bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 13: Chromatin unfolding small molecules as a novel type of anticancer agents
Authors: Gurova Katerina V. 
Published: July 2017

Abstract
Although targeted therapy was the major focus of anti-cancer drug development, recently revealed enormous heterogeneity of tumors planted a seed of doubt in it as a potential cure for cancer. Very few universal cancer targets are known and they lack cancer specificity. DNA is one of this sort, but activity of drugs targeting DNA was traditionally attributed to their ability to block DNA replication and cause DNA damage with a plethora of harmful long lasting effects in normal cells. We have found that reversible binding of DNA by non-DNA damaging small molecules, curaxins, has strong anticancer effect in different preclinical models without deleterious consequences associated with DNA damage (REF). In this study we explained the mechanism of activity of curaxin clinical lead, CBL0137, through alteration of chromatin organization in tumor cells. Intercalation of the curaxin carbazole moiety between base pairs and DNA major and minor groove binding with curaxin side chains cause an increase in inter base pair distance and untwisting of the double helix (~18o). Such alteration of DNA helical shape leads to decreased nucleosome stability and chromatin opening, creating sites for the high affinity binding of histone chaperone complex FACT. We named this phenomenon “chromatin trapping of FACT” or c-trapping. Consequences of C-trapping are much more deleterious for tumor, than for normal cells. First, c-trapping is an equivalent of functional inactivation of FACT. FACT is critical for oncogenic transformation and tumor, but not normal cell, viability and growth (REF). FACT is essential for the activity of several transcription factors, such as NF-kappaB, HSF1, MYC etc., with important roles in tumor cell proliferation and survival (REF). Further, deregulation of transcription caused by curaxin-dependent chromatin decondensation leads to upregulation of transcription from heterochromatin. This leads to the formation of double stranded RNAs from centromeric and pericentromeric repetitive elements, which mimics a viral infection and induces an IFN response, a powerful inhibitor of tumor cell growth. Additionally, c-trapping of FACT leads to casein kinase 2 mediated phosphorylation and activation of wild type p53 leading to p53-dependent death of cells. Thus non-DNA damaging DNA binding small molecules compromise cancer cell viability via alteration of nucleosome stability and chromatin organization. This is a novel mechanism of anti-cancer activity of small molecules with broad applicability to different types of cancer while lacking the harmful effects of DNA damaging chemotherapy.
Citation Format: Katerina V. Gurova. Chromatin unfolding small molecules as a novel type of anticancer agents [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 13. doi:10.1158/1538-7445.AM2017-13
Abstract 1360: Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes
Authors: Wu Hsing-Yu , Yang Ming-Chen , Chu Po-Chen , Kulp Samuel K. , Chen Ching-Shih 
Published: July 2017

Abstract
p21-activated kinases (PAKs) are important effectors of the Rho family GTPases and has been implicated in cytoskelestal remodeling, cell proliferation, apoptosis, and transformation. Based on the sequence, structure homology, and activation mechanism, six PAKs are classified into two groups, PAK 1-3 (group I) and PAK 4-6 (group II). PAK kinases are frequently overexpressed in various human tumors and represent therapeutically relevant targets for cancer treatments. Previous studies have shown that PAK1 and PAK4 are upregulated and/or hyperactivated in pancreatic cancer, and promotes pancreatic cancer cell motility and invasion. In our study, we showed that knockdown of PAK3, but not that of PAK1 or PAK2, inhibited pancreatic cancer cell proliferation in vitro, and tumor growth in vivo. In addition, our data showed that PAK3 regulated the protein stability of β-catenin via Akt/GSK-3β signaling pathway in pancreatic cancer cells. The role of PAK3 in regulating Akt/GSK-3β phosphorylation was further confirmed by the ectopic expression of wild-type versus kinase-dead (K297L) PAK3. Equally important, the mammosphere formation, aldehyde dehydrogenase (ALDH) activity and cancer stem cell-associated markers, were also down-regulated in PAK3 knockdown cells, suggesting the involvement of PAK3 in regulating cancer stem cell-like properties in pancreatic cancer cells. Together, these findings suggested that PAK3 as a primary regulator of Akt/GSK-3β/β-catenin signaling for maintaining cancer stem cell phenotypes and promoting tumor growth, which underlies the potential of targeting PAK3 in fostering new therapeutic strategies for pancreatic cancer.
Citation Format: Hsing-Yu Wu, Ming-Chen Yang, Po-Chen Chu, Samuel K. Kulp, Ching-Shih Chen. Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes [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 1360. doi:10.1158/1538-7445.AM2017-1360
Abstract 1443: Identification of enhancer elements at kidney cancer susceptibility loci using MPRA
Authors: Colli Leandro Machado , Jessop Lea , Machiela Mitchell , Choi Jiyeon , Myers Timothy , Chanock Stephen 
Published: July 2017

Abstract
GWAS is an important tool for discovering regions in the genome associated with cancer susceptibility. For renal cell carcinoma (RCC), only two loci have had their functional basis explained (11q13 and 12p12). Here, we used a massively parallel reporter assay (MPRA) to investigate enhancer activity in 20 GWAS regions that had an RCC association p-value of at least 10-7. We selected 784 SNPs with an r2&gt;0.4 or D’&gt;0.5 and MAF&lt;0.05 that had evidence for enhancer activity based on available ENCODE transcription factor or histone ChIP-seq, FAIRE, and DNase I hypersensitive data. The MPRA library was composed of 47461 oligonucleotides 201 bp in length, compelled of 145 bps contained the SNP in the forward or reverse orientation followed by 10 bp of barcode sequence to allow for identification. Each of the 784 SNPs tested were tagged 10 separate times for both orientations. Controls were constructed by randomizing the 10 nucleotides centered on the SNP. The MPRA library was the cloned into a luciferase reporter vector that was transfected into HEK293T and ACHN cell lines. NGS was performed on 5 replicates using the the Illumina HiSeq 2500. After correcting for multiple comparisons, 50 SNPs from 16 regions showed significant p-values. From these 50 SNPs, 29 showed enhancer activity that was independent of the forward/reverse orientation and had the same effect in both cell lines. This analysis has identified possible functional variants at RCC risk loci and opens opportunities to discover new molecular mechanisms of genetic susceptibility of RCC.
Citation Format: Leandro Machado Colli, Lea Jessop, Mitchell Machiela, Jiyeon Choi, Timothy Myers, Stephen Chanock. Identification of enhancer elements at kidney cancer susceptibility loci using MPRA [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 1443. doi:10.1158/1538-7445.AM2017-1443
Abstract 146: The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models
Authors: Song Kyung W. , Edgar Kyle A. , Kirkpatrick Donald S. , Phu Lilian , Schmidt Stephen , Nannini Michelle , Hong Rebecca , Cheng Eric , Crocker Lisa , Young Amy , Sampath Deepak , Friedman Lori 
Published: July 2017

Abstract
Activating mutations in PIK3CA are commonly found in a wide variety of human cancers, and the dysregulation of the phosphoinositide-3 kinase (PI3K) signaling pathway has been implicated in tumor cell growth and survival. Taselisib (GDC-0032), a novel, oral, selective inhibitor of p110alpha, sparing inhibition of p110beta, is more potent in cancer cells bearing PIK3CA mutants than those with wildtype PIK3CA. Preclinical studies demonstrate that taselisib induces more apoptotic cell death in PIK3CA mutant cancer cells than other PI3K inhibitors.
We have discovered that taselisib has a dual mechanism of action, both blocking PI3K signaling, and inducing a decrease in p110a protein levels. Mass spec analysis reveals that taselisib treatment leads to the specific depletion of mutant p110alpha without significant change in wildtype p110alpha protein levels. This drug-induced p110a protein depletion is rescued by E1 inhibitors and by proteasome inhibitors. Other clinical PI3K inhibitors, including p110alpha selective and pan-PI3K inhibitors, are unable to induce the depletion of mutant p110 alpha protein. Furthermore, we have discovered that taselisib more effectively maintains pathway suppression in PIK3CA mutant cells at 24 hrs in response to feedback. In comparison to other clinical-stage PI3K inhibitors administered at a maximum tolerated dose, taselisib has superior efficacy with increased tumor regressions in PIK3CA mutant xenograft models. In summary, these preclinical studies indicate that PI3K inhibitors, which have the ability to trigger degradation of mutant p110a protein, can more effectively suppress the signaling pathway, which may result in greater anti-tumor activity and improved therapeutic index in PIK3CA mutant tumors.
Citation Format: Kyung W. Song, Kyle A. Edgar, Donald S. Kirkpatrick, Lilian Phu, Stephen Schmidt, Michelle Nannini, Rebecca Hong, Eric Cheng, Lisa Crocker, Amy Young, Deepak Sampath, Lori Friedman. The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models [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 146. doi:10.1158/1538-7445.AM2017-146
Abstract 1483: Alteration of miR-186 expression modifies inflammatory markers in normal epithelial and prostate cancer cell models
Authors: Suman Suman , Jones-Reed Dominique Z. , Schmidt M. L. , Clark Geoffrey J. , Klinge Carolyn , Barve Shirish , Kimbro Kevin S. , Kidd La Creis R. 
Published: July 2017

Abstract
Dysregulation of miRNAs and chronic inflammation are strongly implicated in the development of various malignancies, including prostate cancer (PCa). Previously, our lab identified several inflammatory and immune response sequence variants in CCL5 and CCR5 significantly modified PCa risk. Recently, we propose an oncogenic role for miR-186-5p based on its up-regulation in serum from PCa patients and metastatic PCa cell lines. Moreover, miR-186-5p inhibition reduced proliferation, anchorage independent growth and invasion in metastatic PC cells (PC3, MDA-PCA-2b). We hypothesize dysregulation of inflammatory and immune response markers may enhance immune surveillance leading to a reduced aggressive tumor phenotype. Following modulations in miRNA-186 levels in normal prostate epithelial (RWPE1) and metastatic PCa (PC3) cell lines, we evaluated alterations in mRNA expression using micro-array analysis. Ectopic expression of miRNA-186 in the RWPE1 resulted in a 1.3-2.6-fold down-regulation in TLR2, IRAK2, CCL20, IL1RAP, IL1RAP, IL15, and IL17RD (FDR p-value ≥7.8x10-06). Whereas, inhibition of miR-186 in PC3 cells corresponded with a 1.4-fold up-regulation of IL18R1 (p=0.0095). Notably, these inflammatory markers are involved in cell invasion (TLR2), apoptosis (IL17RD), tumorigenesis (TLR2, IRAK2) and autoimmune diseases (CCL20). Validation of these targets is underway using qRT-PCR, western blots and luciferase reporter assays. We will assess the mechanism by which these miR-186 targets suppress aggressive cancer behavior using knock-out and knock-in cell and ultimately animal models. Future studies may identify inflammatory targets that may guide immune therapies for the effective treatment of aggressive prostate cancer.
Citation Format: Suman Suman, Dominique Z. Jones-Reed, M. L. Schmidt, Geoffrey J. Clark, Carolyn Klinge, Shirish Barve, Kevin S. Kimbro, La Creis R. Kidd. Alteration of miR-186 expression modifies inflammatory markers in normal epithelial and prostate cancer cell models [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 1483. doi:10.1158/1538-7445.AM2017-1483
Abstract 1541: The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation
Authors: Kuznetsov Jeffim N. , Aguero Tristan , Kurtenbach Stefan , Field Matthew G. , King Mary Lou , Harbour J William 
Published: July 2017

Abstract
Introduction: Our lab discovered that mutations in the tumor suppressor BAP1 are strongly associated with metastasis and death in patients with uveal melanoma. Subsequently, other cancers have been found to harbor BAP1 mutations, including skin melanoma, kidney cancer, mesothelioma and others. Germline BAP1 mutations are responsible for a newly described genetic cancer syndrome. Therapeutic molecules that reverse the effects of BAP1 mutations could represent a potent new treatment strategy for BAP1-mutant cancers. Unfortunately, there are several obstacles to developing such therapies. First, BAP1 is a tumor suppressor that is inactivated by mutations, such that targeted therapy would need to be directed against downstream effectors that are deregulated by BAP1 loss. Second, the effectors of BAP1 that are relevant to cancer are not known. Interestingly, most known proteins that interact with Bap1 are developmental epigenetic regulators such as Asxl1/2, Cbx1/3 and Kdm1b. Third, BAP1 is difficult to study in cultured cells because BAP1 loss results in cell cycle exit and stem cell-like behavior. These obstacles led us to shift to Xenopus laevis as an in vivo developmental model to study the functions of BAP1. Results and conclusions: Loss of BAP1 during embryo development results in a failure to turn off pluripotency genes such as ventx 1, ventx2 (Xenopus orthologues of the mammal gene nanog), oct 25, oct 91 (Xenopus orthologues of the mammal gene oct3/4) and pax3, and a failure to induce lineage specification genes such as the prospective epidermis marker keratin1 and the melanocyte precursor marker sox10. This block in the shift from pluripotency to differentiation programs results in a delay in gastrulation, neural crest specification and migration, mesodermal differentiation and other phenotypes. The BAP1-deficient phenotype can be rescued by Xenopus or human wildtype BAP1 or by the histone deacetylase inhibitor SAHA (vorinostat). We conclude that BAP1 is a fundamental regulator of multiple developmental lineages, including the neural crest from which melanomas arises, and that this in vivo model can be used to screen for novel therapeutic compounds that reverse the phenotypic effects of BAP1 loss.
Citation Format: Jeffim N. Kuznetsov, Tristan Aguero, Stefan Kurtenbach, Matthew G. Field, Mary Lou King, J William Harbour. The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation [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 1541. doi:10.1158/1538-7445.AM2017-1541
Abstract 1718: RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell carcinoma
Authors: Zavridou Martha , Strati Areti , Koutsodontis George , Psyrri Amanda , Lianidou Evi 
Published: July 2017

Abstract
Background: Molecular characterization of circulating tumor cells (CTCs) is very challenging since these cells are rare, and the amount of available sample for their analysis is very limited. Moreover, CTC are highly heterogeneous and enrichment technologies based on EpCAM expression present the risk of missing EpCAM-negative CTCs. The Parsortix system (ANGLE plc, UK), is a novel microfluidic technology platform designed for marker-independent capture of CTCs. In this study we used for the first time the Parsortix system to isolate CTCs from patients with Head and Neck Squamous Cell carcinoma (HNSCC), and proceeded to downstream molecular characterization through RT-qPCR gene expression analysis.
Methods: Peripheral blood samples (10 mL) from head and neck squamous cell carcinoma (HNSCC) patients (n=19) and healthy donors used as a control group (n=10) were used for the isolation of CTCs using the Parsortix device. Enriched CTCs were harvested in Trizol reagent, followed by extraction of total RNA and cDNA synthesis. RT-qPCR was performed in the LightCycler (Roche) for the following gene targets: PD-L1, VIM, TWIST, EGFR, and B2M (used as a reference gene). The expression levels of PD-L1, VIM, TWIST and EGFR were normalized using the 2-ΔΔCt approach in respect to the expression of B2M.
Results: All samples analyzed were of excellent RNA quality as this was evaluated by B2M expression. According to our results, PD-L1 overexpression was detected in 5/19(26.3%) samples, VIM was overexpressed in 3/19 (15.7%) and TWIST-1 in 1/19 (5.3%) sample, while EGFR expression was not detected in any patient (0/19, 0%). These are preliminary results and these percentages may change, since the number of samples that we are analyzing is continuously increasing.
Conclusions: This preliminary study is showing for the first time that RT-qPCR can be successfully used for the molecular characterization of CTCs isolated by the label-free Parsortix microfluidic device in HNSCC. Overexpression of individualized immunotherapy important biomarkers such as PD-L1 in CTCs of HNSCC patients could be of significant clinical importance for the selection and follow up of these patients.
Citation Format: Martha Zavridou, Areti Strati, George Koutsodontis, Amanda Psyrri, Evi Lianidou. RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell 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 1718. doi:10.1158/1538-7445.AM2017-1718
Abstract 1811: A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis
Authors: Klemke Richard L. 
Published: July 2017

Abstract
Formation of new blood vessels (angiogenesis) is crucial for proper development, but can also contribute to many diseases including cancer. Vascular endothelial growth factor receptor 2 (VEGFR2) is a receptor tyrosine kinase that mediates angiogenesis in developing vertebrates and is frequently upregulated in many human cancers. However, the underlying mechanisms that regulate VEGFR2 expression in normal and diseased cells are poorly understood. Here we demonstrate that pseudopodium-enriched atypical kinase 1 (PEAK1) mediates developmental and tumor-induced angiogenesis by modulating VEGFR2 expression and downstream signaling. Knockout of peak1 in zebrafish using TALEN technology (Transcription Activator-Like Effector Nucleases) or knockdown by specific peak1 morpholinos (MO) induced severe pericardial edema, blood-pooling defects, and inhibited formation of intersegmental (ISV) and subintestinal vessels (SIV). In Peak1 knockout mice, neonatal retinal vessel development was severely delayed, and the ex vivo angiogenic ability of adult thoracic aorta was greatly reduced. Intravital time-lapse imaging of ISV formation in peak1 knockout zebrafish revealed major defects in endothelial cell migration and proliferation. Similarly, PEAK1 knockdown or overexpression in HUVECs modulated endothelial cell migration, proliferation, and vessel sprouting in vitro. Biochemical studies and quantitative proteomic profiling of PEAK1 knockdown HUVECs revealed a dramatic loss of VEGFR2 mRNA and protein expression, which attenuated downstream signaling to Akt and ERK, leading to loss of VEGF-mediated vessel formation. PEAK1 specifically regulated VEGFR2 levels and did not alter VEGFR1 expression, and reconstitution of PEAK1 knockdown cells with PEAK1 restored VEGFR2 mRNA and protein expression. Mechanistic studies revealed that PEAK1 specifically regulates VEGFR2 mRNA transcription by modulating expression of the transcription factor GATA2. Re-expression of GATA2 in PEAK1 depleted cells restored VEGFR2 mRNA and protein expression as well as downstream signaling, indicating that GATA2 is a necessary downstream component in this response. Also, introduction of gata2 mRNA into PEAK1 knockdown zebrafish restored normal ISV formation and vegfr2 mRNA expression in these animals. Finally, bioinformatics and interrogation of the TCGA RNAseq database revealed significant Pearson’s correlations between PEAK1 and VEGFR2 expression in 17 of 32 different human cancers. Collectively, our findings indicate that PEAK1 regulates developmental and tumor-induced angiogenesis by regulating GATA2-dependent VEGFR2 expression and its downstream signals.
Citation Format: Richard L. Klemke. A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis [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 1811. doi:10.1158/1538-7445.AM2017-1811