bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1888: The FAD-directed LSD1 specific inhibitor, INCB059872, is a promising epigenetic agent for AML therapy by inducing differentiation of leukemic stem/progenitor cells
Authors: Chadderton Antony , Ye Min , Diamond Melody , Roman Valerie , Weber Michael , He Chunhong , Wu Liangxing , Yeleswaram Swamy , Roberts Alan , Yao Wenqing , Hollis Gregory , Huber Reid , Scherle Peggy , Ruggeri Bruce , Lee Sang Hyun 
Published: August 2018

Abstract
Numerous studies have elucidated that the most pivotal functions of lysine specific demethylase-1 (LSD1) are associated with regulating normal or malignant hematopoiesis by maintaining stem cell self-renewal and regulating myeloid differentiation. In preclinical models, studies with either pharmacological inhibition or genetic knockdown of LSD1 demonstrated that LSD1 is essential for differentiation of progenitor cells during normal hematopoiesis. In the clinic, AML manifests itself via clonal expansion of abnormal differentiation and proliferation of myeloid cells and, therefore, the inhibition of LSD1 activity with small molecule inhibitors could be a promising therapeutic approach for AML. Previously, we reported upon the identification of a flavin adenine dinucleotide (FAD) directed LSD1 specific inhibitor, INCB059872, which is efficacious in preclinical mouse models utilizing human AML cell lines and primary AML cells by inducing cell differentiation as indicated by the induction of CD11b and CD86 markers. Using a larger panel of myeloid and HSC flow cytometry markers, our currents efforts expanded upon these observations to ascertain whether INCB059872 enhanced lineage commitment at hematopoietic stem cell (HSC) and/ or promoted monocytic/granulocytic differentiation of human primary AML cells ex vivo and in human systemic AML PDX models. In both human AML PDX models and human primary AML samples, INCB059872 increased myeloid differentiation with increasing populations of monocytes (CD14+) and granulocytes (CD15+). Furthermore, INCB059872 induced the differentiation of early hematopoietic progenitors, CD34+/CD38- to more committed CD34+/CD38+ multipotent/oligopotent progenitors, which in turn gave rise to lineage specific progenitors in the human AML PDX models. These studies support further exploration of INCB059872 as a promising novel epigenetic agent for AML therapy whose mechanism of action lies in part through the induction of differentiation of leukemic stem/progenitor cells to more committed hematopoietic lineages.
Citation Format: Antony Chadderton, Min Ye, Melody Diamond, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee. The FAD-directed LSD1 specific inhibitor, INCB059872, is a promising epigenetic agent for AML therapy by inducing differentiation of leukemic stem/progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1888.
Abstract 19: Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer cells
Authors: Shimoda Masafumi , Hori Ami , Noguchi Shinzaburo 
Published: August 2018

Abstract
Trastuzumab (Tzm) is a drug that targets HER2/ERBB2/Neu, and is essential for the treatment of HER2-positive breast cancer. However, resistance to the drug is a major obstacle in controlling the progression of this devastating disease. We hypothesized that Tzm load might induce a phenotypic change in HER2-positive breast cancer cells, enabling them to escape and survive Tzm activity. We conducted comprehensive immunophenotyping to detect the phenotypic changes in HER2-positive breast cancer cells loaded with Tzm, and compared the immunophenotype of Tzm-loaded cells with that of control cells based on the criteria determined a priori. Out of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated. Surprisingly, all the antigens were related to endothelial and stem cell phenotypes, suggesting that Tzm load induced vasculogenic mimicry (VM). Moreover, we found VM markers like COX2, MMP2, MMP14, phospho-SMAD2/3, VEGFA, HIF1A, and TWIST1 to be upregulated in Tzm-loaded cells. However, Tzm-loaded cells did not exhibit tube formation on Matrigel, a hallmark of VM. Since the Tzm-loaded cells were still sensitive to Tzm, we used three Tzm-resistant cell lines to investigate if Tzm resistance accompanied VM. All Tzm-resistant cell lines exhibited tube formation on Matrigel. Importantly, several growth factors including EGF, FGF2, IGF1, and VEGF promoted VM in these cells, suggesting that single molecular-targeted drugs did not effectively inhibit VM as other growth factors could quickly compensate the VM pathways. We then examined if eribulin, a tubulin-binding chemotherapeutic drug that promotes vascular remodeling, inhibited VM in Tzm-resistant cells. Eribulin inhibited tube formation in Tzm-resistant cells at a clinically relevant concentration. In conclusion, Tzm load induces an incomplete vasculogenic phenotype in HER2-positive breast cancer cells. The cells exhibit VM after eventually acquiring Tzm resistance. Since VM drives metastasis, its regulation in Tzm-resistant HER2-positive breast cancer appears to be a promising approach in suppressing the progression of HER2-positive breast cancer.
Citation Format: Masafumi Shimoda, Ami Hori, Shinzaburo Noguchi. Trastuzumab resistance accompanies vasculogenic mimicry in HER2-positive breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 19.
Abstract 1911: Uncovering novel targets of recurrent glioblastoma using transcriptomic profiling in a patient-derived xenograft model
Authors: Yelle Nicolas , Chokshi Chirayu , Vora Parvez , Brown Kevin R. , Qazi Maleeha A. , Singh Mohini , Adams Jarrett J. , Venugopal Chitra , Sidhu Sachdev , Moffat Jason , Singh Sheila K. 
Published: August 2018

Abstract
Glioblastoma (GBM) is the most common and aggressive adult primary brain tumor feared for its near uniformly fatal prognosis despite advances in multimodal therapy including surgical resection, chemotherapy and radiation. Poor patient survival due to tumor relapse is thought to be linked to intratumoral heterogeneity (ITH), driven by various environmental cues including chemotherapy and radiation treatment. ITH can be explained at the cellular level by the existence of multiple populations of cancer cells, including cancer stem cells (CSCs), which have acquired stemness properties like self-renewal, proliferation, and multilineage differentiation. In brain tumors, CSCs or brain tumor initiating cells (BTICs), have been shown to be resistant to both chemotherapy and radiation treatment, allowing them to escape therapy and allowing for tumor recurrence. To profile ITH as it evolves through therapy delivery, we have developed a novel and dynamic BTIC patient-derived xenograft (PDX) model of treatment-refractory human GBM, allowing for multimodal profiling of GBM BTICs through tumor engraftment, remission, and recurrence. In this study, we present the transcriptomic profiling at each stage, and novel target selection and validation through CRISPR/Cas9 knockouts, well-established in vitro stem cell assays, and in vivo characterization of their tumor initiation, development, and maintenance properties. Despite the fact that the BTIC population is responsible for GBM recurrence and thus patient demise, it remains a largely unknown landscape. Consequently, therapies that focus on targeting the BTIC compartment within the bulk tumor would provide better treatment and prognosis for patients with brain tumors. The study we present provides a unique therapeutic window into the recurrence of GBM, which drives patient mortality, yet is profiled far less than primary treatment-naïve GBM.
Citation Format: Nicolas Yelle, Chirayu Chokshi, Parvez Vora, Kevin R. Brown, Maleeha A. Qazi, Mohini Singh, Jarrett J. Adams, Chitra Venugopal, Sachdev Sidhu, Jason Moffat, Sheila K. Singh. Uncovering novel targets of recurrent glioblastoma using transcriptomic profiling in a patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1911.
Abstract 2012: The generation of a NSCLC EMT reporter cell line for metastatic lung cancer drug discovery and development
Authors: Enuameh Metewo S. , Kumari Sangeeta , Zou Chauzhong , Foulke John , Turner Elizabeth , Shu Weiguo , Newman Robert 
Published: August 2018

Abstract
Cancer metastasis continues to be the leading cause of mortality in cancer patients around the world. One of the prominent biological processes implicated in cancer metastasis is epithelial-to-mesenchymal transition (EMT). EMT has also been shown to have roles in many aspects of cancer initiation and progression, including tumorigenesis and drug resistance. Despite the accumulation of a large body of data on the association of EMT with cancer, to date, EMT has not been an active target for therapeutic development partly due to the lack of appropriate in vitro models. Utilizing some of the basic biology of EMT, we have created a novel advanced in vitro model for use in both basic research and discovery of new anti-EMT drugs.
In lung cancer, vimentin (VIM) intermediate filament (IF) proteins are associated with EMT, and the metastatic spread of cancer. Vimentin expression is generally upregulated when epithelial cells transition to the mesenchymal phenotype. We capitalized on this biological phenomenon, using CRISPR/Cas9 gene editing to generate a VIM RFP (red fluorescent protein) reporter cell line in the A549 non-small cell lung cancer (NSCLC) cell line; one of the most widely used and recognized lung cancer cell lines. The A549 VIM RFP cell line harbors a C-terminal red fluorescent protein (RFP) tag on the vimentin gene which enables end-point or real-time tracking of the EMT status as cells transition from epithelial to mesenchymal phenotype under defined conditions. The EMT reporter cell line was verified at the nucleic acid (genomic and mRNA) and protein levels as well as in cell-based assays. Bio-functional evaluation of the A549 VIM RFP cell line shows sensitivity to metastatic NSCLC drugs PP1 (SRC inhibitor) and A83-01 (ALK5 inhibitor). These results provide the foundation for the use of this cell line in high throughput screening (HTS) applications including the identification of new anti-EMT drugs for metastatic NSCLC. Furthermore, the A549 Vim RFP reporter cell line is also a convenient and sensitive model for basic science research on the mechanisms of metastasis.
Citation Format: Metewo S. Enuameh, Sangeeta Kumari, Chauzhong Zou, John Foulke, Elizabeth Turner, Weiguo Shu, Robert Newman. The generation of a NSCLC EMT reporter cell line for metastatic lung cancer drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2012.
Abstract 2042: Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine-tune the HIF1α/VEGFA axis in breast cancer angiogenesis
Authors: Liang Huichun , Zhou Zhongmei , Chen Ceshi 
Published: August 2018

Abstract
It is well documented that hypoxia activates the hypoxia-inducible factor (HIF1α)/vascular endothelial growth factor A (VEGFA) axis to promote angiogenesis in breast cancer. However, it is unclear how this axis is negatively regulated. A number of studies suggest that miR-153 inhibits tumor growth and metastasis by targeting SNAI1, ZEB2, MTDH, ADAM19, AKT1, HECTD3, and MCL1. We recently reported that miR-153 was induced by mifepristone and inhibited the breast cancer stem cells by down-regulating KLF5. In this study, we demonstrated that miR-153 directly inhibits expression of HIF1α by binding to the 3'UTR of HIF1A mRNA, as well as suppresses tube formation of primary human umbilical vein endothelial cells (HUVECs) and breast cancer angiogenesis by decreasing the secretion of VEGFA. Importantly, expression of miR-153 was induced by hypoxia-stimulated ER stress, which activates IRE1α and its downstream transcription factor XBP1. XBP1 directly binds to the promoter of the miR-153 host gene PTPRN and activates transcription. These results indicate that hypoxia induces miR-153 to fine tune the HIF1α/VEGFA axis in breast cancer angiogenesis and miR-153 could be used for breast cancer anti-angiogenesis therapy.
Citation Format: Huichun Liang, Zhongmei Zhou, Ceshi Chen. Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine-tune the HIF1α/VEGFA axis in breast cancer angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2042.
Abstract 2247: Accelerating cancer research using big data with BioKDE platform
Authors: Pang Xiaodong , Bou-Dargham Mayassa J. , Liu Yuhang , Cui Zihan , Sha Linlin , Zhao Tingting , Zhang Jinfeng 
Published: August 2018

Abstract
Large volumes of data have been generated in biomedical field every day and made publicly accessible. A significant portion of the data are highly under-analyzed. On the other hands, biomedical researchers having problems that can be solved by these data do not have the expertise to access and analyze the data. The BioKDE (Biomedical Knowledge Discovery Engine) platform aims to bridge this gap by accelerating biomedical discovery through integration and mining of large volumes of public genomic data. We have integrated a large volume of genomics data from TCGA (the Cancer Genome Atlas) and GEO (Gene Expression Omnibus) database, which are linked with patient clinical information. Powerful and versatile query functions were built for the integrated data. Basic and advanced analysis tools have been implemented with user-friendly interfaces. Pipelines can be built by chaining the query tools with analysis tools to perform sophisticated data acquisition and analysis tasks very conveniently. Pipelines can be saved and shared among researchers to quickly replicate certain analyses using the same dataset or different datasets. A large number of novel discoveries have been made, which can be used directly to write scientific research papers using these discoveries alone or by combining with additional experimental validation studies. We will present a few case studies published recently to illustrate the power of the BioKDE. We are looking for collaborators to write papers together for the discoveries we made. The platform can be accessed at http://www.insilicom.com.
Citation Format: Xiaodong Pang, Mayassa J. Bou-Dargham, Yuhang Liu, Zihan Cui, Linlin Sha, Tingting Zhao, Jinfeng Zhang. Accelerating cancer research using big data with BioKDE platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2247.
Abstract 2250: Tumor mutational burden: Guidelines for derivation and robustness of measurement
Authors: Mola Natalie , Schu Matthew , Stiegelmeyer Suzy , Jones Wendell , Weigman Victor J. 
Published: August 2018

Abstract
Tumor mutational burden (TMB) is defined as the number of somatic mutations per Mb of the genome and is used to represent accumulation of somatic mutations over the life of the tumor. Recent evidence has shown that high TMB scores are associated with improved response to immune therapies across multiple indications. However, the derivation of this score is not well characterized, nor is this score universally performed across laboratories.
Here we describe our methodology for calculating TMB, which considers an estimation of true germline mutations, the efficacy of different somatic callers, and the identification of regions within a capture panel that most reliably contribute to robust TMB scoring. To accomplish this, we only include positions that fall within high confidence regions of the genome as defined by NIST GIAB datasets HG001-HG005 v3.3.2. The high confidence regions encompass 88% of the exome.
Somatic variant calling is performed utilizing the tumor and normal samples using only positions where there is sufficient depth of coverage in both samples. Any remaining germline variants are excluded, leaving only somatic variants in the targeted, high-confidence regions for the final TMB calculation. TMB calculations utilizing high-confidence regions reduce the contribution of false positive variants in the mutational burden estimate.
We have compared TMB scores using this approach to those provided from evaluating somatic calls from TCGA, where matched tumor/normal pairs exist. In addition, we introduce a method to determine the effect on TMB scores when in silico determination of germline variants is used to derive somatic calls when matching normal samples are not available.
Defining the robustness of this score across and criteria for its derivation will help better position defining analytical range and future utility across indications and NGS panels
Citation Format: Natalie Mola, Matthew Schu, Suzy Stiegelmeyer, Wendell Jones, Victor J. Weigman. Tumor mutational burden: Guidelines for derivation and robustness of measurement [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2250.
Abstract 2775: A novel immunostimulatory OX40/PD-L1 bivalent bispecific antibody (MEDI1109) for the treatment of patients with cancer
Authors: Oberst Michael D. , Kasturirangan Srinath , Sachs Clifford , Auge Catherine , Moynihan James , Rothstein Raymond , Hair James , Neal Francis , Mamidi Srinivas , Hanabuchi Shino , Watkins Amanda , Zheng Yanan , Rosenthal Kim , Freeman Daniel J. , Hammond Scott 
Published: August 2018

Abstract
Targeted immunotherapy utilizing agonist antibodies (Ab) to OX40 shows great promise in preclinical mouse models alone or in combination with various therapies including PD1/PD-L1 antagonist Abs. Ab-mediated signaling through OX40 requires higher-order clustering by Fcγ receptors to co-stimulate antitumor-specific T cells and attenuate regulatory T cell (Treg) immunosuppression, leading to antitumor activity. To date, OX40 agonists are well-tolerated but show limited activity alone or in combination with checkpoint blockade in clinical trials. We hypothesize that the antitumor activity of OX40 agonists in patients may be limited by insufficient intratumoral exposure and an inadequate amount of clustering by Fcγ receptors within the tumor microenvironment. To overcome these limitations, we engineered MEDI1109, a bivalent bispecific Ab composed of an OX40 agonist Ab molecularly fused to two single-chain variable fragments derived from a PD-L1 antagonist. The resulting bispecific Ab retained the functional properties of each parent Ab that included binding and agonizing OX40, binding and full blockage of the PD-L1/PD-1 pathway, depletion of OX40+ Tregs and overcoming Treg suppression. Emerging data suggest that the bispecific Ab also drives novel biology including (1) increased OX40 agonism through clustering by either PD-L1 and Fcγ receptors, (2) improved intratumoral exposure through PD-L1 targeting, (3) elimination of PD-L1 positive tumor cells by NK cell mediated antibody-dependent cellular cytotoxicity and (4) enhanced antitumor immunity through concurrent PD-L1/PD-1 blockade on tumor cells and OX40 co-stimulation of antitumor T cells. Intravenous administration of OX40/PD-L1 bispecific Abs to cynomolgus monkeys resulted in the proliferation of peripheral blood CD4+ and CD8+ total memory T-cell populations, and in the reduction of soluble PD-L1 levels in the plasma. These results demonstrate that MEDI1109 is a unique and potent immune modulating agent and may be utilized to enhance antitumor immunity in patients with cancer.
Citation Format: Michael D. Oberst, Srinath Kasturirangan, Clifford Sachs, Catherine Auge, James Moynihan, Raymond Rothstein, James Hair, Francis Neal, Srinivas Mamidi, Shino Hanabuchi, Amanda Watkins, Yanan Zheng, Kim Rosenthal, Daniel J. Freeman, Scott Hammond. A novel immunostimulatory OX40/PD-L1 bivalent bispecific antibody (MEDI1109) for the treatment of patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2775.
Abstract 2815: Ganoderma lucidum chemosensitizes triple negative breast cancer to carboplatin mediated by DNA damage response
Authors: Suarez-Arroyo Ivette J. , Martinez-Montemayor Michelle M. 
Published: August 2018

Abstract
Management of triple negative breast cancer (TNBC) is challenging because of a lack of targeted therapy, its aggressive behavior and poor prognosis. Interest in using platinum agents, such as carboplatin as a line of treatment emerged from data suggesting frequent DNA repair defects in TNBC. Carboplatin resistance may occur due to multiple factors including increased activation of DNA repair mechanisms. Studies show that Ganoderma lucidum extract (GLE) sensitizes cancer cells to different anti-cancer therapies. Thus, we aim to investigate the effects of GLE in combination with carboplatin in the DDR signaling and in tumorigenesis. To study whether GLE sensitizes TNBC cells to carboplatin therapy, we treated SUM-149 and MDA-MB-231 cells with several concentrations of carboplatin, GLE, or both treatments simultaneously for 72h. Our results demonstrate that when carboplatin and GLE are used in combination the IC50s decreased in both breast cancer cell lines in comparison with treatments alone. Immunobloting assays revealed that GLE and/or the combination decrease the expression of 53BP1, p-CHK2, CHK2, p-CHK1, CHK1, p-ATR, p-ATM and p-BRCA1 in SUM-149. Accordingly, immunofluorescence studies to monitor the recruitment of DNA repair proteins 53BP1 and phosphorylated γH2AX at the lesion sites after treatments suggest that the GLE and/or carboplatin combination impair DDR. To determine tumor progression, severe combined immune deficient mice were injected with SUM-149 cells and then treated with carboplatin/GLE or carboplatin for 10 weeks. The combination significantly decrease tumor volume in comparison with the vehicle. Taken together, our results provide evidence of GLE's potential in chemosensitizing TNBC cells to carboplatin therapy affecting the DDR. These results highlight GLE's anti-breast cancer therapeutic potential.
Citation Format: Ivette J. Suarez-Arroyo, Michelle M. Martinez-Montemayor. Ganoderma lucidum chemosensitizes triple negative breast cancer to carboplatin mediated by DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2815.