bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3448: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in a preclinical model of TNBC
Authors: Sun Yuliang , Lin Xiaoqian , Aske Jennifer C. , Williams Casey , Abramovitz Mark , Leyland-Jones Brian 
Published: August 2019

Abstract
Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); however, not all patients respond to this combination (Rugo HS et al. The New England Journal of Medicine. 2016). The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors (Finn RS et al. Clinical Cancer Research. 2011). In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential.
Methods: The KRAS/BRAF-mutated TNBC cell line, MDA-MB-231, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed.
Results: Surprisingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further inhibited the downstream signaling of Src, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an MDA-MB-231 xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination.
Conclusions: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in patients with KRAS/BRAF-mutated TNBC.
Citation Format: Yuliang Sun, Xiaoqian Lin, Jennifer C. Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in a preclinical model of TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3448.
Abstract 3471: Mutual regulation of MDM4 and TOP2A in cancer cell proliferation
Authors: Liu Tao , Zhang Hailong , Yi Sha , Gu Lubing , Zhou Muxiang 
Published: August 2019

Abstract
MDM4 and topoisomerase IIα (TOP2A) are important cancer-related factors. MDM4 acts as an oncoprotein promoting cancer progression by inhibiting tumor suppressor p53. As a DNA replication- and cell division-regulating enzyme, TOP2A is the main target of many anticancer therapy regimens, even though the exact role of TOP2A in cancer remains elusive. Herein we report that MDM4 and TOP2A bind to each other and are mutually upregulated at the post-translational level, leading to enhanced TOP2A catalytic activity, inhibition of p53, and increased tumor-cell proliferation. We demonstrate that the C-terminal region (CTR) of TOP2A binds to a unique sequence (residues 188-238) of MDM4, which contains an auto-inhibitory segment regulating MDM4-p53 interaction. TOP2A binding in turn activates MDM4 for p53 binding, resulting in enhanced inhibition of p53 and cancer cell proliferation. Conversely, binding of the MDM4 sequence to the CTR of TOP2A upregulates TOP2A protein expression. This in turn interferes with TOP2A DNA-decatenating activity. These results reveal novel functions of MDM4 and TOP2A as well as their interactions in oncogenesis, suggesting that inhibition of the MDM4-TOP2A interaction may represent a novel strategy in specifically and simultaneously targeting TOP2A and MDM4 for cancer treatment.
Citation Format: Tao Liu, Hailong Zhang, Sha Yi, Lubing Gu, Muxiang Zhou. Mutual regulation of MDM4 and TOP2A in cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3471.
Abstract 3486: Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer
Authors: Rupp Christian , Isomursu Aleksi , Aakula Anna , Erickson Andrew , Li Song-Ping , Kaur Amanpreet , Shah Pragya , Pokharel Yuba R. , Trottman Lloyd , Lammerding Jan , Rannikko Antti , Taimen Pekka , Mirtti Tuomas , Paatero Ilkka , Ivaska Johanna , Westermarck Jukka K. 
Published: August 2019

Abstract
Reactivation of tumor suppressor phosphatases may provide entirely novel opportunities for cancer therapy. Here, we discover clinically relevant functional co-operation between loss of activities of two human tumor suppressor phosphatases, PTEN, and PP2A. Analysis of prostate cancer tissue microarray material consisting of 358 patients treated primarily with radical prostatectomy revealed that overexpression of PP2A inhibitor protein PME-1 associates with significantly shorter time to therapy relapse in patients with PTEN-deficient PrCa. Further, PP2A inhibition by PME-1 overexpression in PTEN-deficient cell models inhibits apoptosis induction in anchorage-independent conditions (anoikis). PP2A reactivation by small molecules (SMAPs) was also found to inhibit viability of PTEN-deficient PrCa cells. Importantly, rather than regulating the well-known PP2A target pathways, PME-1 was found to physically associate with, and to regulate deformability of the nuclear lamina in PrCa cells. Mass spectrometry phosphoproteomics analysis identified several PME-1-regulated nuclear lamina constituents, and PME-1 deficient cells with compromised nuclear lamina were particularly vulnerable to apoptosis induction by mechanical stress. As a direct molecular target, Lamin A/C phosphorylation was found to be protected by PME-1-mediated PP2A inhibition under anoikis-inducing conditions. PME-1 inhibition in PrCa cells resulted in increased apoptosis in an in ovo tumor model, and PME-1-depleted cells had compromised long-term survival in zebrafish circulation. In summary we discover that PP2A reactivation by PME-1 targeting sensitizes PTEN-deficient PrCa cells to anoikis. Clinically, the results identify PME-1 as a novel candidate biomarker for increased relapse risk in PTEN-deficient PrCa, and indicate pharmacological PP2A activation as a novel potential therapeutic approach against circulating prostate cancer cells. At the general level, the results clearly emphasize the need for better understanding of phosphatases as key modulators of cancer progression.
Citation Format: Christian Rupp, Aleksi Isomursu, Anna Aakula, Andrew Erickson, Song-Ping Li, Amanpreet Kaur, Pragya Shah, Yuba R. Pokharel, Lloyd Trottman, Jan Lammerding, Antti Rannikko, Pekka Taimen, Tuomas Mirtti, Ilkka Paatero, Johanna Ivaska, Jukka K. Westermarck. Combined inhibition of tumor suppressors PTEN and PP2A drives anoikis resistance and is associated with therapy relapse in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3486.
Abstract 3499: Dianhydrogalactitol (VAL-083) in combination with AZD1775 increases survival in diffuse intrinsic pontine glioma (DIPG), in vivo
Authors: Steino Anne , Yang Xiaodong , Kline Cassie , Bacha Jeffrey , Brown Dennis M. , Mueller Sabine 
Published: August 2019

Abstract
OBJECTION: VAL-083 is a structurally unique bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 induces interstrand crosslinks leading to DNA double-strand breaks and S/G2 cell cycle arrest. By inhibiting the G2 checkpoint regulator kinase Wee1, AZD1775 allows a cancer cell with DNA damage to progress past the G2 checkpoint and into premature mitosis leading to cancer cell death. Herein we assess the activity of VAL-083 as single agent as well as in combination with Wee1 Kinase inhibitor AZD1775 in patient derived model systems of DIPG.
METHODS: DIPG derived cell lines SF8628 and NEM157 (H3.3K27) as well as SF10693 (H3.1K27M) and pediatric glioblastoma cell lines SF188 (H3.3K27 wildtype) were treated with increasing concentrations of single agent VAL-083 as well as in combination with AZD1775. To determine potential synergistic activity, we applied the Chou-Talalay method, which allows the quantitative determination of drug interactions by calculating a combination index (CI). In vivo activity of VAL-083 (3 mg/kg) as single agent as well as in combination with AZD1775 (60 mg/kg) was assessed in an orthotopic engraftment model of pediatric DIPG (SF8628).
RESULTS: The IC50 of VAL-083 as single agent ranged from 1µM to 10µM. VAL-083 exhibited synergistic activity in combination with AZD1775 in cell lines SF8628 and SF188 and additive effect in NEM157 with CI values ranging from 0.04 to 0.95, with CI &lt; 1 indicating synergy. In vivo, treatment with VAL-083 as single agent and in combination with AZD1775 conferred significant survival benefit to mice with engrafted DIPG tumors compared to control as well as single agent treatment with AZD1775. The median survival for mice treated with VAL-083 alone was 54.5 days (p=0.0004, VAL-083 vs. control) and for the VAL-083/AZD1775 combination it was 62 days (p&lt;0.0001, VAL-083/AZD1775 vs. control), compared to 44 days for control and 47 days for mice treated with AZD1775 alone (p=0.0839, AZD1775 vs. control).
CONCLUSION: Our present study highlights that the combination of VAL-083 and AZD1775 might be a promising new therapeutic strategy for children with DIPG. Ongoing studies continue to assess the in vivo activity in other DIPG models as well explore the underlying mechanism of action of the combination strategy.
Citation Format: Anne Steino, Xiaodong Yang, Cassie Kline, Jeffrey Bacha, Dennis M. Brown, Sabine Mueller. Dianhydrogalactitol (VAL-083) in combination with AZD1775 increases survival in diffuse intrinsic pontine glioma (DIPG), in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3499.
Abstract 3525: Achieving reproducibility and accuracy in cancer mutation detection with whole-genome and whole-exome sequencing
Authors: Xiao Wenming ,   The Somatic Mutation Working Group of the SEQC-IIConsortium
Published: August 2019

Abstract
Clinical applications of precision oncology require accurate tests that can distinguish tumor-specific mutations from errors introduced at each step of next generation sequencing (NGS). For NGS to successfully improve patient lives, discriminating between true mutations and artifacts is crucial. We systematically interrogated somatic mutations in paired tumor normal cell lines to identify factors affecting detection reproducibility and accuracy. Different types of samples with varying input amount and tumor purity were processed using multiple library construction protocols. Whole-genome and whole-exome sequencing were carried out at six sequencing centers followed by processing with nine bioinformatics pipelines to evaluate their reproducibility. We identified artifacts due to sample and library processing and evaluated the capabilities and limitations of bioinformatics tools for artifact detection and removal. By examining the interaction and effect of various wet lab and computational parameters concomitantly, here we recommend actionable best practices for mutation detection in clinical applications using NGS technologies.
Citation Format: Wenming Xiao, The Somatic Mutation Working Group of the SEQC-IIConsortium. Achieving reproducibility and accuracy in cancer mutation detection with whole-genome and whole-exome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3525.
Abstract 3526: Incorporation of unique molecular identifiers (UMIs) into unique dual sample indexing (UDI) improves the accuracy of quantitative next generation sequencing
Authors: Liu Pingfang , Krishnan Keerthana , Devoe Camille X. , Langhorst Bradley W. , Dimalanta Eileen , Davis Theodore B. 
Published: August 2019

Abstract
Accurate analysis of quantitative NGS data is critical for low frequency variant detection, identification of differentially expressed transcripts, and correct diagnosis and patient care in a clinical NGS setting. Two major factors affecting sequencing accuracy are 1) PCR duplication arising from amplification of library molecules; and 2) errors introduced during library preparation and actual sequencing on the flow cell. Standard practice for identification and removal of PCR duplicates relies on aligning reads to the same genomic coordinates. However, this approach can not differentiate between PCR duplicates and reads originating from unique molecules with identical ends. The most effective method for error correction is Duplex Sequencing, which utilizes UMIs to tag both strands of each individual DNA duplex followed by building consensus sequences. Unfortunately, this approach is labor intensive and cost-prohibitive for complex genomes and large target panels. Therefore, a simple and reliable approach for duplicate removal and error correction would greatly facilitate the wider adoption of NGS technology for diagnostics and clinical applications.
In this study, we incorporate UMIs into UDI systems and assess the effect on the accuracy of quantitative sequencing assays. We first study the effectiveness of various computational methods to account for UMIs and remove base-calling errors introduced during sequencing. We then analyze the utility of UMIs for 1) unique and low abundance transcript identification and accurate transcript quantification; and 2) error correction in low frequency variant detection in genomic sequencing from both high quality cell line DNA and low quality FFPE DNA. In addition, we demonstrate that combining unique dual sample indexing with UMI molecular barcoding further improves data analysis accuracy, especially on patterned flow cells. Our approach involves a simple new UMI-containing UDI adaptor design that can also be applied to other sequencing methods and platforms.
Citation Format: Pingfang Liu, Keerthana Krishnan, Camille X. Devoe, Bradley W. Langhorst, Eileen Dimalanta, Theodore B. Davis. Incorporation of unique molecular identifiers (UMIs) into unique dual sample indexing (UDI) improves the accuracy of quantitative next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3526.
Abstract 3531: Modular RNA expression analysis using whole transcriptome and targeted analysis in single cells on BD Rhapsody
Authors: Nakamoto Margaret , Lam Gretchen , Chang Christina , Shum Eleen 
Published: August 2019

Abstract
Advances in genomics have allowed high-throughput single-cell whole transcriptome analysis (WTA) to enable the discovery of biomarkers and cellular pathways that may be important in diseases. As a complementary tool to WTA, targeted analysis can provide high sensitivity of single cell gene expression data with lower sequencing cost. Here we demonstrate using the BD Rhapsody platform in a modular fashion to generate both WTA and targeted sequencing libraries from the same sample. Utilizing the archivability of the BD Rhapsody beads, we first subsampled a portion of the beads to generate WTA data, from which we identified genes that are important for T cell exhaustion. We then designed a targeted panel to profile the rest of the beads from the same experiment. The study demonstrates the versatility of the BD Rhapsody single cell platform and the ability to conduct different workflows on the same sample. This approach offers flexibility and choice for users in experimental design and allows users to easily transition from novel target discovery to robust data validation using targeted panels.
Citation Format: Margaret Nakamoto, Gretchen Lam, Christina Chang, Eleen Shum. Modular RNA expression analysis using whole transcriptome and targeted analysis in single cells on BD Rhapsody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3531.
Abstract 3533: Low-frequency variant detection in cell-free DNA by integrating double-stranded unique molecular identifiers with ultrafast amplicon-based library preparations
Authors: Lee Lucie S. , Liu Yang Lily , Pendleton Kathryn , Liu Jeffrey , Lin Lifeng Phil , Liu Guoying , Liu Zhitong 
Published: August 2019

Abstract
The use of liquid biopsy has seen tremendous growth in recent years as cell-free DNA (cfDNA) is a noninvasive and easily obtainable sample type with many diagnostics and prognostic values. While liquid biopsy can potentially enable new applications, such as early cancer detection, treatment monitoring, and drug resistance screening, it also presents challenges to accurate variant detection due to the low fraction of mutant DNA present in theses samples, which can be easily buried by the artifacts and background noise from systematic PCR and sequencing errors. While some success has been made using adapters with unique molecular identifiers (UMIs) in hybrid capture-based methods and performing deep sequencing, such approaches suffer from long, tricky, and tedious workflows and disappointingly low on-target rates. Additionally, the large amount of cfDNA required for hybrid capture workflows is not realistic to obtain from patients.
We have developed the CleanPlex® UMI technology to provide a fast, simple, and reliable NGS solution for low-frequency variant detection. The technology features three simple steps to generate molecular-barcoded and target-enriched NGS libraries in under 4 hours. This amplicon-based method consists of a multiplex PCR reaction for molecular barcoding, followed by a biochemical reaction for removal of redundant PCR products, and finally a second round of PCR to add Illumina adapter sequences and sample indexes. To validate this new method, we designed an NGS panel targeting frequently mutated hotspots in 23 genes associated with lung cancer. NGS libraries were prepared with commercial reference cfDNA at 0.1% to 0.5% minor allele frequencies (mAF) and sequenced on an Illumina NextSeq®.
Overall, we obtain high detection sensitivity for low-frequency alleles even at low DNA inputs. When including UMI in the analysis, we observe significant reductions in false positive calls. Nearly all known mutations covered by the CleanPlex UMI panel (12 out of 13) are detected at 0.1% mAF using 50ng of the reference cfDNA. At 0.25% mAF, all known mutants are detected with 100% PPV using 50ng of DNA. With only 20 ng of cfDNA, the method can achieve the same 100% detection at 0.5% mAF. The CleanPlex® UMI technology demonstrates high sensitivity with low false positive rate, for the detection of low-frequency alleles.
Citation Format: Lucie S. Lee, Yang Lily Liu, Kathryn Pendleton, Jeffrey Liu, Lifeng Phil Lin, Guoying Liu, Zhitong Liu. Low-frequency variant detection in cell-free DNA by integrating double-stranded unique molecular identifiers with ultrafast amplicon-based library preparations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3533.
Abstract 3547: MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1
Authors: Baek Dong Won , Jeong Jae-Hwan , Lee Soo Jung , Lee Jiyeon , Chae Yee Soo , Kim Wan WooK , Kang Jieun , Park Ho Yong , Jung Jin Hyang , Jeong Ji Yun , Park Ji Young , Park Keon Uk 
Published: August 2019

Abstract
Background and Objectives: Del-1 is linked to the pathogenesis of various cancers including breast cancer; however, the regulation of Del-1 expression remains unclear. The current study investigated how microRNA-496 (miR-496) regulates Del-1 expression in triple negative breast cancer (TNBC).
Methods: Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined in MTT, wound healing, and Matrigel Transwell assays, respectively.
Results: In MDA-MB-231, miR-496 levels were remarkably low and Del-1 mRNA was higher compared to other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3′-UTR of Del-1 and that Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P &lt; 0.005) and the levels of Del-1 in the plasma was significantly elevated as compared to normal controls (P = 0.0142). TCGA data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC.
Conclusions: In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and Del-1 might act as modulating factors in TNBC and are new biomarkers for patients with TNBC.
Citation Format: Dong Won Baek, Jae-Hwan Jeong, Soo Jung Lee, Jiyeon Lee, Yee Soo Chae, Wan WooK Kim, Jieun Kang, Ho Yong Park, Jin Hyang Jung, Ji Yun Jeong, Ji Young Park, Keon Uk Park. MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3547.