tbuckley/cabot-search huggingface dataset:
Abstract 5938: <i>In vivo</i> targeting of laminin-411-β1 integrin-Notch signaling pathway using nanobioconjugate alters glioma microenvironment for effective treatment
Authors: Julia Y. Ljubimova
Journal: Cancer Research (2017)

Abstract Introduction: Brain gliomas have been extensively characterized by genomic and molecular marker analysis. These studies have underscored glioblastoma multiforme (GBM) heterogeneity, which may underlie failure of even the newest drugs to improve patient survival. For this reason, we turned to genetic modulation of glioma microenvironment using a novel nanobioconjugate. Methods/Results: Clinical material from 107 GBM patients was analyzed, and tumors with overexpression of “malignant” tumor vascular basement membrane laminin-411 were found to have higher recurrence rate and shorter patient survival. In 92% of human GBM samples, overexpression of laminin-411 was associated with high expression of cancer stem cell (CSC) markers. To examine the interaction mechanisms between GBM cells and their extracellular matrix microenvironment, blood-brain barrier (BBB) passing nanobioconjugates based on poly(β-L-malic acid) (PMLA) were synthesized that specifically inhibit α4 and β1 chains of trimeric laminin-411. In vitro. Normal brain endothelial cells and astrocytes had higher expression of β1 integrin, Notch-1, and Notch ligands when seeded on “malignant” laminin-411 as compared with “normal” laminin-421. All these markers were downregulated in two GBM cell lines treated with antisense oligonucleotides against laminin α4 and β1 chains, suggesting regulation of Notch pathway by laminin-411 through integrin β1. In vivo. In GBM xenograft mouse models increased expression of laminin-411 correlated with overexpression of integrin β1 and Notch signaling pathway members. In two mouse models with intracranial human LN229 and U87MG GBMs, treatment with PMLA-based nanobioconjugate against tumor microenvironment protein laminin-411 led to significantly increased animal survival, associated with marked suppression of laminin-411- β1 integrin-Dll4-Notch axis and CSC markers CD133, Nestin, and c-Myc. Conclusion: BBB crossing and brain tumor-targeted nanodrug therapy using laminin-411 suppression provided a unique tool to study mechanistic interactions between tumor microenvironment and signaling pathways, and showed promise for efficient GBM treatment affecting both the bulk of tumor cells and CSC. Support: NIH grants U01 CA151815, R01 CA136841, R01 CA188743, R01 CA209921 Citation Format: Julia Y. Ljubimova. In vivo targeting of laminin-411-β1 integrin-Notch signaling pathway using nanobioconjugate alters glioma microenvironment for effective treatment [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 5938. doi:10.1158/1538-7445.AM2017-5938
Abstract 5118: A novel polyamine sulfonamide with anti-leukemic activity
Authors: Vindhya Vijay, Amy Meacham, Leylah Drusbosky, Elizabeth Wise, Christopher Cogle
Journal: Cancer Research (2017)

Abstract The greatest challenge in treating Acute Myeloid Leukemia (AML) is refractory disease. Although 60-80% of AML patients achieve complete remission after induction chemotherapy, majority of these patients relapse and die of progressive disease. New treatment options targeting the vulnerabilities of AML biology are highly critical for disease regression, in particular the chemo-resistant leukemia-initiating population, to ensure relapse-free survival in patients. Identifying novel druggable targets that are selective to AML despite their location in the vascular niche is thus highly warranted. We developed an in vitro co-culture model consisting of AML cells and Bone Marrow- derived Endothelial Cells (BMECs), mimicking the protective effect of the vascular niche in the bone marrow microenvironment. Using this unique model, and taking advantage of combinatorial chemistry, we performed high-throughput chemical-phenotypic screening of approximately 30 million novel compounds and identified a novel polyamine sulfonamide 2470-51 that can selectively kill AML cells by overcoming the protective effect of the BMECs. In addition to AML blasts, 2470-51 also exhibited highly selective activity against the leukemic stem and progenitor cell population while sparing normal hematopoietic stem and progenitor cells. In vivo studies using patient-derived xenograft models indicated significant regression in AML engraftment post 2470-51 treatment. Target identification experiments involving unbiased label-free shotgun proteomic analysis in combination with targeted Selected Ion Monitoring (SIM) revealed covalent drug binding targets of 2470-51. By performing differential protein expression analysis using ITRAQ analysis, we identified downstream mechanisms that led to mitotic cell cycle arrest and cell death. Collectively, our findings display the in vitro as well as in vivo efficacy of a novel polyamine sulfonamide in eliminating AML, including the leukemia initiating compartment. We also uncover a novel mechanism in AML that can be taken advantage of for selective toxicity. Furthermore, we establish the role of 2470-51 as a potential therapeutic agent in treating AML. Citation Format: Vindhya Vijay, Amy Meacham, Leylah Drusbosky, Elizabeth Wise, Christopher Cogle. A novel polyamine sulfonamide with anti-leukemic activity [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 5118. doi:10.1158/1538-7445.AM2017-5118
Abstract 1504: Tumor-treating fields (TTFields) interfere with biological key properties of glioma cells in vitro
Authors: Manuela Silginer, Michael Weller, Roger Stupp, Patrick Roth
Journal: Cancer Research (2017)

Abstract Tumor-treating fields (TTFields) are low amplitude alternating electric fields which are supposed to exert anti-tumor effects by targeting dividing tumor cells while sparing cells in the brain not undergoing cell division. Although this novel therapeutic approach has shown encouraging results in phase III trials in glioblastoma, its biological effects on tumor cells have only been poorly understood. Here, we investigated the effects of TTFields on glioma cells in vitro using the inovitroTM system that allows the application of TTFields to cell cultures. Exposure to TTFields potently induce autophagy and necroptosis and interfere with the migration and invasion of long-term glioma cell lines, but also of glioma-initiating. The combination of TTFields with irradiation or temozolomide (TMZ) reduced viability and clonogenic survival in an additive or synergistic manner. Further studies suggest that the O6-methyl-guanine DNA methyltransferase (MGMT) status does not influence the efficacy of TTFields and TMZ-resistant glioma cells remain responsive to TTFields application, thus making TTFields particularly attractive for the majority of glioblastoma patients with tumors that are unlikely to benefit from TMZ treatment. In summary, these findings demonstrate that the application of TTFields may interfere with various biological key properties of glioma cells and may allow for a more detailed clinical evaluation of TTFields beyond the clinical data available so far. Citation Format: Manuela Silginer, Michael Weller, Roger Stupp, Patrick Roth. Tumor-treating fields (TTFields) interfere with biological key properties of glioma cells in vitro [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 1504. doi:10.1158/1538-7445.AM2017-1504
Abstract 929: Dissecting heterogeneity and population dynamics in breast cancer stem cells
Authors: Michael D. Brooks, Max S. Wicha
Journal: Cancer Research (2017)

Abstract The CSC hypothesis posits that there is a subset of tumors cells driving tumor growth and metastasis and that by targeting this population, tumors can be more efficiently eradicated. Recently it was shown that there are two types of CSCs in breast cancer, mesenchymal CSC’s characterized as CD44+/CD24- and an epithelial type marked by ALDH expression. The cellular plasticity of these CSC states may contribute to their metastatic capacity. However, little is known about the heterogeneity of these CSC populations or how they are regulated by the tumor microenvironment. To address these issues we have utilized Drop-Seq to generate single cell RNA-Seq data from thousands of cells across patient derived xenografts from various molecular subtypes of breast cancer. In order to monitor real-time state transitions between the determined cellular populations, we have also designed and constructed fluorescent reporter constructs for genes specific to critical cell populations and cancer stem cells. We used CRISPR/Cas9 to introduce these reporters into the native loci of the genes in order to recapitulate native gene expression patterns. Single cell transcriptomics will help to characterize the molecular heterogeneity of CSC populations. The addition of fluorescent reporters will help to elucidate the mechanisms that regulate breast CSC’s as well as their interaction with the tumor microenvironment and to identify potential therapeutic targets. Citation Format: Michael D. Brooks, Max S. Wicha. Dissecting heterogeneity and population dynamics in breast cancer stem 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 929. doi:10.1158/1538-7445.AM2017-929
Abstract 5350: A comprehensive and integrated approach to genomic and proteomic analysis of FFPE NSCLC tumor specimens
Authors: Douglas Hinerfield, Jennifer Mellen, Gary Geiss, Philippa Webster, Chris Merritt, Kristi Barker, Gokhan Demirkan, Brian Filanoski, Roberto Polakiewicz, Katherine Crosby
Journal: Cancer Research (2017)

Abstract This poster describes a novel fully integrated method for the multiplexed DNA, RNA and Protein analysis of formalin fixed paraffin embedded tumor specimens. Cancer progression is typically a result of aberrations in the molecular pathways that regulate cell growth. Identifying and understanding these changes is necessary for the detection of drug targets as well as the identification of novel biomarkers that can predict response to such drugs. Deep molecular profiling of clinical tumor samples is challenged by limited material and the compromised quality resulting from variable handling and the fixation processes that are commonly employed in the clinical laboratories. While multiplexed gene expression and mutational analysis of such samples has become well established, we describe a new method that enables multiplexed DNA, RNA and protein analysis from a single formalin fixed paraffin embedded (FFPE) tumor specimen on the NanoString nCounter system. We have adapted the sample preparation methods to enable the multi-analyte analysis of FFPE samples and have demonstrated concordance with the clinical gold standard immunohistochemistry (IHC) methodology. As a proof-of-concept, five FFPE non-small cell lung cancer (NSCLC) specimens were simultaneously stained with a panel of antibodies specific to a variety of cancer-relevant proteins, five of which were validated on serial sections by IHC using antibodies from Cell Signaling Technology. In addition to the protein analysis, from the same specimen, expression of 770 cancer-related genes and &amp;gt;100 single nucleotide variants (SNVs) were also analyzed on the nCounter platform. By integrating the analysis of DNA SNV’s, as well as RNA and protein expression from single FFPE specimens, it is now possible to reveal the molecular mechanisms of tumor progression, uncover novel drug targets and identify biomarkers from precious specimens. Citation Format: Douglas Hinerfield, Jennifer Mellen, Gary Geiss, Philippa Webster, Chris Merritt, Kristi Barker, Gokhan Demirkan, Brian Filanoski, Roberto Polakiewicz, Katherine Crosby. A comprehensive and integrated approach to genomic and proteomic analysis of FFPE NSCLC tumor specimens [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 5350. doi:10.1158/1538-7445.AM2017-5350
Racial Disparity in Delivering Definitive Therapy for Intermediate/High-risk Localized Prostate Cancer: The Impact of Facility Features and Socioeconomic Characteristics
Authors: David F. Friedlander, Quoc-Dien Trinh, Anna Krasnova, Stuart R. Lipsitz, Maxine Sun, Paul L. Nguyen, Adam S. Kibel, Toni K. Choueiri, Joel S. Weissman, Mani Menon, Firas Abdollah
Journal: European Urology (2017)
Safe technique for direct percutaneous endoscopic jejunostomy tube placement using single-balloon enteroscopy with fluoroscopy
Authors: Alvaro Martínez-Alcalá, Marco D’Assunção, Thomas Kröner, Lucia Fry, Ivan Jovanovic, Klaus Mönkemüller
Journal: Endoscopy (2017)

Direct percutaneous endoscopic jejunostomy (DPEJ) is a useful method for the delivery of nutrition in patients with a variety of gastrointestinal (GI) problems [1] [2] [3]. However, DPEJ using standard colonoscopes or the push technique remains a technically challenging procedure, with success rates of about 68 % in expert hands [2]. Herein, we present the key steps to conducting a successful DPEJ using a single-balloon enteroscopy technique.
Abstract 1375: Loss of C-MYC and chromatin acetylation induce epigenetic reprogramming in acute lymphoblastic leukemia
Authors: Elodie M. Da Costa, Gregory Armaos, Simon Jacques-Ricard, Annie Beaudry, Pascal St-Onge, Maxime Caron, Daniel Sinnett, Serge McGraw, Noël J. Raynal
Journal: Cancer Research (2017)

Abstract Epigenetic modifications play a key role in establishing and maintaining gene expression. In cancer, they are highly altered and responsable of gene expression deregulation. Epigenetic drugs have the ability to reset cancer cell epigenome producing cancer cell differentiation and apoptosis. In a drug screening initiative, we recently reported a series of FDA-approved drugs with unsuspected epigenetic and anticancer activities. Here, we tested in a secondary screen the activity of these drugs against acute lymphoblastic leukemia (ALL) cell lines (MOLT-4 and NALM-6). We found that Proscillaridin A, a cardiac glycoside used for heart failure treatment, was the most active with IC50 values in the low nanomolar range, suggesting drug repositioning potential. Proscillaridin treatments induced a significant decrease in RNA and protein levels of C-MYC, a master oncogenic driver in ALL. Shortly after proscillaridin A treatment, C-MYC exhibited a 75% reduction in lysine acetylation, a post-translational modification known to prevent its degradation. Loss of acetylation was associated with down-regulation of lysine acetyltransferases CBP, P300 and Tip60, which also correlated with a reduction in histone 3 and 4 acetylation levels (H3K14ac, H3K9ac, H3K27ac and H4K5ac). Preliminary analysis with si-RNA experiments reveal that independent HAT activities are not responsible of C-MYC downregulation. RNA sequencing and gene set enrichment analysis in proscillaridin-treated ALL cells (5 nM for 48h) showed that genes associated with cell differentiation and apoptosis pathways were up-regulated whereas down-regulated genes were associated with C-MYC target genes. Altogether, our findings show that acetylation through lysine acetyltransferase down-regulation simultaneously induces loss of C-MYC and H3 acetylation leading to epigenetic reprogramming in ALL cells. This drug repositioning strategy, using proscillaridin A, has the potential to reprogram cancer cells that are driven by MYC overexpression or hyperactivation. Citation Format: Elodie M. Da Costa, Gregory Armaos, Simon Jacques-Ricard, Annie Beaudry, Pascal St-Onge, Maxime Caron, Daniel Sinnett, Serge McGraw, Noël J. Raynal. Loss of C-MYC and chromatin acetylation induce epigenetic reprogramming in acute lymphoblastic leukemia [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 1375. doi:10.1158/1538-7445.AM2017-1375
Abstract 749: Novel <i>ALK</i> specific mRNA <i>in situ</i> hybridization assay for non-small cell lung carcinoma
Authors: Noriko Hirai, Takaaki Sasaki, Yoshinobu Ohsaki
Journal: Cancer Research (2017)

Abstract A recent technical advance in the mRNA in situ hybridization (mRNA-ISH) assay provides simultaneous signal amplification and background suppression with a unique probe design to achieve single molecule visualization. We assessed the utility of the mRNA-ISH assay as a diagnostic tool to detect anaplastic lymphoma receptor tyrosine kinase (ALK) mRNA in non-small cell lung carcinoma. We compared the mRNA-ISH assay with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The study included 279 surgically resected lung adenocarcinomas and 44 transbronchial biopsied (TBB) adenocarcinomas. mRNA-ISH was conducted using the RNAscope 2.0 system which includes pre-designed detection probes for the tyrosine kinase domain of ALK mRNA. IHC was conducted on all of the 323 samples using ALK-specific antibodies. mRNA-ISH was performed on 279 surgical samples and 6 TBB samples. Break-apart FISH was used to assess cases that were mRNA-ISH or IHC positive. ALK protein expression was detected in 11/279 (3.9%) specimens. ALK mRNA was also detected by mRNA-ISH in these cases, and 9 of the 11 specimens (81%), were also positive by ALK FISH. Using the IHC results as a reference, the sensitivity and specificity of mRNA-ISH was 100%. In the TBB cohort, ALK protein expression was observed in 3/44 (6.8%) of specimens, in which ALK mRNA expression was also detected. ALK mRNA-ISH data were highly correlated with the IHC data, and ALK mRNA-ISH was able to identify every FISH-positive sample. We conclude that mRNA-ISH could play an alternative or complementary role in ALK genetic diagnosis in NSCLC. Citation Format: Noriko Hirai, Takaaki Sasaki, Yoshinobu Ohsaki. Novel ALK specific mRNA in situ hybridization assay for non-small cell lung 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 749. doi:10.1158/1538-7445.AM2017-749
Abstract 3959: CCL18-recruited naïve CD4+ T cells are converted to tumor-infiltrating regulatory T cells in breast cancer and suppress antitumor immunity
Authors: Shicheng Su, Jianyou Liao, Jiang Liu, Qiang Liu, Erwei Song
Journal: Cancer Research (2017)

Abstract Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naïve T cells. Here, full-length TCR α/β repertoire analysis of different T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents suggests that Tregs in human breast cancer are mainly converted from tumor-infiltrating naïve CD4+ T cells. Infiltration of naïve CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naïve CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naïve T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naïve CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Shicheng Su, Jianyou Liao, Jiang Liu, Qiang Liu, Erwei Song. CCL18-recruited naïve CD4+ T cells are converted to tumor-infiltrating regulatory T cells in breast cancer and suppress antitumor immunity [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 3959. doi:10.1158/1538-7445.AM2017-3959
Abstract 5690: Optimized molecular barcoding enables accurate targeted mutation detection in circulating cell-free DNA (cfDNA)
Authors: Carlo G. Artieri, Kyle A. Beauchamp, Valentina S. Vysotskaia, Noah C. Welker, Eric A. Evans, Clement Chu, Haluk Tezcan, Imran S. Haque
Journal: Cancer Research (2017)

Abstract The evaluation of cfDNA allows novel approaches to noninvasive detection of actionable alterations, resistance mechanisms, and tumor monitoring in patients with cancer. Importantly, tumor-specific DNA fragments represent a small minority of the cfDNA and can be obscured by false positive (FP) variants introduced by chemical damage and sequencer error. To address this, we improved key processes in the design of NGS libraries, including a new molecular barcoding approach, that maximize molecular recovery while eliminating spurious variants. We engineered a set of Illumina sequencing chemistry compatible adaptors incorporating unique molecular identifiers (barcodes) enabling reconstruction of the sequence of both strands of the original DNA molecule. These barcodes incorporate a number of key design improvements as compared to published methodologies, which enhance sequencer cluster density, thereby increasing library diversity and molecular recovery. Our new design identified both chemical and sequencer errors, reducing incorrect base calls to rates below 5e-7. We validated our methodology for use in cfDNA using both dilution experiments and patient blood samples with known oncogenic alterations via a custom capture panel targeting actionable genomic alterations in a 55kb region. By identifying the molecular origin of each read, we found that the sensitivity of detection obtained from barcoded libraries followed ideal binomial sampling expectations. We obtained an average molecular depth of 1,000 molecules per site from the plasma extracted from a single blood collection tube, which corresponded to an 80% sensitivity of detection of known oncogenic single-nucleotide and indel mutations at 0.15% mutant allele frequency (MAF) in cfDNA with no FP calls. Furthermore, we successfully detected known gene-fusions at 0.5%, and amplifications (&amp;gt;10 copies) down to 1% MAF. We designed and validated a custom-engineered error-correcting sequencing adapters, ideal for broad range of applications requiring high accuracy detection of ultra-low frequency alterations. Note: This abstract was not presented at the meeting. Citation Format: Carlo G. Artieri, Kyle A. Beauchamp, Valentina S. Vysotskaia, Noah C. Welker, Eric A. Evans, Clement Chu, Haluk Tezcan, Imran S. Haque. Optimized molecular barcoding enables accurate targeted mutation detection in circulating cell-free DNA (cfDNA) [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 5690. doi:10.1158/1538-7445.AM2017-5690