bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B34: PDGFR-ID4-Notch axis is a common signaling pathway activated in glioma stem cells and endothelial cells
Authors: Jeon Hye-Min , Kim Hyunggee 
Published: May 2016

Abstract
Glioma stem cells (GSCs), which reside within the perivascular niche (PVN) to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling GSCs and endothelial cells in the PVN are poorly understood. Here, we report that PDGF-driven activation of nitric oxide (NO) synthase increases NO-dependent ID4 expression, which promotes Jagged-Notch activity through miR-129 suppression in GSCs and endothelial cells. ID4 also increases PDGF-PDGFR signaling in a direct or miR-129-dependent manner, which drives the PDGFR-NO-ID4 signaling in GSCs and endothelial cells. This signaling circuit promotes tumor progression along with increased GSC self-renewal and growth of tumor vasculature in the PVN, which is dramatically suppressed by Notch inhibitor. ID4 levels correlate positively with NOS2, Hes1, and Hey1 and negatively with miR-129 in primary GSCs. Thus, targeting the PDGFR-NO-ID4 signaling circuit and Notch activity in the PVN might serve as an efficacious therapeutic modality for glioblastoma.
Citation Format: Hye-Min Jeon, Hyunggee Kim. PDGFR-ID4-Notch axis is a common signaling pathway activated in glioma stem cells and endothelial cells. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B34.
Abstract B37: Tumor heterogeneity contributes to anti-EGFR therapy resistance in glioblastoma
Authors: Zanca Ciro , Cavenee Webster , Furnari Frank 
Published: May 2016

Abstract
Introduction: Glioblastoma is the most aggressive tumor type affecting the adult brain, with an overall patient survival from the time of diagnosis of about 15 months. Tumor promoting proteins such as EGFR (Epidermal Growth Factor Receptor) and its mutant form, EGFRvIII, are amplified in a subgroup of patients and have attracted attention as potential therapeutic targets. Unfortunately, kinase inhibition of EGFR or EGFRvIII has been proven to be ineffective due to resistance mechanisms that prevent the onset of cell death. Here we hypothesize that the presence of cytokines in the tumor microenvironment, in addition to their previously shown promotion of glioblastoma growth, also promote resistance to EGFR-directed therapies. To address this, we investigated core pathways known to protect cancer cells from induced cell death and tested novel treatment strategies of EGFR blockade in combination with inhibitors of cytokine-induced signaling effectors, activated by inter-clonal communication between heterogeneous tumor cell populations expressing EGFRvIII and EGFR.
Experimental procedures: For these studies we used human and mouse glioma cell lines engineered to express wild type (wt) EGFR, EGFRvIII, or an analog-sensitive (as)-allele of EGFRvIII, as well as primary human glioma neurospheres expressing amplified EGFRvIII. Expression of cell death-related molecules was determined by RT-qPCR to identify potential survival factors regulated by conditioned medium (CM) produced from EGFRvIII-expressing glioma cells. Findings were validated in vivo by orthotopic engraftment of heterogeneous tumors and measurement of tumor burden by fluorescence molecular tomography technology during single and combined drug therapy regimens.
Results and discussion: Previous results demonstrated that CM from EGFRvIII-expressing glioma cells enhances in vitro and in vivo growth of wtEGFR cells through an EGFRvIII-prompted IL-6/LIF paracrine mechanism. Here, our data indicate that EGFRvIII-CM additionally promotes resistance to EGFR inhibition in cells and tumors expressing wtEGFR. We show that IL-6/gp130-mediated signaling specifically promotes this resistance through mTORC2/NF-κB upregulation of the anti-apoptotic protein, Survivin (BIRC5). Blocking Survivin expression or pharmacologically inhibiting mTORC2 restores sensitivity to EGFR inhibitors.
Conclusion: The mTORC2/NF-κB/Survivin axis promotes resistance to EGFR inhibitors in glioblastoma and nominates targeting this pathway as a means to enhance efficacy of EGFR blockade.
Citation Format: Ciro Zanca, Webster Cavenee, Frank Furnari. Tumor heterogeneity contributes to anti-EGFR therapy resistance in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B37.
Abstract IA11: Targeting enhancers in CNS tumors
Authors: Bradner James 
Published: May 2016

Abstract
Master regulatory transcription factors instruct cell specification and dynamically modulate cell state via interactions with cis-regulatory elements, or enhancers, that together coordinate transcriptional programs. With an interest in understanding chromatin-dependent signal transduction to RNA polymerase in developmental and disease biology, we have undertaken to discover and optimize small molecule modulators of chromatin regulatory factors that function at enhancers. This research has produced informative chemical probes, with which we have validated hypotheses regarding BRD4 in chromatin-dependent signal transduction from MYC to promote cell growth, and the influence of EZH2 on silencing developmental programs. The mechanistic study of protoypical inhibitors of BRD4 and EZH2 led to the development of genome-wide measurements of drug localization, leading to insights into how small molecules modulate chromatin structure and function as well as fundamental insights into the organization of the regulatory landscape of the human genome. Here, mechanistic insights into the role of enhancers and enhancer factors in CNS tumors will be discussed, as well as translational opportunities for the development of epigenome-directed drugs in adult and pediatric tumors.
Citation Format: James Bradner. Targeting enhancers in CNS tumors. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA11.
Abstract IA22: Developing improved diffuse intrinsic pontine glioma mouse models
Authors: Becher Oren Josh 
Published: May 2016

Abstract
Recent genomic studies have identified novel drivers in DIPG pathogenesis. These include gain of function histone mutations (K27M in H3.3 or H3.1) found in 80% of DIPGs as well as activating mutations in Activin A Receptor, Type I (ACVR1) found in 25% of DIPGs. These studies also provide support for the existence of subtypes of DIPG with H3.3K27M mutations co-occurring with PDGFRA amplifications with an older age at presentation and H3.1K27M mutations co-occurring with ACVR1 mutations with a younger age at presentation. My laboratory has been using the RCAS/tv-a system to develop genetic mouse models for these DIPG subtypes that recapitulate the genetic alterations of the human disease. Our results thus far suggest that H3.3K27M is not sufficient to drive brainstem gliomagenesis on its own or with p53 loss in the early postnatal period but cooperates with platelet-derived growth factor-B (PDGF-B) in brainstem gliomagenesis. Similarly, mutant ACVR1 (R206H or G328V) cooperates with H3.1K27M and p53 loss to induce glioma-like lesions in mice. By contrast to the PDGF-B; H3.3K27M lesions that express Olig2, the mutant ACVR1; H3.1K27M; p53 deficient lesions are Olig2 negative but express CD44 and nestin. To examine whether the cell-of-origin will influence DIPG tumor incidence or latency, we induced murine DIPGs with PDGF-B, H3.3K27M, and p53 loss in three cell populations that express the following markers in the postnatal mouse brainstem: nestin, pax3 and Olig2. We will highlight the differential expression of these markers in the postnatal brainstem and resulting differences in tumorigenesis between these murine DIPGs induced in these three putative cells-of-origin. Lastly we will demonstrate the use of these models as preclinical tools.
Citation Format: Oren Josh Becher. Developing improved diffuse intrinsic pontine glioma mouse models. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA22.
Abstract A18: Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage
Authors: Ding Ning , Bonham Emily M. , Hannon Brooke E. , Baylin Stephen B. , O'Hagan Heather M. 
Published: May 2016

Abstract
At sites of chronic inflammation, epithelial cells are exposed to high levels of reactive oxygen species and undergo cancer-associated DNA methylation changes, suggesting that inflammation may initiate epigenetic alterations. Previously, we demonstrated that oxidative damage causes epigenetic silencing proteins to become part of a large complex that is localized to GC-rich regions of the genome, including promoter CpG islands that are epigenetically silenced in cancer. However, whether these proteins were recruited directly to damaged DNA or during the DNA repair process was unknown. Here we demonstrate that the mismatch repair protein heterodimer MSH2-MSH6 participates in the oxidative damage-induced recruitment of DNA methyltransferase 1 (DNMT1) to chromatin. Hydrogen peroxide treatment induces the interaction of MSH2-MSH6 with DNMT1, suggesting that the recruitment is through a protein−protein interaction. Importantly, the reduction in transcription for genes with CpG island-containing promoters caused by oxidative damage is abrogated by knockdown of MSH6 and/or DNMT1. Our findings provide evidence that the role of DNMT1 at sites of oxidative damage is to reduce transcription, potentially preventing transcription from interfering with the repair process. This study uniquely brings together several factors that are known to contribute to colon cancer, namely inflammation, mismatch repair proteins, and epigenetic changes.
Citation Format: Ning Ding, Emily M. Bonham, Brooke E. Hannon, Stephen B. Baylin, Heather M. O'Hagan. Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A18.
Abstract A19: A novel MECP2 acetylation site regulates binding with ATRX and HDAC1
Authors: Pandey Somnath , Simmons Glenn E. , Malyarchuk Svitlana , Calhoun Tara N. , Pruitt Kevin 
Published: May 2016

Abstract
Tumorigenesis stems from errors incorporated in the genetic code and impaired epigenetic mechanisms involved in tumor suppression. Mutation in methyl-CpG-binding protein 2 (MeCP2) is known to cause a neurological disorder, rett syndrome (RTT), however its role in tumorigenesis remains poorly understood. We wanted to characterize how novel post-translational modifications might contribute to its function. MeCP2 regulates gene expression by recruiting co-repressors and histone deacetylases (such as HDAC1) to methylated gene promoters. MeCP2 modulates heterochromatin association by interacting with heterochromatin protein 1 (HP1). It was shown that MeCP2 interacts with and recruits ATRX, a SWI2/SNF2 DNA helicase/ATPase, to regulate gene expression at a subset of imprinted domains. A recent study showed that overexpression of Sirtuin1 (SIRT1) deacetylase leads to reduced levels of acetylation of ectopically expressed MeCP2. Using mass spectrometry, we report that upon pharmacological inhibition of SIRT1 in colon and breast cancer cell lines, endogenous MeCP2 is acetylated at key sites known to be critical for binding to DNA and transcriptional regulators. We mapped several novel acetylated sites and then created an acetylation mimetic mutation in MeCP2 (K171Q) and found that this mutant shows decreased binding to HDAC1 and ATRX in RKO cells. Similar results were obtained when SIRT1 was pharmacologically inhibited. Herein we show that conditions that induce MeCP2 acetylation in RKO cells do not alter its promoter occupancy at a subset of target genes analyzed but do cause a decreased binding to co-repressors such as HDAC1 and ATRX and also alters ATRX binding at a specific gene promoter. We also demonstrate that RKO cells over-expressing our acetylation mimetic mutant show reduced proliferation as compared to those over-expressing MeCP2-wild type (WT).
Citation Format: Somnath Pandey, Glenn E. Simmons Jr., Svitlana Malyarchuk, Tara N. Calhoun, Kevin Pruitt. A novel MECP2 acetylation site regulates binding with ATRX and HDAC1. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A19.
Abstract A35: Innovative technologies for cancer research – NCI Strategy for supporting next generation of tools needed against cancer
Authors: Dickherber Tony 
Published: May 2016

Abstract
The development of highly innovative technologies continues to be a high priority for accelerating or challenging existing basic and clinical cancer research paradigms. Epigenetic regulation and chromatin structural biology have offered compelling new opportunities for cancer researchers, but existing tools for investigating this biology are insufficient and new technology development research is needed. The National Institutes of Health (NIH) is the principle biomedical research funding agency of the US federal government, and recognizes that it is often difficult to achieve support for such research through existing program structures. The National Cancer Institute (NCI) is the largest institute of the NIH, and has established the Center for Strategic Scientific Initiatives (CSSI) to pioneer unique scientific and technology initiatives that help keep the NCI ahead of the scientific curve with respect to new and exciting cancer research areas and discoveries. This has involved the development and application of advanced technologies (e.g., Clinical Proteomic Technologies Against Cancer initiative), synergy of large-scale and investigator-initiated research (e.g., NCI Physical Sciences Oncology Network and Alliance for Cancer Nanotechnology), and/or forging novel partnerships that emphasize innovation, trans-disciplinary teams and convergence of scientific disciplines (e.g., The Cancer Genome Atlas) to enable the translation of discoveries into new interventions, both domestically and internationally, to detect, prevent and treat cancer more effectively.
The longest standing program from CSSI is specifically tailored to address the need for highly innovative technology development necessary for advancing cancer research, and it is called the Innovative Molecular Analysis Technologies (IMAT) program. This program employs unique solicitation and review mechanisms better suited to appreciating the longer term potential of transformative technologies and designed to be more tolerant of the substantial risks often associated with such research. Research funding opportunities through this program were recently reissued, with a larger set-aside budget to grant up to 120 new awards through 2017. The unique aspects of both the solicitation and review of applications to this program will be presented, and several recently-supported research projects relevant to chromatin and epigenetics research will be highlighted to demonstrate the variety and high level of innovation evident in the IMAT portfolio of supported research. Potential projects of interest and identified technology gaps will also be discussed.
Citation Format: Tony Dickherber. Innovative technologies for cancer research – NCI Strategy for supporting next generation of tools needed against cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A35.
Abstract A46: Effects of genistein supplementation on genome-wide DNA methylation and gene expression in patients with localized prostate cancer
Authors: Bilir Birdal , Lee Jeongseok Edward , Sharma Nitya V. , Lazarevic Bato , Svindland Aud , Kucuk Omer , Moreno Carlos S. 
Published: May 2016

Abstract
Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer death among men in the United States, with an estimated 220,800 new cases and 27,540 deaths in 2015. Epidemiological studies have shown that dietary compounds have significant effects on prostate carcinogenesis. Among dietary agents, genistein, the major isoflavone in soybean, is of particular interest because high consumption of soy products has been associated with a low incidence of prostate cancer, suggesting a preventive role of genistein in prostate cancer. In spite of numerous studies to understand the effects of genistein on prostate cancer, the mechanisms of action have not been fully elucidated. Here, we investigated the differences in methylation and gene expression levels of prostate specimens from a clinical trial of genistein supplementation prior to prostatectomy (Lazarevic B, et al. Nutr Cancer 2011). This study was a randomized, placebo-controlled, double-blind clinical trial on forty-seven Norwegian patients who received 30 mg genistein or placebo capsules daily for 3-6 weeks before prostatectomy. Whole genome methylation and expression profiling identified significantly differentially methylated sites and expressed sites between placebo and genistein groups. Differentially regulated genes were involved in developmental processes, stem cell markers, proliferation, and transcriptional regulation. These findings highlight the effects of genistein on global changes in DNA methylation and gene expression in prostate cancer, and provide additional insight into the multiple molecular pathways involved in prostate tumorigenesis.
Citation Format: Birdal Bilir, Jeongseok Edward Lee, Nitya V. Sharma, Bato Lazarevic, Aud Svindland, Omer Kucuk, Carlos S. Moreno. Effects of genistein supplementation on genome-wide DNA methylation and gene expression in patients with localized prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A46.
Abstract A51: DNA methylation in tumor, adjacent non-tumorous and normal breast tissues
Authors: Wagner Erin , Wu Wenting , Liu Yunlong , Nephew Kenneth , Han Jiali , He Chunyan 
Published: May 2016

Abstract
DNA methylation is an essential epigenetic mechanism involved in gene regulation. Aberrant DNA methylation plays an important role in breast cancer initiation and progression via inactivation of tumor suppressor genes and activation of oncogenes. Conventional approaches comparing DNA methylation profiles in tumor and adjacent non-tumorous tissue have shown that changes in DNA methylation contribute to deregulation of gene expression in breast cancer. However, adjacent non-tumorous tissue represents a suboptimal baseline control because its molecular profile may have been altered, and to some extent, similar to that of tumor. Consequently, important breast cancer-associated DNA methylation may not be identifiable in such comparisons. Using RNA-sequencing data generated from freshly-frozen breast tissue samples, we examined expression of methylation-related genes in 119 breast tumor, 47 adjacent normal-appearing breast tissue samples, and 23 normal breast tissue samples from healthy donors. Bowtie and RESM algorithms were used to align raw reads and quantify transcript abundance. Differential expression analyses were performed using edgeR software and normalized transcript counts. Normal breast tissue from healthy women compared to tumor from cancer patients identified differentially expressed cancer genes that are methylated in tumor, such as BRCA1, ESR1, ESR2, CDKN2A, HIC1, CDCP1, and SFRP1. A subset of these genes were found to be deregulated in adjacent non-tumorous tissue in a similar way as in tumor tissue, including PTGS2, SFN, SYK, FHIT , CST6, GADD45A, and THBS1, and are thus undetectable in the comparison between tumor and adjacent non-tumor tissue. In addition, a set of methylation-related genes were identified only in the comparison between tumor and normal tissue, including genes directly involved in the methylation/epigenetic process (HIST1H4A, KDM1B, MAT2B and SAP18) as well as novel target genes that may be methylated and play an important role in carcinogenesis (NFIA, ARHGAP18, and GRHL2). These findings suggest that normal breast tissue from healthy women is the most desirable control in comparison with tumor tissue to identify novel, tissue-specific methylation changes that may be important for carcinogenesis.
Citation Format: Erin Wagner, Wenting Wu, Yunlong Liu, Kenneth Nephew, Jiali Han, Chunyan He. DNA methylation in tumor, adjacent non-tumorous and normal breast tissues. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A51.