bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 343: A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages
Authors: Chen Hung-Kai , Hsiao Huey-Wen , Lu Li-Ming , Hsiao Chih-Lun , Wang Yin-Ping , Huang Jing-Yi , Liao Chu-Bin , Peng Shao-Zheng , Shih Daw-Tsun 
Published: August 2019

Abstract
We have found that tumor-associated macrophages (TAMs) isolated from metastatic tumors displayed a predominant M2 phenotype. Preclinical studies show that M2-polarized TAMs forge an immunosuppressive microenvironment at metastatic niches to facilitate colonization. Colony-stimulating factor 1 receptor (CSF-1R) signaling is known to regulate the survival and maintenance of M2 TAMs, suggesting targeting CSF-1R might have therapeutic potential in halting cancer progression. To this end, we developed an orally active and selective small-molecule CSF-1R inhibitor EI-1071.
Experimental procedures: EI-1071 was evaluated in kinase and cell-based bioassays, including macrophage proliferation and osteoclast differentiation. In vivo activity was verified using murine syngeneic models of colorectal cancer and breast cancer. EI-1071 was administered individually or in combination with an anti-PD1 antibody. Tumor infiltrating leucocytes were profiled using flow cytometric analysis.
Results: EI-1071 exhibited nanomolar potency for inhibition of CSF-1R but not other 453 kinases tested. In cell-based bioassays, EI-1071 inhibited CSF-1R activity in human monocytes/macrophages, AML-5 leukemia, MNFS-60 leukemia, and human osteoclasts. In preclinical studies, EI-1071 displayed a favorable ADME properties, including hepatocyte stability, high Caco-2 permeability, and pharmacokinetic profiles. Oral administration of EI-1071 reduced TAM infiltration in the MC38 colorectal cancer and EMT6 breast cancer models. Moreover, EI-1071 dosed with an anti-PD-1 antibody showed further enhanced antitumor activity in vivo .
Conclusions: Preclinical characterization of EI-1071 demonstrated that it is a potent and selective CSF-1R inhibitor and has a favorable drug like properties for further clinical evaluation. Therefore, EI-1071 is undergoing IND-enabling activities for the First-In-Human (FIH) Phase 1 study.
Citation Format: Hung-Kai Chen, Huey-Wen Hsiao, Li-Ming Lu, Chih-Lun Hsiao, Yin-Ping Wang, Jing-Yi Huang, Chu-Bin Liao, Shao-Zheng Peng, Daw-Tsun Shih. A potent and selective cfms inhibitor EI-1071 inhibits CSF1R signaling and regulates the tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 343.
Abstract 3430: TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling
Authors: Nyati Shyam , Gregg Brandon , Xu Jiaqi , Young Grant , Kimmel Lauren , Mukesh Nyati , Ray Dipankar , Yu Hongtao , Rehemtulla Alnawaz 
Published: August 2019

Abstract
The Ser/Thr kinase BUB1 (budding uninhibited by benzimidazoles-1) is required for efficient signaling by the TGF-β receptor. Recruitment of BUB1 to the activated heteromeric TGF-β-receptor complex including SMAD2 and SMAD3, is required for ligand mediated canonical and non-canonical downstream cascades (Nyati et. al. 2015). In an effort to delineate the structure-function basis for this, we utilized in vitro kinase reactions followed by mass spectrometry to demonstrate that TGFBR2 phosphorylates BUB1 at Serine 318. To elucidate the functional significance of TGFBR2 mediated phosphorylation of BUB1, S318 was substituted with alanine (S318A) or aspartic acid (S318D). Co-immunoprecipitation studies of these phospho-deficient or phospho-mimicking BUB1 mutants with TGFBR1, and SMAD2 revealed that the S318A mutant interacted more efficiently to TGFBR1 and SMAD2 compared to the S318D BUB1. To investigate if the Ser318 residue was involved in mediating BUB1 interaction with TGF-β signaling components, we utilized deletion mutants of BUB1. Our findings reveal that the N-terminal (1-241) and C-terminal (482-723) domains of BUB1 independently interact with SMAD2, SMAD3, TGFBR1, or TGFBR2. The middle domain (241-482) having a S318A mutation interacted efficiently with TGFBR2 while the S318D mutant did not. Additionally, the 241-482 S318D mutant exhibited an increased interaction with SMAD2. Over-expression of 241-482 S318D resulted in a decrease in TGFBR1-TGFBR2 interaction as well as TGFBR1-SMAD2 interaction, suggesting that TGFBR2 mediated BUB1 phosphorylation at S318 maybe the trigger for the dissociation of the activated receptor complex, and therefore a key regulator of TGF-β signaling. Taken together, we show that TGFBR2 phosphorylates BUB1 at Ser318 and propose a model with the following steps: (i) BUB1 is recruited to TGFBR1-TGFBR2 complex in response to ligand, (ii) BUB1 participates in the recruitment of SMAD2/3 to the receptor, (iii) TGFBR2 phosphorylates BUB1 at S318, which triggers the disassembly of the activated complex.
Citation Format: Shyam Nyati, Brandon Gregg, Jiaqi Xu, Grant Young, Lauren Kimmel, Nyati Mukesh, Dipankar Ray, Hongtao Yu, Alnawaz Rehemtulla. TGFBR2 mediated phosphorylation of BUB1 at Ser-318 is required for transforming growth factor-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3430.
Abstract 3433: IL11 promotes the PhIP/DSS-induced colon carcinogenesis
Authors: Wang Hong , Wang David , Sun Yuhai , Yang Xu , Yang Chung S. 
Published: August 2019

Abstract
Inflammation of the large intestine, such as colitis, is known to increase the risk of colorectal cancer in human. The colitis induced by dextran sodium sulfite (DSS) has been shown to promote carcinogen- and genetic-induced colon tumorigenesis in rodent models. In a CYP1A-humanized (hCYP1A) mouse colon cancer model that we developed to study dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), DSS-induced colitis was required for colon tumor development after the PhIP treatment. Nevertheless, the mechanism for DSS-induced colitis to promote carcinogenesis is not clear. To uncover the key cancer promotion factor induced by colitis is important in understanding the mechanism of colon cancer development. By investigating the gene expression profiles of PhIP/DSS-induced colon tumors and normal colon epithelium, we found that cytokine IL11 was significantly upregulated in all tumors. The elevated levels of IL11 are also found in the human colon cancer genomic data available in The Cancer Genome Atlas (TCGA), suggesting an important role of IL11 in human colon cancer. Consistently, the activation/phosphorylation of STAT3, a key downstream factor of IL11 signaling, was also positively identified in tumors but not the normal adjacent tissues. To investigate the role of IL11 signaling, we generated hCYP1A:IL11Rα1-/- mice for investigating the role of IL11 signaling in PhIP/DSS-induced carcinogenesis by crossing the IL11Rα1-/- mice with hCYP1A mice. These mice are infertile as the phenotype reported previously for the IL11Rα1 knockout mice, and need to be maintained through the breeding by the heterozygous. The experimental mice were maintained on the AIN93M diet. We found that the tumor incidence was reduced by 51.0% in hCYP1A:IL11Rα1+/- mice and 80.0% in hCYP1A:IL11Rα1-/- mice, suggesting that IL11 signaling plays critical roles in PhIP/DSS-induced colon carcinogenesis. By immunohistochemical staining for pSTAT3, we found the pSTAT3 staining in the colitis epithelial tissues induced by the DSS treatment in both heterozygous and homozygous mice were significantly reduced; whereas the tissues from the wildtype mice displayed strong positive staining in the nucleus. IL11 signaling could be a potential therapeutic target for colon cancer prevention. (supported by the John L. Colaizzi Chair Endowment Fund and GI Pilot Study from Rutgers Cancer Institute of New Jersey Cancer Center Support Grant P30CA072720)
Citation Format: Hong Wang, David Wang, Yuhai Sun, Xu Yang, Chung S. Yang. IL11 promotes the PhIP/DSS-induced colon carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3433.
Abstract 3434: Selective inhibition of mTORC2 by disruption of mLST8 scaffolding function
Authors: Kim Laura C. , Hwang Yoonha , Song Wenqiang , Cook Rebecca S. , Chen Jin 
Published: August 2019

Abstract
Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. We assessed mLST8 loss in a panel of normal and cancer cells, finding little to no impact on mTORC1 activity, nor on assembly of mTOR with the mTORC1 co-factor Raptor. However, mLST8 loss blocked mTOR association with the mTORC2 co-factors Rictor and Sin1, and impaired mTORC2 kinase activity, including its phosphorylation of AKT at S473. We identified two sites within mLST8 governing its interaction with mTOR, finding that simultaneous mutation of these sites together, but not individually, disrupted not only mTOR-mLST8 interactions, but also blocked mTOR assembly with Rictor and Sin1, thus disrupting mTORC2 activity. Similary, a single mutation on mLST8 with a corresponding mutation on mTOR interfered with mTORC2 assembly, without affecting mTORC1 assembly or activity. We further discovered a direct interaction between mLST8 and the NH2-terminal domain of the mTORC2 cofactor Sin1. Using PTEN-null prostate cancer xenografts, we found that mLST8 mutations disrupting the mTOR interaction motif inhibited AKT S473 phosphorylation, decreased tumor cell proliferation, and increased tumor cell death in vivo. Together, these data suggest that the scaffolding function of mLST8 is critical for assembly and activity of mTORC2, but not mTORC1, an observation which could enable therapeutic mTORC2-selective inhibition, while sparing the activity of mTORC1.
Citation Format: Laura C. Kim, Yoonha Hwang, Wenqiang Song, Rebecca S. Cook, Jin Chen. Selective inhibition of mTORC2 by disruption of mLST8 scaffolding function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3434.
Abstract 3438: PI3Kα/δ inhibitor, copanlisib is highly effective in ER-positive breast cancer
Authors: De Pradip , Aske Jennifer C. , Williams Casey , Dey Nandini , Leyland-Jones Brian 
Published: August 2019

Abstract
Purpose: Over 60% of ER+ breast cancer (BC) cases are associated with activation of the PI3K-AKT-mTORC1/C2 pathway. PIK3CA, the catalytic subunit of PI3K, is by far the most frequently mutated gene in luminal ER+ BC patients. It has long been known that hormone receptor and oncogene cooperation plays a key role in driving tumor development and that most hormone therapy-resistant BC depends on the PI3K pathway. Here, we present the results of a preclinical study of the PI3K α/δ (dominant) inhibitor copanlisib alone and in combination with letrozole in ER+ BC cell lines.
Method: Anti-proliferative, apoptotic, cell cycle, and intracellular signaling effects of copanlisib alone and in combination with letrozole were evaluated in a panel of ER +/PIK3CA mutated, and ER+/PTEN mutated breast cancer cell lines.
Results: 1) Copanlisib inhibited PI3K, mTOR and their downstream signaling molecules in ER+/PIK3CA or ER+/PTEN mutated BC cell lines; 2) interestingly, copanlisib also inhibited RAS-MAPK signaling in the earlier time points in ER+/PIK3CA mutated cells (T47D & MCF7) but not in ER+/PTEN mutated cells (CAMA1); 3) copanlisib caused a strong differential growth inhibition in ER+ BC cell lines as shown by 3D-ON-TOP clonogenic assay and real-time monitoring in an IncuCyte Zoom. Inhibition was greater when copanlisib was combined with letrozole; 4) administration of copanlisib induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependent manner; 5) unlike everolimus, copanlisib blocked HIF1α accumulation in hypoxic conditions and this blocking effect was reversed by prior treatment with the proteasome inhibitor carfilzomib, suggesting copalnisib enhanced proteasome-mediated HIF1α degradation; and 6) copanlisib also attenuated ER+ cell migration, an important phenotypic feature for metastasis, along with integrin-mediated RAC1 activation.
Conclusions: Copanlisib is highly effective (blocks proliferation, induces apoptosis, and inhibits PI3K and its downstream signaling targets) in ER+ BC cell lines (both PIK3CA and PTEN mutated). The addition of copanlisib to aromatase inhibitor might represent an improved treatment strategy for patients with hormone-resistant/relapse ER+ BC.
Citation Format: Pradip De, Jennifer C. Aske, Casey Williams, Nandini Dey, Brian Leyland-Jones. PI3Kα/δ inhibitor, copanlisib is highly effective in ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3438.
Abstract 3441: A RPL39-SGK3 signaling pathway that may play a key role in breast cancer therapy resistance
Authors: Liu Dan , Dave Bhuvanesh 
Published: August 2019

Abstract
Breast cancer is the most common cancer in the United States, where 1 in 8 women are affected by it during their lifetime. In 2018, an estimated 266,120 new cases of invasive breast cancer are expected to be diagnosed in women in the U.S., along with 63,960 new cases of non-invasive (in situ) breast cancer. In order to identify novel targets and better understand the mechanism of survival of these cancers, we describe the mechanism of action of ribosomal protein like 39 (RPL39) as one potentially useful target for therapy resistance. RPL39 is over-expressed in breast cancer and regulated by nitric oxide signaling (NOS). In the present study we examine the detailed mechanism of action of RPL39 as it relates to treatment-resistant breast cancers and the role of SGK3 in modulating its signal transduction pathway. Methods and Results: Mass spectrometric analysis following immunoprecipitation of RPL39, in two breast cancer cell lines SUM159 and MDAMB231, indicated that proteins involved in translation, specifically the mTOR-dependent translational pathway, were part of the complex. In order to verify that the results we observed were due to targeting of the translational arm of mTOR signaling, we knocked down both the 4EBP-1 (translation) and S6K (cell size) arms of the mTOR pathway in three breast cancer cell lines (SUM159, MDAMB231 and MDAMB436). Analysis of these pathways by proliferation, apoptosis, sphere formation and western blotting in all three breast cancer cell lines demonstrated that the translation arm was significantly altered: self-renewal (p&lt;0.05, Student's t test) and proliferation (p&lt;0.05, student's t test) in a NOS signaling dependent manner. Additional bioinformatic analysis determined a potential role for SGK3 upstream of RPL39. SGK3 is an AGC kinase family member that is over-expressed in ER+ breast cancers. It functions downstream of PI 3-kinase and can activate the mTOR pathway. Conclusion: RPL39 gene may be modulated by the selective translational initiation complex which affects self-renewal and proliferation through SGK3 and NOS signaling. The significance of targeting SGK3 and RPL39 pathway allows a potentially novel therapeutic strategy for the treatment of breast cancer.
Citation Format: Dan Liu, Bhuvanesh Dave. A RPL39-SGK3 signaling pathway that may play a key role in breast cancer therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3441.
Abstract 3451: Interpreting gene lists from -omics experiments
Authors: Luna Augustin , Wong Jeffrey V. , Demir Emek , Rodchenkov Igor , Babur Özgün , Sander Chris , Bader Gary D. 
Published: August 2019

Abstract
Understanding the mechanisms responsible for a cellular behavior often begins with observations of genes and gene products. Depending on the type of experiment, the number of resulting genes can be small, but increasingly, researchers are faced with many thousands of measurements, as in the case of transcriptomic or protein-DNA binding observations. Here, we describe ways to pair experimental results consisting of one or more genes with analysis tools with the overall aim being to make results more biologically interpretable. In certain cases, experimental approaches such as screens for essential genes can generate one or a few ‘genes of interest’ and there is a desire to understand their relationship to one another as well as discover links to additional, interesting genes. To this end, ‘GeneMANIA’ is a web tool that accepts gene names and returns a network visualization of related genes based on similarity in expression, localization, protein domains and those involved in physical interactions. Likewise, ‘PCViz’ is a web tool that displays a network of interactions drawn from Pathway Commons, a web resource for pathway and interaction knowledge. In cases where experiments generate a lengthy list of genes, for instance, transcriptomic measurements, there is a desire to understand their relevance to a phenotype of interest. Pathway enrichment analysis methods aim to summarize gene lists as pathways, which have a closer link to cell function. An online ‘Guide’ by Pathway Commons includes workflows that illustrate how to chain together software tools to identify pathways from the corresponding gene-level data then organize and summarize the pathway-level results in an interactive visualization known as an Enrichment Map. For those wishing to drill-down to individual pathways, Pathway Commons offers a set of web apps, including ‘Search’ that enables users to query by keyword and visualize ranked search results. Ongoing development of web apps aims to enhance the accessibility to pathways and integrate support for analysis and visualization of experimental data. The full complement of data, tools and resources offered by Pathway Commons in support of pathway analysis are described.
Citation Format: Augustin Luna, Jeffrey V. Wong, Emek Demir, Igor Rodchenkov, Özgün Babur, Chris Sander, Gary D. Bader. Interpreting gene lists from -omics experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3451.
Abstract 3452: hnRNPUL1 regulation by ATR in DNA damage response
Authors: Zhang Hui , Head PamelaSara E. , Duong Duc M. , Seyfried Nicholas T. , Yu David S. 
Published: August 2019

Abstract
The DNA damage response (DDR) is a signaling network that recognizes damages to DNA and orchestrates a variety of DNA repair and cell cycle checkpoint pathways. The DDR is pivotal for cancer prevention. Ataxia Telangiectasia And Rad3-Related Protein (ATR), a protein kinase, functions as an essential transducer of the DDR signaling cascade. ATR primarily responds to single-stranded DNA (ssDNA) generated from double-strand break resection or at stalled replication forks. Depletion of ATR leads to cellular senescence and cancer related phenotypes. The mechanisms regarding how the ATR signal pathway is regulated, however, remain elusive. To discover novel DDR proteins regulated by ATR, we performed proteomic analysis to identify proteins that partner with ATR in response to DNA damage in cells. Our analysis revealed a network of proteins as potential ATR substrates, including Heterogeneous nuclear ribonucleoprotein U-like 1 (hnRPUL1), a protein functions in RNA metabolism. We validated that ATR interacts with hnRNPUL1. In addition, hnRPUL1 is phosphorylated on SQ/TQ sites in response to IR. ATR depletion suppresses the IR induced hnRPUL1 phosphorylation. Our results identify hnRNPUL1 as a novel ATR substrate, critical for the DNA damage response and provide insight into how DDR and RNA metabolism might work synergically in maintaining genomic stability and preventing cancer. Additionally, hnRNPUL1 phosphorylation by ATR may be targeted as an adjunct to improve the efficacy of ionizing radiation for cancer therapy.
Citation Format: Hui Zhang, PamelaSara E. Head, Duc M. Duong, Nicholas T. Seyfried, David S. Yu. hnRNPUL1 regulation by ATR in DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3452.
Abstract 3460: MPRIP-ALK,a novel ALK rearrangement that responds to ALK inhibitor in non-small-cell lung cancer
Authors: Fang Wenfeng , Gan Jiadi , Lu Feng , Deng Yangyang , Chen Liang , Yang Yunpeng , Zhang Li 
Published: August 2019

Abstract
Oncogenic rearrangements of the anaplastic lymphoma receptor tyrosine kinase (ALK gene) have recently been described in 3% to 5% of lung adenocarcinomas. Kinds of fusion partners of ALK have been reported in non-small-cell lung cancer (NSCLC), with echinoderm microtubule-associated protein-like 4 (EML4)-ALKbeing the most prevalent one. Several tyrosine kinase inhibitors have been approved for treating patients with advanced-stage ALK-positive, NSCLC by Food and Drugs Administration (FDA).
Comprehensive genomic profiling performed by means of next-generation sequencing assay demonstrated a novel myosin phosphatase-Rho-interacting protein gene (MPRIP)-ALK fusion in our case, in which a translocation involving chromosomes 2 and 9 has taken place. The rearrangement was verified by reverse transcription reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing. ALK immunohistochemistry demonstrated strong staining in patient’s tumor sample as extracted from formalin-fixed paraffin-embedded (FFPE) sections.
We expressed MPRIP-ALK cDNA construct in non-cancer cell line Ba/F3 which showed IL-3-independent growth compared the growth stop of cells carrying empty vector, moreover, hyper-activation of the protein ALK, ERK, AKT were detected in Ba/F3 cells with MPRIP-ALK over-expressed. Furthermore, the colonies and activations of ALK downstream signaling pathways could be inhibited by crizotinib. The patient received standard chemotherapy on the first-line. She experienced progressive disease after 7 months, and commenced on crizotinib (250mg, twice per day) from March 2018. The patient showed significant improvement in cough, dorsalgia, and polypnea within one week. Partial response was gained after one month treatment and confirmed at the third month. She still remains on the crizotinib treatment without disease relapse up to now. In this study, we report a novel ALK rearrangement in a patient with NSCLC by RNA-seq. Our in vivo and in vitro studies have shown that the novel MPRIP-ALK fusion is a driver gene and can be targetable by crizotinib.
Citation Format: Wenfeng Fang, Jiadi Gan, Feng Lu, Yangyang Deng, Liang Chen, Yunpeng Yang, Li Zhang. MPRIP-ALK,a novel ALK rearrangement that responds to ALK inhibitor in non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3460.