bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5385: A novel cell-based kinase assay panel paired with high content phenotypic profiling to correlate kinase inhibitor specificity and cellular activity
Authors: Wehrman Tom S. , O'Donnell Erika A. , Lumpe M. Jared , Osetek Benjamin E. , Krutzik Peter O. 
Published: May 2015

Abstract
In many cancers, drugs that target a single kinase often lack efficacy due to the presence of alternate oncogenic signaling pathways that may compensate for the inhibition of the targeted kinase. Although completely non-selective kinase inhibitors are highly toxic, selective and simultaneous inhibition of a number of kinases can lead to greater responses. Here we describe the development of a multiplexed cellular kinase assay platform in which compounds are simultaneously profiled against more than 12 kinase targets in a single sample. Using this high-throughput platform, target activity and selectivity in cells can be optimized concurrently, enabling the selection of specific multi-targeted compounds. Using this platform, 300 kinase inhibitors were fully characterized for cellular activity and potency across a large panel of tyrosine kinases. These inhibitors were then tested across a panel of diverse cancer cell lines in a phenotypic screen for their ability to affect viability, cell cycle, and apoptosis under different growth conditions. The resulting comprehensive data set of existing in vitro data, cellular kinase data, and phenotypic screening results provided novel insights into the relationship between inhibitor selectivity, cell cycle effects, and the correlation to anti-cancer activity.
Citation Format: Tom S. Wehrman, Erika A. O'Donnell, M. Jared Lumpe, Benjamin E. Osetek, Peter O. Krutzik. A novel cell-based kinase assay panel paired with high content phenotypic profiling to correlate kinase inhibitor specificity and cellular activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5385. doi:10.1158/1538-7445.AM2014-5385
Abstract 5392: High-throughput screening of compounds for targeting system Xc(-) in human breast cancer cells
Authors: Lin Han-xin , Fazzari Jennifer , Linher-Melville Katja , Singh Gurmit 
Published: May 2015

Abstract
Breast cancer cells often metastasize to bone, causing severe and untreatable pain, which greatly compromises the quality of life of patients. We discovered that breast cancer cells secrete large amounts of glutamate via an amino acid antiporter Xc(-). Glutamate is an important neurotransmitter that has been associated with pain and it is also critical in bone metabolic remodeling. Excessive glutamate secreted by invading breast cancer cells can cause excitotoxic injury to bone neurons, disturb bone homeostasis, and activate or sensitize nociceptors, thereby causing acute and chronic pain. Another important activity of system Xc(-) is the import of cystine into cells, which is critical for antioxidant defence mechanism in cancer cells. These make system Xc(-) a potential target to overcome breast cancer induced-pain and sensitize cancer cells to oxidative damage.
A cell-based Amplex red glutamate assay was optimized and miniaturized to be compatible with high throughput screening (HTS) setting. The library for screening is the Canadian Compound Collection containing ∼30,000 compounds. We utilized the blockade of glutamate release to identify potential compounds.
We identified 320 compounds that effectively inhibit glutamate release of human breast cancer cell MDA-MB-231. However on closer scrutiny and stringent conditions we narrowed our potential compounds to 8 for further characterization. These compounds were tested in vitro for cytotoxicity and dose response effects on glutamate release.
In conclusion we have identified several lead compounds for in vivo pain monitoring tests. Information obtained from this study will not only advance our understanding of the role of system Xc(-) in breast cancer cells, but also help design novel drugs for blocking breast cancer induced-bone pain, thereby improving the quality of life for breast cancer patients.
(This project was supported by Canadian Breast Cancer Foundation-Ontario)
Citation Format: Han-xin Lin, Jennifer Fazzari, Katja Linher-Melville, Gurmit Singh. High-throughput screening of compounds for targeting system Xc(-) in human breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2014-5392
Abstract 5405: Self-emulsifying nanoemulsions target intracranial glioblastoma tumors: In vivo optical imaging and fluorescence microscopy evidences
Authors: Liu Xinli , Qhattal Hussaini Syed Sha , Hye Tanvirul 
Published: May 2015

Abstract
Introduction: As the most aggressive form of brain tumor, glioblastoma has limited treatment options due to highly invasive nature, the largely impermeable blood-brain barrier (BBB) and presence of efflux transporters at BBB. We aimed to investigate the ability of self-emulsifying nanoemulsions to delivery BBB-impermeable molecules to the brain of orthotopic U87-luc human glioblastoma xenografts.
Methods: Oil-in-water nanoemulsions containing medium-chain triglycerides oil and co-surfactants (polysorbate-80:transcutol 6:4 w/w) were prepared by a spontaneous self-emulsification method. Luciferase transfected U87-luc human glioblastoma cells were injected intracranially as well as subcutaneously to Nu/Nu mice and tumor growth was monitored by bioluminescence imaging. Seventeen days after tumor implantation, near infrared dye DiD labeled nanoemulsions and size matched pegylated stealth liposomes were injected intravenously in U87-luc xenografts and the real-time biodistributions of formulations were monitored by whole animal imaging.
Results: Nanoemulsions had a mean particle size ∼120 nm with slightly negative charge (-10 mV). It is biocompatible with no hemolysis in vitro. In orthotopic U87-luc xenograft tumor model, intravenous administration of DiD labeled nanoemulsions revealed enhanced accumulation of the nanoemulsions in the brain and subcutaneous tumor at 1-9 hours post injection, comparing to that of the free dye and pegylated liposomes. The brain accumulations of nanoemulsions were persistent till 96 hours. The ex vivo fluorescence microscopy analysis showed that the DiD-nanoemulsions specifically accumuolated at the U87-luc tumor region, not at the surrounding normal brain tissue. In the normal CD-1 mice with intact BBB, the nanoemulsions accumulation in the brain was still significantly higher than the free dye, albeit lower than the brain level achieved in the U87-luc xenografts. The nanoemulsions were non-toxic to both CD-1 and Nu/Nu mice after daily repeated doses for three weeks.
Conclusion: Our data indicates that nanoemulsion is a promising nanocarrier to deliver imaging or therapeutic agents for the diagnosis or systemic treatment of GBM.
Citation Format: Xinli Liu, Hussaini Syed Sha Qhattal, Tanvirul Hye. Self-emulsifying nanoemulsions target intracranial glioblastoma tumors: In vivo optical imaging and fluorescence microscopy evidences. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5405. doi:10.1158/1538-7445.AM2014-5405
Abstract 5406: The CendR pathway: A novel cell penetration and transcytosis pathway regulated by nutrient availability
Authors: Pang Hong-Bo , Braun Gary B. , Friman Tomas , Aza-Blanc Pedro , Ruidiaz Manuel E. , Sugahara Kazuki N. , Teesalu Tambet , Ruoslahti Erkki 
Published: May 2015

Abstract
Transport of molecules across the vascular wall, through tissue, and into target cells plays an important role in various physiological and pathological processes. We previously described a novel class of tumor-targeting peptides (CendR peptides) that penetrate into cells and tumor tissue through an as yet incompletely characterized transport pathway initiated by peptide binding to neuropilin-1 (NRP1). This pathway has shown promise in enhancing drug delivery into tumors. Here we perform a genome-wide RNAi screen to identify components responsible for cell penetration of CendR peptides. We show that the binding of CendR peptides to NRP1 initiates a novel endocytic process that depends on a subset of genes and a transport route distinct from those of known endocytic pathways. Strikingly, we found the internalization of CendR peptides to be controlled by nutrient-sensing and cell growth-regulatory pathways. Nutrient deprivation stimulated the cell penetration and intercellular transport of CendR peptides, both in vitro and in vivo. These data suggest a physiological role for CendR pathway in nutrient sensing and transport. The ability to activate this pathway with peptides provides immediate applications to drug delivery.
Citation Format: Hong-Bo Pang, Gary B. Braun, Tomas Friman, Pedro Aza-Blanc, Manuel E. Ruidiaz, Kazuki N. Sugahara, Tambet Teesalu, Erkki Ruoslahti. The CendR pathway: A novel cell penetration and transcytosis pathway regulated by nutrient availability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5406. doi:10.1158/1538-7445.AM2014-5406
Abstract 541: The role of long noncoding RNA SChLAP1 in prostate cancer
Authors: Sahu Anirban , Iyer Matthew K. , Prensner John R. , Chinnaiyan Arul M. 
Published: May 2015

Abstract
Prostate cancer is the second most common epithelial cancer and second leading cause of cancer death in men. Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority of patients. The molecular basis for this clinical heterogeneity remains incompletely understood. Long noncoding RNAs (lncRNAs) have emerged as a prominent layer of transcriptional regulation implicated in various biological and disease processes, including several types of cancer. Therefore, we hypothesized that lncRNAs may play a role in mediating aggressive prostate cancer.
Previously, our lab utilized RNA sequencing across a cohort of prostate tissues to discover differentially expressed lncRNAs in cancer versus benign samples. We identifed a novel transcript termed SChLAP1 (Second Chromosome Locus Associated with Prostate-1) overexpressed in a subset of localized and metastatic cancers. Clinical analyses showed that SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality. In vitro and in vivo experiments indicated that SChLAP1 is critical for cancer cell invasiveness and metastasis. Mechanistically, we found that SChLAP1 binds to and antagonizes the genome-wide localization of the tumor-suppressive SWI/SNF nucleosome-remodeling complex.
Given the scaffolding capabilities of lncRNAs, previous studies describing an inhibitory role of SWI/SNF on PRC2 function, and the known oncogenic role of PRC2 in prostate cancer, we hypothesized that SChLAP1 may mediate PRC2 activity in conjunction with SWI/SNF to promote aggressive disease. Here, we show that a SChLAP1-associated gene signature nominates PRC2-related concepts, and in vitro studies indicate an interaction between SChLAP1 and PRC2 that enhances PRC2 genome-wide localization as well as its histone methyltransferase activity. These results suggest a mechanistic model in which SChLAP1 simultaneously engages multiple epigenetic complexes, inhibiting tumor-suppressive functions of SWI/SNF while enhancing oncogenic activity of PRC2, which leads to aggressive prostate cancer.
Citation Format: Anirban Sahu, Matthew K. Iyer, John R. Prensner, Arul M. Chinnaiyan. The role of long noncoding RNA SChLAP1 in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 541. doi:10.1158/1538-7445.AM2014-541
Abstract 5412: Antitumor properties of ouabain in lipid double emulsion in orthotopic canine osteosarcoma xenografted mouse model
Authors: Wu Jun , Hsieh Meng-Yin , Wang Yan , Roberts Eugene , Vallejo Derek , Lee Abraham , Ermel Richard 
Published: May 2015

Abstract
Canine cancers develop in immunocompetent environments and share many similar features observed in human cancers, such as long periods of latency for initiation, progression and development, metastasis, acquired drug resistance and recurrence. Osteosarcoma is a primary bone tumor that occurs in dogs. It is highly aggressive and metastatic in nature, and the therapeutic methods utilized to treat this primary canine tumor are very limited. We have successfully established canine osteosarcoma orthotopic xenograft models with NSG mice (from Jackson Lab) in vivo. Ouabain, known as Na+, K+ ATPase inhibitor, has been used for many years in human clinical applications for the treatment of congestive heart failure. Recently, ouabain has been investigated for potential anticancer properties. However, the therapeutic dose window is very narrow because the side effects of ouabain overdose can be lethal. In an attempt to mitigate such narrow therapeutic margin of safety, ouabain was formulated in lipid double emulsion by using microfluidic synthesis method or membrane emulsification method. Our preliminary results showed enhanced antitumor activities of ouabain in double emulsion or nanoemulsion against canine osteosarcoma cell lines in vitro and in orthotopic xenograft models in vivo. The safety and delivery efficiency of ouabain in vivo was also improved, suggesting a therapeutic application of ouabain double emulsion could be benefit in canine osteosarcoma targeting therapy.
Citation Format: Jun Wu, Meng-Yin Hsieh, Yan Wang, Eugene Roberts, Derek Vallejo, Abraham Lee, Richard Ermel. Antitumor properties of ouabain in lipid double emulsion in orthotopic canine osteosarcoma xenografted mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5412. doi:10.1158/1538-7445.AM2014-5412
Abstract 5426: Assessing factors predictive of response to ADCs for companion diagnostic strategies
Authors: Krueger Joseph S. , Lange Holger , Potts Steve , Young David 
Published: May 2015

Abstract
One premise of antibody-drug conjugates (ADC) is that the bound mAb-antigen complex on the cell surface will internalize and be metabolized by lysosomal proteases to release the free drug. Thus, the efficacy of an ADC is dependent not only on the presence of cell surface antigens, but also in-tact delivery of the conjugated drug, and an active pathway of receptor-mediated endocytosis. On a cellular level, the biological mechanisms behind receptor internalization and turnover have not been elucidated for novel therapeutic targets. On a tissue level, vascularization and hypoxic profile will affect delivery of the antibody into the tissue. Varying expression of the antibody target within the tissue (antigen density) will also affect the uptake of the ADC. Furthermore, the extracellular stability of the ADC may be affected by the activity of the various proteases in the tumor microenvironment (TME), outside of the lysozome. These concepts are critical for efficacy, and thus are especially important for companion diagnostic approaches (CDx) meant to predict response to ADCs. Thus, a predictive assay which would account not only for the degree of cell surface expression of the target, but also receptor internalization and potential effects of tumor microenvironment is required. To answer this need, Flagship Biosciences has invented several proprietary approaches for measuring critical properties of the therapeutic target on the cell surface or inside the cell, as well as properties of the TME which could be used to understand and predict efficacy to an ADC using FFPE biopsies. These quantitative pathology approaches are based on image analysis approaches which been designed specifically for ADC CDx programs to answer these critical questions: 1) Defining cell surface target expression independent of cytoplasmic expression; 2) Estimating receptor flux (turnover, internalization) based on staining profile; 3) Assessing critical factors in the TME which may affect delivery of the in-tact drug to the intracellular target; 4) Assaying vascular properties which may affect delivery of the drug; and 5) Heterogeneity of the target within a tumor. We are able to provide these as discrete evaluations or multiplex these evaluations for an integrative answer which can be derived from a typical clinical biopsy. Incorporation of these novel tools will enable ADC developers to create efficacy and patient stratification paradigms which incorporate the critical biological endpoints unique to ADCs.
Citation Format: Joseph S. Krueger, Holger Lange, Steve Potts, David Young. Assessing factors predictive of response to ADCs for companion diagnostic strategies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5426. doi:10.1158/1538-7445.AM2014-5426
Abstract 5428: Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin
Authors: Ali-Rahmani Fatima , Fitzgerald David , Martin Scott , Patel Paresma , Thomas Craig , Pastan Ira 
Published: May 2015

Abstract
Discoidin domain receptor 1 (DDR1) is an emerging anti-cancer target that belongs to the family of tyrosine kinases that are activated by collagen, the most abundant component of extracellular matrix (ECM). Collagen mediated induction of DDR1 facilitates cell adhesion, migration, proliferation and matrix remodeling. The collagen/DDR1 axis is also thought to modulate tumor-stromal interaction and potentially can affect tumor response to therapy. Mesothelin is a cell-surface tumor-associated antigen over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a second-generation less immunogenic recombinant immunotoxin (RIT) consisting of an Fv portion of an anti-mesothelin antibody attached to a portion of Pseudomonas exotoxin A in which immunogenic B cell epitopes were silenced. Activation of tyrosine kinase mediated signaling in tumor cells has been shown to modulate the activity of RITs. Therefore, we hypothesized that DDR1 regulates RIT action and its inhibition might enhance the activity of RG7787. Knockdown of DDR1 by siRNA or its inhibition with a novel and specific inhibitor, ‘7rh’, synergistically enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed increased inhibition of protein synthesis in cells treated with combination of ‘7rh’ and RG7787. Furthermore, stimulation of DDR1 activity by collagen treatment protected cancer cells from killing by RG7787. In conclusion, we report that collagen protects cells from killing by RITs through DDR1 and that lowering DDR1 protein or inhibiting DDR1 kinase activity enhances the cytotoxic activity of RITs. Our data suggest that the combination of ‘7rh’ and RG7787 represents a novel therapeutic strategy to target mesothelin-expressing cancers.
Citation Format: Fatima Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Craig Thomas, Ira Pastan. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5428. doi:10.1158/1538-7445.AM2014-5428
Abstract 5433: Binding of multivalent CD147 extracellular domain on U937 cells induces apoptosis via activation of caspase-9 and downregulation of MCT-1
Authors: Intasai Nutjeera , Pata Supansa , Tragoolpua Khajornsak , Tayapiwatana Chatchai 
Published: May 2015

Abstract
CD147 is highly expressed in activated lymphocytes and cancer cells. CD147 plays many important roles in cellular functions. We have previously reported that binding of multivalent CD147 extracellular domain displayed on phage particles (multivalent CD147Ex phages) induced apoptosis in a monocytic cell line, U937, by triggering caspase-3 activation. Activation of caspase-8, caspase-9 and MCT-1 was investigated in this study. Levels of intracellular procaspase-9 and membrane MCT-1 were noticeably decreased in multivalent CD147Ex phage-induced U937 cells in comparison to controls. However, activation of caspase-8 was not obvious. Multivalent CD147Ex phages also induced DNA fragmentation and growth arrest of U937 cells. Taken together with previous studies, we hypothesize that the CD147 extracellular domain on phage particles may bind to its ligand(s) on the cell surface of U937 leading to inhibition of MCT-1 cell surface expression, intracellular activation of caspase-9, followed by caspase-3 activation, DNA fragmentation and growth arrest. We identified a mechanism of CD147 in triggering its ligand(s) on U937 cells leading to U937 apoptotic cell death. This may contribute to the conceptual development of novel cancer drugs based on CD147 polymers.
Citation Format: Nutjeera Intasai, Supansa Pata, Khajornsak Tragoolpua, Chatchai Tayapiwatana. Binding of multivalent CD147 extracellular domain on U937 cells induces apoptosis via activation of caspase-9 and downregulation of MCT-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5433. doi:10.1158/1538-7445.AM2014-5433