast interactions
Authors: Yu-Chih Chen, Zhixiong Zhang, Yu-Heng Cheng, Euisik Yoon, Max S. Wicha
Journal: Cancer Research (2017)

Abstract Considerable evidence suggests that cancer-stem-cells (CSCs) play critical roles in tumorigenesis and metastasis .Although surface marker expression or enzymatic activity of CSC has proven useful, variability of expression highlights the need for the development of high throughput functional CSC assays. One such approach utilizes the capability of CSC’s to form single-cell-derived spheres in suspension environments (functional CSCs). Microfluidic tools are suitable for handling and monitoring a large number of single cells in suspension as well as for examining the interaction of these cells with those in the tumor micro-environment including cancer associated fibroblasts (CAF’s).In order to accomplish this, we have developed a high-throughput (10,000-well), simple-to-use, vertical platform for CSC/CAF co-culture. The platform consists of a non-adherent substrate having 10,000 micro wells for single-cell-derived sphere formation and a porous trans well for CAF adherent co-culture. As predicted by Poisson’s distribution, approximately 30% of micro wells capture single cells when T47D breast cancer cells are loaded at a concentration of 200k/ml. After cell seeding, trans wells containing CAFs are placed onto the substrate. 0.4µm pores on the trans well allow for secretion-based cellular interaction while preventing direct CSC/CAF cell contact. This cell separation facilitates sample cell retrieval without cell cross contamination. Utilizing this device, we determined that co-culture of tumor cells with CAF’s doubled the frequency of sphere formation. Spheres derived from individual CSCs were then retrieved and dissociated for single-cell transcriptome analysis utilizing RNA barcoding followed by RNAseq. Molecular analysis revealed significant cellular heterogeneity among sphere derived cells. In addition, principal component analysis of single cell RNAseq, reveled significant differences in gene expression between mono-cultured and CAF co-cultured cells isolated from tumor spheres. These genes represent potential therapeutic targets for interfering with CSC stromal cell interactions in the tumor microenvironment. The vertical adhesion suspension co-culture platform provides a system to identify and evaluate novel CSC targeted therapeutics. Citation Format: Yu-Chih Chen, Zhixiong Zhang, Yu-Heng Cheng, Euisik Yoon, Max S. Wicha. Microfluidic vertical adhesion-suspension co-culture platform for studying cancer stem cell-fibroblast interactions [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 5909. doi:10.1158/1538-7445.AM2017-5909
Abstract 5724: Circulatory microRNA expression profiling between HCV-infected African & Caucasian Americans: implications for racial health disparities
Authors: Pradip Devhare, Robert Steele, Adrian M. Di Bisceglie, David E. Kaplan, Ratna B. Ray
Journal: Cancer Research (2017)

Abstract The purpose of the study: Hepatocellular carcinoma (HCC) is global problem and incidence of HCC is increasing in last several years. Hepatitis C virus (HCV) infection is one of the major cause towards development of HCC. HCV infection is highly prevalent in African American population compared to other ethnic groups and these people are less likely to naturally clear HCV. Higher incidence of HCC and mortality was noted in HCV infected African Americans as compared to Caucasians. However, the explanation for this disparity and the molecular mechanisms behind this are currently unknown. Circulating microRNAs in the blood are emerging as biomarkers for pathological conditions. Differential expression of miRNAs among ethnic groups would be important for optimizing personalized treatment strategies. Experimental procedures: In this study, we assessed the differential expression of circulatory miRNAs from HCV infected African Americans and Caucasians by cancer specific miRNA array profiling. Expression of significantly altered miRNAs was validated by qRT-PCR. Results: We identified increased expression of miR-146a, miR-150 and miR-155 in HCV infected African Americans patient sera as compared to sera of Caucasians. Further analysis demonstrated that these miRNAs were significantly elevated in African Americans diagnosed with HCV-mediated HCC. Higher expression of miR-150 was also noted in cirrhosis and HCC in African Americans, which may serve as predictor of liver disease progression in this population. Conclusion: The differential expression of miRNAs suggests that these miRNAs and their target genes could be useful to gain further mechanistic insight of racial disparity associated with HCV pathogenesis. Citation Format: Pradip Devhare, Robert Steele, Adrian M. Di Bisceglie, David E. Kaplan, Ratna B. Ray. Circulatory microRNA expression profiling between HCV-infected African &amp; Caucasian Americans: implications for racial health disparities [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 5724. doi:10.1158/1538-7445.AM2017-5724
Abstract 99: Identify potential kinetochore protein inhibitors to overcome cisplatin resistance
Authors: Chen Yin-Ju, Jeng-Fong Chiou
Journal: Cancer Research (2017)

Abstract Cisplain is the most commonly used chemotherapeutic drug for cancer, while the resistance causes treatment failure. Cisplatin resistance may involve in many molecular changes so identify aberrations in cisplatin-resistant (CR) genes and find new therapeutic strategies could provide valuable information to reduce therapeutic resistance. The aim of this study is to search CR genes and identify potential novel drugs to overcome cisplatin resistance. To identify aberrations in CR genes, three CR genetic signatures were collected and analyzed differential expression genes from lung, ovarian and oral cancer cells. After integration of CR signatures, the kinetochore associated proteins, including NUF2, SPC25, PC24, DSN1, SKA2, KNTC1, MIS18A and SKA1 were up-regulated in various CR cells. Silencing of kinetochore associated proteins increased cisplatin sensitivity. For identification of kinetochore associated protein inhibitors to overcome cisplatin resistance, CR signatures were queried to the Connectivity map (Cmap) database to search for potential drugs which may reverse cisplatin resistance. 3 compounds exhibited cytotoxicity effect on the cisplatin-resistant cells and reduced kinetochore associated proteins expression level. Taking together, this study demonstrates kinetochore associated proteins participate in cisplatin resistance and identify potential inhibitors to overcome cisplatin resistance. Citation Format: Chen Yin-Ju, Jeng-Fong Chiou. Identify potential kinetochore protein inhibitors to overcome cisplatin resistance [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 99. doi:10.1158/1538-7445.AM2017-99
Abstract 1127: Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma
Authors: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles
Journal: Cancer Research (2017)

Abstract Background: Recurrent/metastatic head and neck squamous cell carcinoma (SCCHN) and salivary gland malignancies are difficult to treat with limited standard of care options at the present time. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. Our in vivo studies demonstrated that our novel GSK-3 inhibitors significantly potentiated the effects of conventional chemotherapy in patient-derived xenograft models of glioblastoma and breast cancer leading to regression of tumors. In order to develop a rationale to test our novel GSK-3 inhibitors in head and neck (H&amp;N) malignancies, we evaluated the expression pattern of GSK-3beta in human H&amp;N benign tissue and malignant tumors. Methods: We used immunohistochemical staining of H&amp;N tumor tissue Microarray (TMA), 48 total cases (20 benign tissues, 28 malignant), to study the expression pattern of GSK-3beta. GSK-3beta nuclear accumulation was defined as positive staining of more than 50% of cancer cell nuclei throughout the tumor regardless of cytoplasmic staining. Results: Of the 20 malignant H&amp;N samples (15 SCCHN, 1 nasopharyngeal and 5 other histology), 13 (65%) were found to have aberrant nuclear accumulation of GSK-3beta. Amongst SCCHN, 73% (11 of 15 samples) had aberrant nuclear accumulation of GSK-3beta. In contrast, none (0%) of the 11 benign non-salivary H&amp;N tissue showed detectable expression of GSK-3beta. Of interest, 60% of salivary adenoid cystic carcinoma specimens and 44% of benign salivary gland tissue showed GSK-3beta expression. Conclusions: Our results demonstrate for the first time, that there is aberrant nuclear expression of GSK-3beta in SCCHN. This finding supports further exploring of our novel GSK-3beta inhibitor as a potential therapeutic target for recurrent/metastatic SCCHN and also, as a potential prognostic and predictive biomarker for risk of recurrent disease and chemo- or radio-resistance. Its role in salivary gland malignancies requires further studying. Citation Format: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles. Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma [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 1127. doi:10.1158/1538-7445.AM2017-1127
Abstract LB-212: Antioxidant therapy reprograms macrophages from protumor M2 to antitumor M1
Authors: Brandon Griess, Kaustubh Datta, Melissa Teoh-Fitzgerald
Journal: Cancer Research (2017)

Abstract Macrophages (Mϕ) have high plasticity and can polarize to two extremes, pro-inflammatory M1 Mϕ and immuno-suppressive M2 Mϕ. In triple negative breast cancer, tumor-associated Mϕ (TAM) have a pro-tumor M2-like phenotype and are associated with decreased survival. Thus, it is vital to develop treatments to reprogram TAM away from protumor M2 Mϕ toward antitumor M1 Mϕ. A recent study reported a lipid peroxide scavenger selectively inhibits M2 Mϕ markers and cytokines. However, little is known about the differences in ROS metabolism between M1 Mϕ and M2 Mϕ. Our hypothesis is pro-tumorigenic M2 Mϕ possess a distinct profile of pro- and anti-oxidant enzymes, as well as a different sensitivity to ROS modulation versus the anti-tumor M1 Mϕ. Our results show M2 Mϕ, derived from primary human monocytes, have a significant 20-30% reduction in intracellular ROS levels versus M1 Mϕ by DCFH and DHE staining. Extracellular ROS synthesis was dramatically reduced by ~70% in M2 Mϕ, in part due to reduced mRNA expression of Nox2, Nox5, and their accessory protein CYBA in M2 Mϕ. Another contributing factor to lower ROS levels is that M2 Mϕ have significantly increased Catalase and Gpx4 mRNA expression, as well as increased Cu/ZnSOD and Gpx1 protein and activity. These data suggest M2 Mϕ have increased ROS metabolism versus M1 Mϕ, which may provide an advantage in the oxidative tumor microenvironment. Furthermore, EcSOD re-expression in MB231, a triple negative breast cancer cell line, inhibited the MB231-mediated increase in M2 Mϕ markers and decrease in M1 Mϕ markers. We moved forward utilizing Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE), a small molecule SOD mimetic, shown to have anti-tumor effects. MnTE treatment increased M1 Mϕ markers, IL-12b and CD86, while concurrently decreasing M2 Mϕ markers, IL-10, CD163, and CD206. MnTE also inhibited the ability of M2 Mϕ to inhibit T cell activation suggesting ROS is required for M2 Mϕ polarization and function. Increasing ROS levels by addition of exogenous H2O2, lead to increased M2 markers and decreased M1 markers, which implicates the oxidative tumor microenvironment in promoting a M2-like TAM phenotype. These studies provide the rationale for antioxidant treatment of breast cancer to reprogram TAM from pro-tumorigenic M2-like TAM phenotype to a more tumoricidal M1-like phenotype. Citation Format: Brandon Griess, Kaustubh Datta, Melissa Teoh-Fitzgerald. Antioxidant therapy reprograms macrophages from protumor M2 to antitumor M1 [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 LB-212. doi:10.1158/1538-7445.AM2017-LB-212
Abstract 2103: NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors
Authors: Andreas Weiss, Diana Graus Porta, Flavia Reimann, Alexandra Buhles, Christelle Stamm, Robin A. Fairhurst, Jacqueline Kinyamu-Akunda, Dario Sterker, Masato Murakami, Markus Wartmann, Youzhen Wang, Jeffrey A. Engelman, Francesco Hofmann, Wiliam R. Sellers
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a deadly disease. Treatment options are limited and prognosis generally is poor. Aberrant signaling through the fibroblast growth factor 19 (FGF19) - fibroblast growth factor receptor 4 (FGFR4) axis has been implicated in the development of HCC, and recently FGF19 has been determined as a specific driver gene amplification in a subset of liver tumors and cancer cell lines. Here, we describe the cellular and in vivo profile of NVP-FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. NVP-FGF401 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. We show that among the FGF19-amplified liver cancer cells in the cancer cell line encyclopedia (CCLE), only those with concomitant expression of β-klotho (KLB), a co-receptor for FGF19 that facilitates its binding to FGFR4, are sensitive to NVP-FGF401. NVP-FGF401 has good oral PK properties and shows an excellent in vivo PK/PD relationship. NVP-FGF401 has remarkable anti-tumor activity in mice bearing HCC tumor xenografts and PDX models that are positive for FGF19, FGFR4 and KLB. NVP-FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a PhI/II study is currently ongoing in HCC and other types of solid tumors. Citation Format: Andreas Weiss, Diana Graus Porta, Flavia Reimann, Alexandra Buhles, Christelle Stamm, Robin A. Fairhurst, Jacqueline Kinyamu-Akunda, Dario Sterker, Masato Murakami, Markus Wartmann, Youzhen Wang, Jeffrey A. Engelman, Francesco Hofmann, Wiliam R. Sellers. NVP-FGF401: Cellular and in vivo profile of a novel highly potent and selective FGFR4 inhibitor for the treatment of FGF19/FGFR4/KLB+ tumors [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 2103. doi:10.1158/1538-7445.AM2017-2103
Abstract 4061: Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies
Authors: A. Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Jennifer Park, John M. Burke, Joshua Apgar
Journal: Cancer Research (2017)

Abstract The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules. This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. This work employs a computational quantitative systems pharmacology (QSP), or mechabistic PK/PD approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular properties on overall PK and relative payload disposition as observed in preclinical and clinical studies. Our work establishes the benefit of using computational models to design novel ADCs and to optimize the discovery and development of existing ADCs. Citation Format: A. Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, Jennifer Park, John M. Burke, Joshua Apgar. Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies [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 4061. doi:10.1158/1538-7445.AM2017-4061