bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4945: Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation
Authors: Axelrod Haley D. , Valkenburg Kenneth C. , Simons Brian W. , Pienta Kenneth J. 
Published: July 2017

Abstract
The majority of prostate cancer (PCa) deaths are attributed to bone metastases, which may not arise until years after the primary tumor has been removed. Disseminated tumor cells (DTCs) have been shown to already be present in the bone marrow of patients at the time of prostatectomy, and it is thought that they undergo a period of dormancy, allowing them to remain undetected for years before manifesting into clinically detectable metastases. It is not known what allows PCa DTCs to undergo and persist in this dormant state, but it is likely that factors in the bone marrow niche play an essential role. Previously our group has shown that one of these niche factors, Gas6, can regulate growth of PCa cells. The growth restraining effects of Gas6 on PCa cells is likely mediated through the tyrosine kinase receptor Axl, whose expression was found to be increased on dormant DTCs compared to proliferating metastases in a xenograft mouse model. Here, we utilized the TRAMP model, a genetically engineered mouse model of spontaneous PCa progression, to compare the frequency of Axl-hi and Axl-low bone marrow DTCs that are proliferating versus non-proliferating. Further, we also compared Axl expression and proliferation in matched primary tumors. To investigate the functional significance of Gas6/Axl signaling in mediating PCa dormancy, we have generated Axl knockout PCa cells to test the requirement of Axl in maintaining dormancy, and Axl overexpressing PCa cells to test the sufficiency of Axl in mediating dormancy. Determining the role of Axl and any other regulatory mechanisms of PCa DTC dormancy will be crucial in efforts to prevent lethal and incurable metastasis.
Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Brian W. Simons, Kenneth J. Pienta. Axl-hi DTCs in the bone marrow of a genetically engineered mouse model of prostate cancer exhibit decreased proliferation [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 4945. doi:10.1158/1538-7445.AM2017-4945
Abstract 4947: Her2 inhibition and dormant cell metabolism
Authors: Fox Douglas B. , Alvarez James V. 
Published: July 2017

Abstract
Breast cancer is the most diagnosed cancer in women in the United States, and despite improved prognosis resulting from targeted therapies, tumors commonly re-emerge upon development of therapeutic resistance. In order to overcome this, it is critical to explore the cellular pathways that change in tumors following treatment. While many mechanisms of resistance to targeted therapies have been identified, the metabolic changes that occur following treatment have not been well defined. We believe that these changes may offer a general therapeutic target. Using a doxycycline-inducible Her2 mouse model of breast cancer, we are exploring the molecular and cellular consequences Her2 inhibition. Using in vitro mammosphere cultures derived from these mice, we showed that Her2 loss quickly downregulates ERK and Akt signaling. There is a corresponding decrease in proliferation, and apoptosis is induced in 25-50% of cells. However, a population of cells survives Her2 withdrawal and remains dormant for upwards of one month. We are using these models to study how metabolic pathways are rewired following Her2 inhibition, and we believe that the metabolic pathways adapted upon Her2 inhibition may represent targetable vulnerabilities.
Note: This abstract was not presented at the meeting.
Citation Format: Douglas B. Fox, James V. Alvarez. Her2 inhibition and dormant cell metabolism [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 4947. doi:10.1158/1538-7445.AM2017-4947
Abstract 495: Somatic copy number variants detection using the NEBNext Direct target enrichment method
Authors: Patel Kruti M. , Bowman Sarah K. , Henig Noa , Emerman Amy B. , Barry Andrew , Elfe Charles , Adams Scott , Russello Salvatore , Davis Ted , Hendrickson Cynthia L. 
Published: July 2017

Abstract
Variations in copy number are the most common type of DNA structural variations. Many of these alterations are associated with disease or indicate disease susceptibility. Detection of copy number variants (CNVs) for clinical applications requires efficient, fast and cost effective methods.
Here we describe the use of the NEBNext Direct® hybridization-based target enrichment method to identify somatic CNVs with high sensitivity. This approach begins with target enrichment followed by enzymatic digestion of off-target sequences and ligation of adapters that contain unique molecular identifiers (UMIs). The UMIs enhance the identification of duplicate reads and further increase the final number of on-target reads used for variant detection.
We used a cell line known to contain a deletion in the CDKN2A gene and spiked DNA isolated from the cell line into a HapMap DNA sample that contains full diploid copies of CDKN2A. We were able to detect the gene deletion as a somatic CNV in a dose dependent manner with high sensitivity. Thus, we demonstrate that the NEBNext Direct approach is an efficient technique to detect somatic CNVs of high and low frequencies.
Citation Format: Kruti M. Patel, Sarah K. Bowman, Noa Henig, Amy B. Emerman, Andrew Barry, Charles Elfe, Scott Adams, Salvatore Russello, Ted Davis, Cynthia L. Hendrickson. Somatic copy number variants detection using the NEBNext Direct target enrichment method [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 495. doi:10.1158/1538-7445.AM2017-495
Abstract 4956: Transcriptome-wide association study identifies new prostate cancer susceptibility genes in the OncoArray data
Authors: Mancuso Nicholas , Zheng Wei , Penney Kathryn ,   The PRACTICAL Consortium, Kote-Jarai Zsofia , Haiman Christopher , Gayther Simon , Freedman Matthew , Pasaniuc Bogdan 
Published: July 2017

Abstract
Genome-wide association studies (GWAS) have identified over 150 genomic regions harboring risk variants for prostate cancer which explain one third of all familial risk. However, with some notable exceptions, the causal variants and target susceptibility genes at these risk loci have yet to be identified. Recent work has shown a strong overlap between loci associated with gene expression levels (eQTLs) in prostate tissue and GWAS loci, which suggests that the causal mechanism at a significant proportion of risk loci includes causal alleles that regulate expression levels of nearby susceptibility genes. While overlapping eQTLs with GWAS is a powerful method to prioritize susceptibility genes, it is often the case that multiple eQTLs co-localize at the GWAS risk region (due to linkage disequilibrium (LD) and correlations across transcript levels). This prohibits the identification of the true susceptibility gene as opposed to spurious co-localization at the same locus.
We recently leveraged gene expression imputation to perform transcriptome-wide association studies (TWAS) as a principled approach to measure the strength of association between gene expression and disease status. Here, we use imputed expression to identify new susceptibility genes for prostate cancer in the OncoArray GWAS data. We integrate gene expression data from more than 44 tissues across ~4,000 individuals with GWAS of prostate cancer from the OncoArray in ~140,000 individuals. Our approach identified 118 susceptibility genes for prostate cancer that reside in 90 independent loci across the genome. Of these, we report 7 genes located more than 0.5 Megabases away from any previously reported GWAS loci for prostate cancer, thus providing new risk loci. Second, we use TWAS to investigate genes previously reported as susceptibility genes for prostate cancer through overlaps of eQTL and GWAS. We find 36 (out of 86 previously reported genes) to be significant in TWAS. Overall, our findings highlight the power of integrating gene expression data with GWAS and provide testable hypotheses for future functional validation of prostate cancer risk.
Citation Format: Nicholas Mancuso, Wei Zheng, Kathryn Penney, The PRACTICAL Consortium, Zsofia Kote-Jarai, Christopher Haiman, Simon Gayther, Matthew Freedman, Bogdan Pasaniuc. Transcriptome-wide association study identifies new prostate cancer susceptibility genes in the OncoArray data [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 4956. doi:10.1158/1538-7445.AM2017-4956
Abstract 4969: Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell
Authors: Lu Yanxin , Liu Yang , Su Yu-Ting , Bautista Wendy , Gilbert Mark R. , Wu Jing , Yang Chunzhang 
Published: July 2017

Abstract
INTRODUCTION: Mutations in isocitrate dehydrogenase (IDH1/2) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of IDH mutations in glioma are prognostic for better clinical outcomes with longer patient survival, and greater sensitivity to chemotherapy. In the present study, we explore the molecular mechanisms that determine the chemosensitivity in IDH1-mutated glioma cells, and seek a potential therapeutic strategy by targeting DNA repair pathway in IDH1-mutated cells.
METHODS: We established IDH1-mutated cell lines by introducing pathogenic IDH1 mutations into glioma cells via lentivirus. We confirmed the metabolic deficiency and enhanced chemosensitivity in cells expressing IDH1 mutant enzyme. Further, we measured the intracellular level of nicotinamide adenine dinucleotide (NAD+), Poly (ADP-ribose) polymerase (PARP)-associated DNA repair and DNA damage level in these cells when treated with temozolomide (TMZ). Moreover, we evaluated a PARP inhibitor Olaparib and its synergic effect on TMZ-associated cytotoxicity.
RESULTS: Our results show that the IDH1-mutated cells are more vulnerable to chemotherapy. TMZ treatment resulted in over 20-fold increase of cell death in IDH1-mutated cells compared with their wild type counterpart. IDH1-mutated cells exhibited an over 1.3-fold increase in DNA damage and over 1.42-fold increase in cellular apoptosis under TMZ treatment. Accordingly, IDH1-mutated cells produced 83.8% less poly (ADP-ribose) polymer (pADPR), an important substrate for PARP-associated DNA repair, during TMZ treatment; suggesting their incompetence to maintain genomic integrity due to decreased availability of NAD+. Targeting the PARP-associated DNA repair pathway using Olaparib remarkably potentiated TMZ-induced cytotoxic effects by 2.16 fold in IDH1 mutated cells.
CONCLUSION: Our findings demonstrate that metabolic defects in IDH1-mutated cells affect PARP-associated DNA repair pathway via NAD+ depletion, and therefore prompt the sensitivity to chemotherapies. Targeting PARP-associated DNA repair pathway may represent a novel therapeutic avenue for IDH1-mutated gliomas.
Citation Format: Yanxin Lu, Yang Liu, Yu-Ting Su, Wendy Bautista, Mark R. Gilbert, Jing Wu, Chunzhang Yang. Impaired PARP1 DNA repair defines chemosensitivity in IDH1 mutant cell [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 4969. doi:10.1158/1538-7445.AM2017-4969
Abstract 4975: A small molecule pan Id protein antagonist shows strong antitumor activity
Authors: Wojnarowicz Paulina M. , Desai Bina , Chin Yvette , Lee Sang Bae , Garcia-Cao Marta , Ouerfelli Ouathek , Yang Guangli , Xu Sijia , Goldgur Yehuda , Miller Meredith A. , Chaudhary Jaideep , Garland William A. , Albanese Steven K. , Soni Rajesh , Philip John , Norton Larry , Rosen Neal , Hendrickson Ronald C. , Zhou Xi Kathy , Iavarone Antonio , Dannenberg Andrew J. , Chodera John D. , Pavletich Nikola , Lasorella Anna , Benezra Robert 
Published: July 2017

Abstract
The Id family of helix-loop-helix (HLH) proteins, Id1, Id2, Id3 and Id4, play a critical role in inhibiting differentiation during mammalian embryogenesis. They function in part by sequestering ubiquitously expressed E protein bHLH transcription factors via direct protein-protein interactions. Various Id proteins are re-expressed in adults in a number of pathologic states including cancer and diseases of the vasculature, where their activity has been shown to be essential for disease progression. The present study describes the solving of the Id1-E47 dimer crystal structure and subsequent development and characterization of a small molecule antagonist of the Id protein family, AGX51. AGX51 was identified in an in silico screen for compounds that could bind a hydrophobic crevice adjacent to the loop region of Id1, highly conserved in the Id family. AGX51 inhibits the endogenous Id1-E protein interaction leading to the degradation of Id1 via ubiquitin-mediated proteolysis. The stability of all four members of the Id family are antagonized by AGX51 leading to a G0-G1 arrest and profound inhibition of viability with no acquired resistance observed in multiple cell lines after continuous exposure to the compound. Administration of AGX51 is well tolerated in mice and phenocopies genetic loss of Id expression analyses: suppression of breast cancer metastases to the lung associated with a reduced mesenchymal-to-epithelial transition, perturbation of the vasculature within the primary tumor, and growth regression of paclitaxel resistant breast tumors in combination with paclitaxel therapy. These studies identify a novel, first-in-class compound capable of antagonizing the activity of a protein family formerly considered undruggable and point to the possible utility of AGX51 in the management of multiple disease processes in patients.
Citation Format: Paulina M. Wojnarowicz, Bina Desai, Yvette Chin, Sang Bae Lee, Marta Garcia-Cao, Ouathek Ouerfelli, Guangli Yang, Sijia Xu, Yehuda Goldgur, Meredith A. Miller, Jaideep Chaudhary, William A. Garland, Steven K. Albanese, Rajesh Soni, John Philip, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Robert Benezra. A small molecule pan Id protein antagonist shows strong antitumor 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 4975. doi:10.1158/1538-7445.AM2017-4975
Abstract 498: Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids
Authors: Moorthy Bhagavatula , Jiang Weiwu , Wang Lihua , Kondraganti Sudha R. , Zhou Guodong 
Published: July 2017

Abstract
3-Methylcholanthrene (MC) and benzo[a]pyrene (BP) are potent polycyclic aromatic hydrocarbons (PAHs) carcinogens. PAHs are present in cigarette smoke, diesel exhausts, and charcoal broiled meats, etc. Cytochrome P450 (CYP) 1A/1B1 enzymes play key roles in the activation of PAHs to carcinogenic metabolites, which initiate carcinogenesis by binding covalently to DNA, and the adducts, if not repaired, could lead to tumorigenesis. In this study we tested the hypothesis that pre-treatment of mice with omega-3-fatty acids, i.e. [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will lead to attenuation of PAH-mediated pulmonary DNA adduct formation and pulmonary tumorigenesis. Twelve week old male and female A/J mice received EPA (60 mg/kg) and DHA (40 mg/kg) from day 1 to day 24. Control mice were treated with vehicle corn oil. On day 3, mice were treated with BP (40 µmol/kg) or 3-methylcholanthrene (MC, 40 µmol/kg) by i.p. In the short-term experiment (DNA adduct studies), 3-5 mice from each group were terminated at day 10 (7 days after BP or MC treatment). EPA/DHA significantly suppressed formation of BP-DNA and MC-DNA adducts in lung and liver of both male and female mice. In the long-term experiment (tumor studies), 8 mice for each group continued to receive EPA/DHA twice per week till end of experiment (16 weeks). Pulmonary tumor incidence and multiplicity was significantly suppressed in mice given EPA+DHA, compared to those given the PAHs, BP or MC alone. These studies suggest that the omega 3-fatty acids could be developed as novel candidates for the prevention of PAH-mediated lung cancers in humans.
Citation Format: Bhagavatula Moorthy, Weiwu Jiang, Lihua Wang, Sudha R. Kondraganti, Guodong Zhou. Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids [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 498. doi:10.1158/1538-7445.AM2017-498
Abstract 4983: T cells expressing chimeric PD1 receptors that contain a Dap10 costimulatory domain are a potential treatment for multiple types of cancer
Authors: Deal Kelsey , Nylen Emily , Barber Amorette E. 
Published: July 2017

Abstract
Adoptive transfer of tumor-reactive T cells is a promising anti-tumor therapy for many cancers. To enhance tumor recognition by T cells, chimeric antigen receptors (CAR) consisting of signaling domains fused to receptors that recognize tumor antigens can be created and expressed in T cells. One receptor that is a prospective target for a new chimeric antigen receptor is PD1 because the ligands for the PD1 receptor are expressed on many cancer types. Therefore we developed a murine chimeric PD1 receptor (chPD1) consisting of the PD1 receptor extracellular ligand recognition domain and the activation domain of CD3 zeta. In addition, current chimeric antigen receptor therapies utilize various costimulatory domains to enhance anti-tumor efficacy. Therefore, we also compared the inclusion of CD28, Dap10, 41BB, GITR, ICOS, or OX40 costimulatory domains in our chPD1 receptor to determine which costimulatory domain induced optimal anti-tumor immunity. To determine if this novel CAR could potentially target a wide variety of tumors, the anti-tumor efficacy of chPD1 T cells against murine lymphoma, melanoma, kidney, pancreatic, liver, and colon cancer cell lines was measured. Of the ten cell lines tested, all expressed PD1 ligands on their cell surface, making them potential targets for chPD1 T cells. Regardless of the costimulatory domain in the CAR, all of the chPD1 T cells induced similar levels of T cell proliferation and tumor cell lysis. However, differences were observed in the cytokine secretion profiles depending on which costimulatory receptor was included in the CAR. While most of the chPD1 T cell receptor combinations secreted both pro-inflammatory (IFNγ, TNFα, IL-2, GM-CSF, IL-17, and IL-21) and anti-inflammatory cytokines (IL-10 and IL-5) as determined by ELISA and LegendPlex analysis, chPD1 T cells containing a Dap10 costimulatory domain secreted high levels of proinflammatory cytokines, but did not secrete a significant amount of anti-inflammatory cytokines. Therefore, adoptive transfer of chPD1 T cells could be a novel therapeutic strategy to treat multiple types of cancer and inclusion of the Dap10 costimulatory domain in chimeric antigen receptors may induce a preferential cytokine profile for anti-tumor therapies.
Citation Format: Kelsey Deal, Emily Nylen, Amorette E. Barber. T cells expressing chimeric PD1 receptors that contain a Dap10 costimulatory domain are a potential treatment for multiple types of cancer [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 4983. doi:10.1158/1538-7445.AM2017-4983
Abstract 4984: BNip3 suppresses hepatocellular carcinoma (HCC) growth by limiting lipogenesis
Authors: Macleod Kay F. 
Published: July 2017

Abstract
BNip3 is a mitochondrial protein that promotes the turnover of mitochondria at the autophagolysosome when nutrient supplies are low. BNip3-null livers exhibit lipid accumulation and develop a phenotype mimicking non-alcoholic steatohepatitis, a known precursor for development of hepatocellular carcinoma (HCC). Additionally, BNip3 is silenced in human HCC and other malignancies and this loss often correlates with more aggressive tumors and worse outcomes. However, the functional significance of BNIP3 loss for growth and progression of HCC has not been determined. We utilized the diethylnitrosamine (DEN)-induced mouse model of HCC to determine how loss of BNip3 affected HCC development in the mouse. Wild type and BNip3-null mice were treated with DEN, and tumor burden (size and number) was assessed at 6, 8, and 10 months of age. We also generated primary HCC cell lines from the tumors arising in BNip3-null mice for in vitro analysis of tumor cell growth and metabolism. We observed that BNip3-null mice had reduced tumor latency and enhanced tumor growth rate in the liver following DEN treatment compared to wild type mice consistent with BNip3 functioning as a tumor suppressor of HCC. Interestingly, tumors arising in BNip3-null mice accumulated increased lipid and qPCR analysis of primary tumors and cell lines revealed increased expression of lipogenesis genes compared to wild type. Treatment with a novel fatty acid synthase inhibitor or re-expression of BNip3 in the BNip3-null HCC cell lines reduced tumor cell growth and lipogenesis, and promoted oxidative metabolism. These results indicate that BNip3 acts as a tumor suppressor in HCC by limiting de novo lipogenesis and suggest that fatty acid synthase inhibitors could be effective therapeutically against BNIP3 deficient HCC in patients.
Citation Format: Kay F. Macleod. BNip3 suppresses hepatocellular carcinoma (HCC) growth by limiting lipogenesis [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 4984. doi:10.1158/1538-7445.AM2017-4984