bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-290: Multiple distinct mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma
Authors: Powers John T. , Tsanov Kaloyan M. , Roles Frederik , Ebright Richard , Seligson Marc , de Soysa Yvanka , Cahan Patrick , Theissen Jessica , LaPier Grace S. , Pearson Dan S. , Berthold Frank , Daley George Q. 
Published: August 2015

Abstract
The let-7 microRNA family are known tumor suppressors often deregulated in cancer, yet the underlying mechanisms of let-7 disruption remain poorly understood. Neuroblastoma, a neural crest derived tumor, is defined in part by poor prognosis associated with genetic amplification of MYCN, itself a let-7 target. The let-7 biogenesis inhibitor LIN28B has recently been implicated as a critical regulator of MYCN, but we have employed siRNA and CRISPR-mediated gene disruption to show that LIN28B is dispensable for both MYCN protein expression and growth of MYCN-amplified neuroblastoma cell lines despite robust de-repression of let-7, which prompted us to explore additional mechanisms for let-7 disruption. Consequently, we have found that amplified MYCN mRNA is a potent let-7 sponge that through exceptionally high expression defines a sub-class of self-sponging amplified-competing-endogenous-RNA (aceRNA), which reconciles the dispensability of LIN28B in NB cell lines. In addition, by analyzing a large cohort of tumor samples from patients, we observe frequent genomic loss of let-7 that inversely associates with MYCN-amplification, providing a functional explanation for the known MYCN-amplification-independent pattern of chromosome 3p and 11q loss, which harbor let-7g and let-7a2, respectively. We thus propose a model whereby let-7 disruption by genetic loss, LIN28B expression, or aceRNA sponging is a unifying mechanism of neuroblastoma pathogenesis. Indeed, our data show that the majority of neuroblastomas have at least one let-7 disruption event and that genetic loss in non-MYCN-amplified tumors marks decreased survival, further underscoring its importance. The inverse selective relationship between allelic loss and sponging of let-7 from highly expressed or amplified oncogenes may have broad implications for oncogenesis.
Note: This abstract was not presented at the meeting.
Citation Format: John T. Powers, Kaloyan M. Tsanov, Frederik Roles, Richard Ebright, Marc Seligson, Yvanka de Soysa, Patrick Cahan, Jessica Theissen, Grace S. LaPier, Dan S. Pearson, Frank Berthold, George Q. Daley. Multiple distinct mechanisms disrupt let-7 miRNA biogenesis and function in neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2015-LB-290
Abstract LB-291: microRNA regulation of Nrf2: A link between autophagy and oxidative stress
Authors: Pokrzywinski Kaytee L. , Rao V. Ashutosh 
Published: August 2015

Abstract
Understanding the relationship between autophagy and excessive oxidative stress is crucial for determining the fate of cancer cells exposed to redox-active chemotherapeutic agents. Previous studies have shown that Mitoquinone (MitoQ), a redox active, mitochondrialy targeted ubiquinone derivative, can induce autophagy through the generation of excess reactive oxygen species and stimulate the antioxidant response involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in breast cancer cells. Nrf2 is a transcription factor that is up-regulated during oxidative stress and activates the antioxidant response element, which in turn regulates antioxidant expression. The aim of this study was to evaluate microRNA (miRNA) as a link between oxidative stress and autophagy through modulation of Nrf2 activity. miRNA are endogenous 18-22 bp double stranded RNA that become active when bound to the 3′ UTR of target messenger RNA (mRNA). The primary goal was to suppress Nrf2 activity with miRNA so that oxidative stress, in the absence of antioxidants, can result in apoptosis rather than autophagy. miRNA expression was evaluated using Illumina RNA sequencing analyses in MDA-MB-231 human breast cancer cells after treatment with DMSO or MitoQ (5 μM), in the presence and absence of Nrf2 silencing RNA (siRNA). Preliminary results show that Nrf2 is the most active at or before 18hrs of treatment (tested up to 72hrs) accompanied by a significant increase in nuclear Nrf2 levels. We are currently evaluating the transcriptome to identify key miRNAs that were up-regulated during Nrf2 suppression and down-regulated during Nrf2 activation. Nrf2 activity was also assessed using a stably transfected GFP modified MDA-MB-231 cell line containing the 3′ UTR region of Nrf2. Prior to obtaining the transcriptome, preliminary Nrf2-miRNA tests were performed with miR-93 as this miRNA has been shown to regulate Nrf2 expression in other studies on human breast cancer cell lines. We are currently assessing the effect of miR-93 on Nrf2 regulation, autophagy and apoptosis to decipher how miR-93 and other microRNA regulate Nrf2 signaling following excessive oxidative stress.
Citation Format: Kaytee L. Pokrzywinski, V. Ashutosh Rao. microRNA regulation of Nrf2: A link between autophagy and oxidative stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2015-LB-291
Abstract LB-292: Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention
Authors: To Kenneth K.W. , Leung Wing Wah , Ng Simon S.M. 
Published: August 2015

Abstract
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. It develops in a complex multi-step process. The majority of studies to date have focused on genetic mutations and epigenetic changes that drive the CRC carcinogenesis process. Xenobiotic transporters play an important role in safeguarding our body from external toxic substances. These transporters lining the gastrointestinal tract may thus protect us from the dietary carcinogens. This study aims to investigate the downregulation of an efflux transporter ABCG2 in colorectal cancer versus normal colon mucosa, so as to shed some light on its relevance to CRC initiation and progression. We found that ABCG2 expression is at least 50-fold lower in adenomatous polyps and colon carcinoma specimens obtained from CRC patients than in their matched pair of adjacent normal colon mucosa. This may facilitate the accumulation of genotoxins to propel tumor initiation and progression. The underlying mechanism(s) for ABCG2 under-expression in CRC is currently not known. To this end, aberrant promoter methylation of ABCG2 has been reported to cause its repression in a few cancer types including renal carcinoma and multiple myeloma. On the other hand, ABCG2 promoter demethylation has been reported to upregulate the transporter to mediate multidrug resistance in lung cancer and acute lymphoblastic leukemia. In this study, miR-203 was found to be downregulated in all polyps and CRC specimens, relative to adjacent normal colon mucosa. We demonstrated that the de novo DNA methyltransferase DNMT3 is a direct target of miR-203. Importantly, by relieving the repression on DNMT3, the lower expression of miR-203 in CRC caused remarkable ABCG2 promoter methylation and lower ABCG2 expression in colon cancer cell lines and the patient CRC specimens. In spite of the complex sequential genetic mutations and epigenetic changes leading to CRC formation, we proposed that the restoration of the xenobiotic transporter ABCG2 function via modulating this new microRNA-DNA methylation mechanism in precancerous cells may represent an attractive strategy to stop or delay the carcinogenesis process.
Citation Format: Kenneth K.W. To, Wing Wah Leung, Simon S.M. Ng. Epigenetic downregulation of ABCG2 in colorectal cancer by a novel microRNA-DNA methylation mechanism - an attractive target for cancer prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-292. doi:10.1158/1538-7445.AM2015-LB-292
Abstract LB-294: Cellular microRNAs whose expression is altered by the oncogenic mouse polyomavirus
Authors: Chokkalingam Neethu , Sung Chang K. 
Published: August 2015

Abstract
microRNAs are non-coding small RNAs that regulate expression of many genes and have been proposed as useful biomarkers for diverse diseases including cancer. Studies of the highly oncogenic mouse polyomavirus (Py) have identified many pathways in tumor development. The pathways found altered in Py-induced tumors strongly overlap with those affected in various human cancers, highlighting the Py-mouse systems's broad applicability to oncology. In spite of the resolving power of microRNA expression analysis and the relevance of the oncogenic mouse virus to human cancer, currently there is a lack of systematic profiling analysis on microRNAs in the context of the early phases of Py-induced tumor development and progression. We focused our investigation on cellular microRNAs that may be targeted by Py during viral infection for possible microRNA biomarkers of oncogenesis. To explore the effects of Py infection on the host microRNA expression and to identify those microRNAs that are functionally involved in Py-induced tumorigenesis, microRNA expression in uninfected and Py-infected mouse cells were compared using the microRNA Array kit. This qRT-PCR based screening and further validation assays revealed that the levels of seven murine microRNAs were elevated in Py-infected cells which include miR-let7a, miR-32, miR-124, miR-141, miR-146a, miR-215, and miR-218.Our further research focuses on identification of genes targeted by these microRNAs and their roles during viral infection. This study will bring a better understanding of microRNA involvement in tumor development, progression and possibly prevention.
Citation Format: Neethu Chokkalingam, Chang K. Sung. Cellular microRNAs whose expression is altered by the oncogenic mouse polyomavirus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2015-LB-294
Abstract NG07: Immunomodulatory and tumor cell killing effects of the demethylating agent 5-azacytidine in ovarian cancer
Authors: Chiappinelli Katherine B. , Strissel Pamela , Yen Ray-Whay Chiu , Li Huili , Stone Meredith L. , Murphy Lauren , Akman Benjamin , Zahnow Cynthia A. , Strick Reiner , Baylin Stephen B. 
Published: August 2015

Abstract
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Citation Format: Katherine B. Chiappinelli, Pamela Strissel, Ray-Whay Chiu Yen, Huili Li, Meredith L. Stone, Lauren Murphy, Benjamin Akman, Cynthia A. Zahnow, Reiner Strick, Stephen B. Baylin. Immunomodulatory and tumor cell killing effects of the demethylating agent 5-azacytidine in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr NG07. doi:10.1158/1538-7445.AM2015-NG07
Abstract PL02-04: Drastically reducing HPV-associated cancers through etiologically-based primary and secondary prevention
Authors: Lowy Douglas R. 
Published: August 2015

Abstract
HPV infection causes more than 25,000 anogenital and oropharyngeal cancers annually in US men and women and is responsible for about 10% of all female cancers worldwide. In the developing world, where cervical cancer is the main HPV-associated cancer, a woman's lifetime risk of dying from this cancer is estimated to be about 1%. Persistent infection by more than 10 HPV types can lead to cervical cancer; HPV16 and HPV18 account for about 70% of these tumors. These two HPV types account for more than &gt;90% of the HPV-positive non-cervical cancers. Primary prevention by the FDA-approved HPV vaccines has the potential to reduce the incidence and mortality attributable to the HPV-positive anogenital and oropharyngeal cancers, while secondary prevention through HPV-based screening for cervical cancer can lower the incidence and mortality for this cancer. The first generation virus-like particle HPV vaccines, which target HPV16 and HPV18, can prevent more than 90% of new persistent infections attributable to these HPV types. These vaccines are already having an impact on HPV-induced early disease markers in vaccinated populations, including evidence of herd immunity. The high immunogenicity of these vaccines suggests that it should be possible to safely reduce the number of recommended vaccine doses from three to two - and perhaps eventually even to one dose - in young adolescents, who represent the main target group for the vaccine. A second generation vaccine, which targets the seven most oncogenic HPV types and has the potential to prevent ∼90% of cervical cancer, was recently approved by the FDA. HPV-based testing was recently approved by the FDA for primary cervical cancer screening in women 25 or older. Compared to cytology-based screening, HPV-based testing has higher sensitivity for detecting infections that may lead to squamous cell carcinoma and adenocarcinoma. It is predicted that the greater sensitivity of HPV-based testing will be even more important for cervical cancer screening of vaccinated women.
Citation Format: Douglas R. Lowy. Drastically reducing HPV-associated cancers through etiologically-based primary and secondary prevention. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr PL02-04. doi:10.1158/1538-7445.AM2015-PL02-04
Abstract RAOS15-03: Pancreatic tumor stroma as a therapeutic target
Authors: Evans Ronald M. 
Published: August 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) occurs in the context of an exuberant desmoplastic response that produces a ‘living chimera’ of tumor and activated stromal components. A prominent feature of the stromal response is the transformation of the Vitamin A storing pancreatic stellate cell (PSC) to activated myofibroblasts. We hypothesized that restoration of the quiescent PSC phenotype could disrupt tumor-stroma crosstalk and thus improve response to chemotherapy. Recently, we have shown that the vitamin D receptor (VDR) is expressed at high levels in activated human pancreatic tumor stroma and, in response to ligand, acts as a master transcriptional regulator of PSCs to reprise the quiescent state. In vivo, a synthetic VDR agonist (Cal) induced signal-dependent transcriptional remodeling of tumor stroma, enhancing the anti-tumor effects of gemcitabine by increasing intra-tumoral concentration 5-fold to reduce tumor growth. A survival study in KPC mice shows that addition of CAL results in a 57% increase in lifespan relative to Gemcitabine treatment alone. An approved IND enables the exploration of CAL in the neo-adjuvant setting in patients with resectable PDAC. This Phase I trial is designed to establish whether CAL (Zemplar) is able to reach the tumor and alter genes and other measurable responses linked to stromal reprogramming.
Citation Format: Ronald M. Evans. Pancreatic tumor stroma as a therapeutic target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr RAOS15-03. doi:10.1158/1538-7445.AM2015-RAOS15-03
Abstract SY04-03: Molecular networks defining cell identity
Authors: Daley George Q. 
Published: August 2015

Abstract
Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineering cell identity for applications in research and regenerative medicine. I will describe CellNet, a network biology platform developed to assess the fidelity of cellular engineering and to generate specific hypotheses for improving cell derivations. Analyzing published accounts, we have confirmed that reprogramming to pluripotency is remarkably robust, and found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell type gene regulatory networks. We have applied CellNet to two cell fate conversion paradigms: conversion of B cells to macrophages and fibroblasts to hepatocyte-like cells, and learned provocative new lessons about the nature of these engineered cells. CellNet analysis, iteratively coupled to experimental validation, provides a rational strategy to enhance the derivation of target cells for research and therapy.
Citation Format: George Q. Daley. Molecular networks defining cell identity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY04-03. doi:10.1158/1538-7445.AM2015-SY04-03
Abstract SY07-04: The evolutionary landscape of CLL: Therapeutic implications
Authors: Wu Catherine J. 
Published: August 2015

Abstract
Clonal evolution is a key feature of cancer progression and relapse. Recent studies across cancers have demonstrated the extensive degree of intratumoral heterogeneity present within individual cancers. We hypothesized that evolutionary dynamics contribute to the variations in disease tempo and response to therapy that are highly characteristic of chronic lymphocytic leukemia (CLL). We have recently investigated this phenomenon by developing a pipeline that estimates the fraction of cancer cells harboring each somatic mutation within a tumor through integration of whole-exome sequence (WES) and local copy number data (Landau et al., Cell 2013). By applying this analysis approach to 149 CLL cases, we discovered earlier and later cancer drivers, uncovered patterns of clonal evolution in CLL and linked the presence of subclones harboring driver mutations with adverse clinical outcome. Thus, our study, generated from a heterogeneous sample cohort, strongly supports the concept that CLL clonal evolution arises from mass extinction and therapeutic bottlenecks which lead to the emergence of highly fit (and treatment resistant) subclones. We further hypothesized that epigenetic heterogeneity also shapes CLL clonal evolution through interrelation with genetic heterogeneity. Indeed, in recent work, we have uncovered stochastic methylation disorder as the primary cause of methylation changes in CLL and cancer in general, and that this phenomena impacts gene transcription, genetic evolution and clinical outcome. Thus, integrated studies of genetic and epigenetic heterogeneity in CLL have revealed the complex and diverse evolutionary trajectories of these cancer cells.
Immunotherapy is exquisitely suited for specifically and simultaneously targeting multiple lesions. We have developed an approach that leverages whole-exome sequencing to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in multi-epitope personalized therapeutic vaccines. We are pioneering this approach in an ongoing trial in melanoma and will now expand this concept to address diverse malignancies. Our expectation is that the choice of tumor neoantigens for a vaccine bypasses thymic tolerance and thus generates highly specific and potent high-affinity T cell responses to eliminate tumors in any cancer, including both ‘trunk’ and ‘branch’ lesions.
Citation Format: Catherine J. Wu. The evolutionary landscape of CLL: Therapeutic implications. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY07-04. doi:10.1158/1538-7445.AM2015-SY07-04
Abstract SY09-04: Cancer crosstalk: miR-200-containing extracellular vesicles promote breast cancer cell metastasis
Authors: Lieberman Judy , Le Minh 
Published: August 2015

Abstract
Metastasis is the major cause of death of breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and nonmetastatic cancer cells via extracellular vesicles. miR-200 was secreted in extracellular vesicles from metastatic murine and human breast cancer cell lines, and miR-200 levels were increased in sera of mice bearing metastatic tumors. In culture, murine and human metastatic breast cancer cell extracellular vesicles transferred miR-200 microRNAs to nonmetastatic cells, altering gene expression and promoting mesenchymal-to-epithelial transition. In murine cancer and human xenograft models, miR-200-expressing tumors and extracellular vesicles from these tumors promoted metastasis of otherwise weakly metastatic cells either nearby or at distant sites and conferred to these cells the ability to colonize distant tissues in a miR-200-dependent manner. Together, our results demonstrate that metastatic capability can be transferred by the uptake of extracellular vesicles.
Citation Format: Judy Lieberman, Minh Le. Cancer crosstalk: miR-200-containing extracellular vesicles promote breast cancer cell metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY09-04. doi:10.1158/1538-7445.AM2015-SY09-04
Abstract SY13-03: Novel targeted therapies in myelodysplastic syndrome
Authors: Ebert Benjamin 
Published: August 2015

Abstract
Ubiquitin ligases target specific proteins for degradation, and pharmacologic modulation of ubiquitin ligase activity has the potential for therapeutic efficacy in cancer by altering the abundance of proteins that are required for tumor cell survival. Thalidomide and its derivatives, lenalidomide and pomalidomide, represent the first class of drugs that act by binding and changing the activity of a specific ubiquitin ligase. These compounds bind the CRL4-CRBN ubiquitin ligase, inducing the ubiquitination and consequent degradation of specific protreins. Lenalidomide is a highly effective drug for the treatment of myelodysplastic syndrome (MDS) with del(5q), multiple myeloma, and some additional B cell lymphomas. In multiple myeloma cells, lenalidomide increases the binding of two substrates, IKZF1 and IKZF3, to the CRBN substrate adapter; increases the ubiquitination of these substrates; and causes the targeted degradation of IKZF1 and IKZF3, transcription factors that are essential for the differentiation and survival of plasma cells including multiple myeloma cells. In del(5q) MDS, lenalidomide targets CSNK1A1 for destruction. Haploinsufficiency for CSNK1A1, a gene located within the common deleted region on chromosome 5q, results in selective targeting of the del(5q) clone. Recent studies indicate that lenalidomide, pomalidomide, and thalidomide modulate the CRl4-CRBN ubiquitin ligase in distinct ways, raising the possibility that new molecules may induce degradation of other proteins, creating new therapeutic opportunities.
Citation Format: Benjamin Ebert. Novel targeted therapies in myelodysplastic syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2015-SY13-03