tbuckley/cabot-search huggingface dataset:
Abstract 1533: Transcriptional inhibition of brachyury in chordoma is associated with adoption of quiescent phenotype
Authors: Ashlee N. Seldomridge, Jinkyu Jung, Heather M. Sonnemann, Amber Giles, Kristan Meetze, Mark R. Gilbert, Claudia M. Palena, Deric M. Park
Journal: Cancer Research (2017)

Abstract BACKGROUND: Brachyury is a mesoderm specification transcription factor involved in notochord development and overexpressed in a variety of cancers, including chordoma. High levels of brachyury protein expression in cancers is associated with a poor prognosis in part due to its role in mediating epithelial-mesenchymal transition (EMT). TG02 is a multikinase inhibitor that targets transcriptional regulation of cyclin-dependent kinases (CDKs). Because chordoma is characterized by a relative paucity of genomic mutations and largely driven by the super-enhancer activity of brachyury expression, we investigated the downstream effect of a transcriptional inhibitor, TG02, in chordomas. METHODS: Established chordoma cell lines, UCH-1 and UM-Chor1, were exposed to increasing concentrations of TG02 to determine effect on brachyury protein expression. qPCR was used to analyze brachyury mRNA expression as well as the mesenchymal proteins, vimentin and fibronectin, typically associated with brachyury expression in tumor cells. Cell migration was evaluated using wound healing assay. CellTiterGlo Luminescence Assay was used to quantify cell viability. RESULTS: TG02 down-regulated protein expression of brachyury in a dose-dependent manner. Attenuation of brachyury expression was seen within 4 hours and persisted for 5 days upon single exposure to a clinically relevant concentration of TG02. Brachyury downregulation did not affect cell count or viability, and was associated with a quiescent phenotype, including impaired migration. Expression of vimentin and fibronectin, both associated with EMT, was also suppressed within 4 hours of TG02 treatment and persisted for 24 hours. CONCLUSIONS: Inhibition of brachyury expression and its downstream signaling is associated with quiescent behavior of chordoma cells. Pharmacologically induced transcriptional targeting of brachyury using TG02, a potent CDK9 inhibitor, represents a potential therapeutic strategy. Citation Format: Ashlee N. Seldomridge, Jinkyu Jung, Heather M. Sonnemann, Amber Giles, Kristan Meetze, Mark R. Gilbert, Claudia M. Palena, Deric M. Park. Transcriptional inhibition of brachyury in chordoma is associated with adoption of quiescent phenotype [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 1533. doi:10.1158/1538-7445.AM2017-1533
Abstract 2662: Statins modulate MMP-9 and beta catenin in epithelial cells
Authors: Nadeem Fazal, Walid Al-Ghoul
Journal: Cancer Research (2017)

Abstract The effect of statins (Simvastatins) mediated mechanisms that affect inflammatory or non-inflammatory pathways causing formation and progression of cancer need to be investigated. Currently, sufficient data are lacking to support the use of statins for the prevention of cancer and further research is clearly warranted. We studied these antineoplastic mechanisms in rodent inflammatory model, which might be instrumental in drug discovery research for the development of future cancer therapeutics. MMP9 is a member of the family of zinc-containing endopeptidases, which degrade various components of the extracellular matrix, thereby regulating matrix remodeling. Since matrix remodeling plays an important role during growth and progression of cancer and considering the fact that, tumor cells switch to aerobic glycolysis as its major energy source, this study was designed to analyze the effect of Statins on MMP9 and epithelial cell integrity at gastrointestinal gut barrier. We used an established model of thermal injury (TI) to study the effects of simvastatins. We found that the percentage of stained MMP-9 in the control tissue and TI+SMV tissue was lower than the percentage in thermal injury tissue (P&amp;lt; 0.05). Moreover, fluorescent stained sections of intestinal epithelial from control, thermal injury and thermal injury+SMV. β-catenin determination was performed with fluorescence microscope. β-catenin levels were significantly (p&amp;lt;0.05) decreased in thermal injury tissue, which was reversed by statins. Our studies conclude that statins have anti-neoplastic effects and affect metallopeptidases, β-catenin and e-cadherins. Note: This abstract was not presented at the meeting. Citation Format: Nadeem Fazal, Walid Al-Ghoul. Statins modulate MMP-9 and beta catenin in epithelial 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 2662. doi:10.1158/1538-7445.AM2017-2662
Abstract B45: An early treatment window to target FAK-dependent collective invasion in Lkb1-mutant lung adenocarcinoma
Authors: Melissa Gilbert-Ross, Jessica Konen, John Shupe, Junghui Koo, Gabriel L. Sica, Suresh S. Ramalingam, Haian Fu, Fadlo R. Khuri, Wei Zhou, Adam I. Marcus
Journal: Cancer Research (2016)

Abstract LKB1 is the 2rd most commonly mutated tumor suppressor gene in human lung adenocarcinoma, and a biomarker of aggressive disease in stage IV KRAS mutant lung cancer patients. We have previously published that LKB1 acts to limit focal adhesion kinase (FAK) activity in human lung cancer cells to restrict cell adhesion and migration. Based on our prior published data we hypothesize that FAK inhibition will suppress invasion and metastasis in LKB1-mutant tumors in vivo , and represent a viable clinical strategy to target this high-risk patient population. To investigate our hypothesis, we have developed a novel lentiviral-Cre KrasG12D; Lkb1fl/fl Rosa-luciferase genetically engineered mouse model (GEMM) (KLLLenti) that develops 100% adenocarcinomas, and produces a bioluminescent output that correlates with tumor burden, tumor grade, and degree of metastatic colonization of the lymph node. We show that stage IV KLLLenti primary tumors have elevated levels of active FAK in a subset of invasive cells that maintain collective contact via E-Cadherin. Importantly, treatment of KLLLenti mice with a pharmacologic FAK inhibitor potently suppresses invasive progression of primary tumors. Moreover, KLLLenti tumors treated at later stages progress to the same degree as vehicle-treated mice. This result suggests a ‘therapeutic window’ of opportunity, and argues that FAK inhibitors should be part of first-line therapy to treat LKB1-mutant lung cancer patients. We further pursue mechanistic studies to investigate how Lkb1-mutant tumor tissue gains a metastastic advantage in vivo, and using a combination of 3D tumor spheroid assays and multiphoton microscopy present results that Lkb1-mutant tumors use a unique form of hybrid or transitional invasion that on depends on both FAK-based adhesion and collective migration and in doing so, are equipped to more efficiently invade into the collagen-dense microenvironment of the lung. Our studies suggest that when used early, FAK inhibitors may be a viable clinical strategy to prevent metastasis in the LKB1-mutant patient population, and begin to define alternate escape pathways by which this highly invasive cell population may escape first-line therapy. Citation Format: Melissa Gilbert-Ross, Jessica Konen, John Shupe, Junghui Koo, Gabriel L. Sica, Suresh S. Ramalingam, Haian Fu, Fadlo R. Khuri, Wei Zhou, Adam I. Marcus. An early treatment window to target FAK-dependent collective invasion in Lkb1-mutant lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B45.
Abstract 3578: Methyl2Acetyl: predicting epigenetic and transcriptomic activity from DNA methylation
Authors: Xiang Chen
Journal: Cancer Research (2017)

Abstract DNA methylation and histone modifications are interconnected and interdependent epigenetic mechanisms that regulate chromatin accessibility in cells. They establish cell’s developmental identity and modulate individual response to endogenous developmental stimuli and environmental changes. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is a popular assay to study genomewide histone modification profiles. However, ChIP-seq assays require relatively large amounts of starting materials (ranging from ~105 cells using a low cell number protocol to 107 cells in a standard protocol), which remains as a major obstacle for precious biological samples including primary tumor specimens. On the other hand, tagmentation-based whole genome bisulfite sequencing (TWGBS) protocol enables unbiased assessment of the genomewide methylation pattern using ~3,000 cells. Therefore, a quantitative relationship between DNA methylation and epigenetic/transcriptomic activity is in great demand. In the current study, we developed Methyl2Acetyl, a machine learning framework to infer promoter epigenetic activities (e.g. H3K27Ac enrichment) using TWGBS data as input. The proposed model utilizes random forest learners, which allow automatic extraction of complex interactions among DNA methylation features surrounding transcription start sites. We applied Methyl2Acetyl to a set of pediatric solid tumor samples with high quality H3K27Ac ChIPseq data to evaluate its performance. The model accurately predicted promoter H3K27Ac enrichment in independent test samples (Pearson correlation against measured enrichment: 0.81 ± 0.02). To further test the robustness of our model, we trained a Methyl2Acetyl model on solid tumors and applied it to a set of 10 pediatric leukemia samples. Despite dramatic global methylome differences between solid tumors and leukemia, Methyl2Acetyl predicted promoter H3K27Ac enrichment showed strong concordance with target gene expression level in the same sample (Pearson correlation: 0.75 ± 0.02, classification AUC: 0.89 ± 0.01). Collectively, our data suggested that DNA methylation is predictive of promoter active histone modification enrichment and gene expression activity. Epigenetically active promoters can be imputed from TWGBS data in samples with limiting starting materials. Citation Format: Xiang Chen. Methyl2Acetyl: predicting epigenetic and transcriptomic activity from DNA methylation [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 3578. doi:10.1158/1538-7445.AM2017-3578
Abstract 3871: Modeling the chromatin and transcriptional landscape of MYC and MYCN driven neuroblastoma in zebrafish
Authors: Mark W. Zimmerman, Shuning He, Shizhen Zhu, Song Yang, Yi Zhou, Leonard I. Zon, A Thomas Look
Journal: Cancer Research (2017)

Abstract Elevated expression levels of MYC family genes are frequently observed in human cancer cells and correlate with tumor aggressiveness and poor prognosis. In neuroblastoma 40% of all cases are high-risk, of which 20% harbor amplification of the MYCN proto-oncogene. In high-risk cases lacking MYCN gene amplification, high expression levels of c-MYC (MYC) are often present and are associated with unfavorable histology and a poor survival. Unlike MYCN amplification, which is frequently observed in the presence of segmental chromosomal aberrations, MYC overexpression is not associated with genetic abnormalities or somatic mutations. In order to study this newly defined subgroup, we have created a novel transgenic zebrafish model in which overexpression of MYC alone in the peripheral sympathetic nervous system (PSNS) drives early-onset neuroblastoma in nearly every fish by seven weeks of age. The tumors resulting from MYC overexpression arise in the interrenal gland, which is the fish counterpart of the adrenal medulla, and are histologically identical to human neuroblastoma. We next performed the Assay for Transposase Accessible Chromatin (ATAC) sequencing and RNA-seq to identify open chromatin regions that correlate with activation of gene transcription. Lineage specific genes essential for neuronal precursor cell identity, such as PHOX2B, HAND2, and TFAP2A are highly expressed in both MYC-expressing and MYCN-amplified human neuroblastoma cell lines and are actively transcribed in zebrafish models of MYC and MYCN driven neuroblastoma. Furthermore, these studies reveal shared and differential regulatory of effects of MYC relative to MYCN activity in maintaining the malignant phenotype of neuroblastoma in vivo. Additional insight into the mechanisms of aberrant transcriptional regulation will inform the future design and use of therapeutic strategies targeting transcription in this high-risk malignancy of childhood. Citation Format: Mark W. Zimmerman, Shuning He, Shizhen Zhu, Song Yang, Yi Zhou, Leonard I. Zon, A Thomas Look. Modeling the chromatin and transcriptional landscape of MYC and MYCN driven neuroblastoma in zebrafish [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 3871. doi:10.1158/1538-7445.AM2017-3871
Abstract 5763: Investigating the carcinogenic potential of various types of mineral fibers in the development of mesothelioma
Authors: David Larson, Mika Tanji, Andrea Napolitano, Sandra Pastorino, Michele Carbone, Haining Yang
Journal: Cancer Research (2017)

Abstract Malignant mesothelioma is a very aggressive tumor and has been linked to occupational and environmental exposure to carcinogenic mineral fibers such as asbestos. It was discovered recently that individuals carrying germline BAP1 mutations are predisposed to mesothelioma in presence of even minimal exposure to carcinogenic mineral fibers. Mesothelioma causes about 3,200 deaths per year in the U.S. and over 40,000 deaths per year worldwide. Most malignant mesothelioma studies have focused on carcinogenesis due to occupational exposure to the six regulated industrial mineral fibers collectively called ‘asbestos’. Besides this family of six regulated asbestos minerals, there are other non-regulated fibers that possess physical and chemical structures that are similar to industrial asbestos, and may also be carcinogenic. However, many of those mineral fibers are unknown for their carcinogenesis. We conducted serious studies on this topic and established in vitro and in vivo assays to help determine the carcinogenesis of various types of mineral fibers. We found that high mobility box 1 protein (HMGB1) is a key initiator of asbestos-induced inflammation, which plays critical roles in the development and growth of mesothelioma, and that HMGB1 may be a good indicator for fiber carcinogenesis and a biomarker for fibers exposure. Moreover, we found that specific immune system changes that occur after exposure to carcinogenic fibers, which may be a useful tool to help interrogate the carcinogenic potential of mineral fibers. In particular, the ability to induce an M2 macrophage response appears related to the potent tumor-inducing capacity of carcinogenic mineral fibers. Citation Format: David Larson, Mika Tanji, Andrea Napolitano, Sandra Pastorino, Michele Carbone, Haining Yang. Investigating the carcinogenic potential of various types of mineral fibers in the development of mesothelioma [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 5763. doi:10.1158/1538-7445.AM2017-5763
Abstract 334: PTEN-L regulates epithelial growth and macrophage function
Authors: Andrew L. Wolfe, Benjamin D. Hopkins, Sebastián A. Riquelme, Kipyegon Kitur, Sait Ozturk, Kyeongah Kang, Romain Remark, Adeeb Rahman, Chyuan-Sheng Lin, Miriam Merad, Matthias Szabolcs, Shu-Hsia Chen, Alice Prince, Ramon Parsons
Journal: Cancer Research (2017)

Abstract PTEN is among the most frequently mutated and deleted tumor suppressor genes in many malignancies, including breast cancer. An alternatively translated long form of PTEN, termed PTEN-L, has divergent functionality from PTEN, although its function at the organism level has not been studied. Here, we report a knockout mouse with specific ablation of PTEN-L expression but intact expression of PTEN. These mice display mammary ductal hyperplasia characterized by increased luminal growth and increased numbers of macrophages in the surrounding stroma. Macrophages are particularly affected by PTEN-L loss, with significant changes to their secretomes and functional deficiencies in clearing bacterial infections, consistent with a shift toward an M2-like polarization. Overall, these findings demonstrate that PTEN-L has unique functions in regulating mammary epithelial growth and macrophage functionality that are independent of canonical PTEN. Citation Format: Andrew L. Wolfe, Benjamin D. Hopkins, Sebastián A. Riquelme, Kipyegon Kitur, Sait Ozturk, Kyeongah Kang, Romain Remark, Adeeb Rahman, Chyuan-Sheng Lin, Miriam Merad, Matthias Szabolcs, Shu-Hsia Chen, Alice Prince, Ramon Parsons. PTEN-L regulates epithelial growth and macrophage function [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 334. doi:10.1158/1538-7445.AM2017-334
Abstract 164: Enhanced antitumor efficacy by recruiting macrophages as effector cells via bispecific antibodies mediated by CD89
Authors: Bingyu Li, Lijun Xu, Kun Xie, Fei Tao, Renhao Li, Hua Gu, Jianmin Fang
Journal: Cancer Research (2017)

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC) is one of key mechanisms through which antibody therapeutics can lyse tumor target cells. ADCC is usually mediated by IgG through recruiting effector cells, mostly NK cells, via IgG Fc receptor. In order to enhance specific tumor lysis by ADCC, a common strategy is to design a bispecific antibody that binds a tumor cell surface antigen and T cell marker CD3, thus to recruit T cells as effector cells. An example of this type of design is the FDA-approved bispecific antibody blinatumomab. We are interested in designing novel bispecific strategies to achieve improved ADCC effect. Since tumors are often infiltrated by macrophages and neutrophils, it would be advantageous to turn these types of cells into effector cells for ADCC. We have designed several bispecific strategies that can target a tumor associated antigen (TAA) and CD89 (FcαRI). The aim is to lyse tumors through connecting tumor cells to CD89-expressing immune effector cells, such as macrophages and neutrophils. The CD89 bispecific antibodies were produced by HEK293 cells and showed binding activities to both CD89 and TAA. The CD89 bispecific antibodies can recruit CD89-expressing immune cells and induced enhanced tumor cells-killing in human whole blood ADCC assays. Since mouse does not express human CD89 homologue, we generated a transgenic mouse strain with specific expression of CD89 on macrophages and monocytes. In this transgenic mouse model, the CD89 bispecific antibodies showed significant anti-tumor activities, demonstrating that the bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector function in tumor microenvironment. Citation Format: Bingyu Li, Lijun Xu, Kun Xie, Fei Tao, Renhao Li, Hua Gu, Jianmin Fang. Enhanced antitumor efficacy by recruiting macrophages as effector cells via bispecific antibodies mediated by CD89 [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 164. doi:10.1158/1538-7445.AM2017-164
Abstract 566: A pathway based drug selection for cancer precision medicine
Authors: Varshini Vasudevaraja, Lijun Cheng, Sai Mounika Inavolu, Milan Radovich
Journal: Cancer Research (2017)

Abstract Background and Purpose: Precision medicine tailors the right therapy to the right patient based on his/her tumor molecular profiles. In clinic and ongoing clinical trials, drug-targeted selection schemes depends more or less on drug targets’ mutations or expression status. However, there is a lack of systematic pathway based method to connect individual genomics information with properly drug target and treatment in precision medicine. The paper aims to integrate various knowledge-bases, including cancer drugs, drug-targets and gene-gene regulatory pathway, to construct a drug target and properly drug selection algorithm for individual patient in precision medicine. Materials and Methods: In the drug selection algorithm, drug targets and properly drugs recommendation are based on the patient specific molecular profile data, including copy number variation, mutation, and gene expression. Our target and drug selections are based on whether these drug targets act as hub genes that either regulate or control the signaling pathways for many other genes in the biological pathways. Only those patients whose molecular profiles do not show targets, the usual chemotherapy treatment will be recommended. This novel algorithm is applied to individual Pancreatic Adenocarcinoma (PAAD) for drug target and drug selection. All of patients’ genomic data obtained from the Cancer Genome Atlas (TCGA). The pathway information is from Pathway Commons and FDA approved cancer drugs and their targets is from DrugBank. The Cancer Cell Line Encyclopedia (CCLE) 46 pancreases cancer cell line are used to validate the algorithm result reliability. Results: Our algorithm identifies targets, such as ERBB2, CDK2, SRC, CDK9, SMAD2, CDK4, HDAC1, PPP1CA, AKR1B1, EGFR, IGF1R, AKT and MEK, for pancreatic adenocarcinoma cancer patients. In which, they cover the clinic first line effective drug targets, such as Gemcitabine for the Akt-mTOR signaling pathway (AKT) and CDK4/6 inhibitor and Erlotinib for HER2 Kinase Family (ERBB2, EGFR) activation inhibitor. In addition, new inhibitors include Src inhibitors (dasatinib, saracatinib and bosutinib), TGF beta inhibitor for target SMAD2 (galunisertib) and IGF-1R/insulin receptor inhibitors (ceritinib, brigatinib) are recommended accordingly and validated in pancreatic cancer cells. Conclusion: This novel algorithm might act as a better source for off-label drug selection and further cell line validations may help in providing a better treatment strategy in precision medicine. Note: This abstract was not presented at the meeting. Citation Format: Varshini Vasudevaraja, Lijun Cheng, Sai Mounika Inavolu, Milan Radovich. A pathway based drug selection for cancer precision medicine [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 566. doi:10.1158/1538-7445.AM2017-566