bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 338: Inhibition of phosphatidylinositol 3-kinase signaling antagonizes paclitaxel-mediated resistance in cervical cancer
Authors: Choi Youn Jin , Jung Yoo Yeon , Liu Jing Jing 
Published: August 2019

Abstract
Paclitaxel is used as an effective treatment against advanced cervical cancer. However, acquired resistance limits its success and results in cancer progression. We investigated whether the inhibition of phosphatidylinositol 3-kinase (PI3K) signaling overcomes paclitaxel resistance in cervical cancer. Two human cervical cancer cell lines (Me180 and HeLa) were used. We established paclitaxel-resistant cell lines (PTX-R Me180/PTX-R HeLa) and confirmed inhibitory concentrations (IC)50 and cell death rates by tetrazolium dye (MTT) and apoptosis assays, respectively, after exposure to a combination of paclitaxel with PI3K inhibitors (LY294002 and BYL-719). Migration and invasive abilities were explored by wound healing and transwell assays, respectively. Western blots were performed to determine the mechanism underlying the antitumor effects of PI3K inhibitors.PTX-R Me180 and PTX-R HeLa cells were gradually established from parental cell lines by stepwise exposure to paclitaxel over 7 months and with stable resistance at under 20 nM. We found that the activation of the PI3K pathway in paclitaxel-resistant lines increased tumor growth and invasiveness, and impeded cell apoptosis. The combination of LY294002 or BYL-719 with paclitaxel significantly enhanced drug sensitivity and synergistic apoptosis through the activation of Bax, caspase-3, and cleaved poly ADP ribose polymerase compared with paclitaxel alone. In addition, PI3K inhibition also suppressed tumor migration and invasive ability by targeting vimentin, matrix metalloproteinase-9 and vascular endothelial cell growth factor.We suggest that a combination of a PI3K inhibitor with paclitaxel may enhance antitumor activity through a cascade of PI3K signaling events.
Note: This abstract was not presented at the meeting.
Citation Format: Youn Jin Choi, Yoo Yeon Jung, Jing Jing Liu. Inhibition of phosphatidylinositol 3-kinase signaling antagonizes paclitaxel-mediated resistance in cervical 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 338.
Abstract 3390: RNA interactome topology perturbation analysis reveals candidate driver mutations in cancer
Authors: Li Yongsheng , McGrail Daniel J. , Xu Juan , Li Junyi , Yi Song , Sahni Nidhi 
Published: August 2019

Abstract
Identification of the driver genomic variants is important for precision therapy of human cancer. Interaction between RNA-binding proteins (RBPs) and RNA plays important roles in regulating cellular function. Decoding genome-wide protein-RNA regulatory networks as well as how cancer-related mutations impair RNA regulatory activities in cancer will help prioritizing candidate driver mutations.
Here, we first explored the genetic alteration patterns of RBPs and found that candidate driver mutations are likely to occur on the surface of RBPs. This observations indicate that the driver mutations may perturb the RBP regulatory network in cancer. We then constructed protein-RNA interactome networks by integration of target binding screens and expression profiles. Regulatory network analysis highlights regulatory principles among interacting RBPs. In addition, somatic mutations selectively target functionally important genes (cancer genes, core fitness genes or conserved genes) in cancer. These regulatory patterns were further validated using independent data. A computational method (MERIT) and a web-based user friendly resource were further proposed to analyze the RBP-gene regulatory network perturbation induced by mutations across cancer types. Pan-cancer analysis also suggests that cancer cells selectively target "vulnerability" genes to perturb protein-RNA interactome that is involved in cancer hallmark-related functions. Based on the expression of perturbed RBP and target genes, we identified three subtypes of liver cancer with different survival rates. Specifically, we experimentally validated four pairs of RBP-gene interactions perturbed by mutations, which play critical roles in cell proliferation.
Taken together, our results provide a valuable resource for characterizing somatic mutation-perturbed protein-RNA regulatory networks in cancer, yielding valuable insights into the genotype-phenotype relationships underlying human cancer, and potential biomarkers for precision medicine.
Note: This abstract was not presented at the meeting.
Citation Format: Yongsheng Li, Daniel J. McGrail, Juan Xu, Junyi Li, Song Yi, Nidhi Sahni. RNA interactome topology perturbation analysis reveals candidate driver mutations in 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 3390.
Abstract 3395: TargetTranslator: Big data identifies non-canonical targets for high risk neuroblastoma
Authors: Almstedt Elin , Wärn Caroline , Elgendy Ramy , Hekmati Neda , Rosén Emil , Larsson Ida , Jörnsten Rebecka , Crona Cecilia , Nelander Sven 
Published: August 2019

Abstract
Despite the many advances in the molecular characterization of neuroblastoma, effective treatments for high-risk patients are currently lacking. Using publically available data, integrated computational analysis offers new opportunities to uncover druggable subgroups. In the TargetTranslator project, we have combined state-of-the-art Big Data techniques to identify new targets in high-risk subgroups of neuroblastoma. Starting with clinical or genomic risk factors, TargetTranslator builds a consensus molecular signature across cohorts. This signature is scored against a massive amount of data from (i) childhood tumor biobanks (TARGET, R2), (ii) drug profiling data from cancer cell models (NIH-LINCS), and (iii) drug targets and pathways (STITCH, STRING, MSIGDB). As output, the system provides ranked lists of compounds, molecular targets and pathways for each risk factor, as well as an aggregated probability score. In a proof-of-concept study, we used TargetTranslator to recommend treatments for high-risk neuroblastoma subgroups, including COG high-risk, MYCN amplification, 11q deletion, and signatures of differentiation and ALK activation. Depending on risk group stratification, we detected between 21 and 680 substances (p&lt;0.001), most of which were strongly associated to approximately 10 key targets. In addition to confirming a key role for the PI3K/mTOR and MAPK pathways, we detected high scoring compounds in non-canonical pathways, including neurotransmission, GLI/SMO, ROCK and PKA. Experimental validation of 11 predicted drugs in patient-derived neuroblastoma lines confirmed our signatures and reduced viability. We also identified four new compounds that significantly (p&lt;0.05) suppressed MYCN protein levels (ROCK inhibitor fasudil, CNR2 agonist GW405833, CDK inhibitor AZD5438, lovastatin) at concentrations non-toxic in zebrafish embryos. By integrating data from patients, drugs, and drug-protein networks, we establish a new computational pipeline that predicts protein targets in specific patient subgroups. The TargetTranslator introduces a way to bridge drug effects with patient data and will be available as a user-friendly web tool on www.targettranslator.org in 2018.
Citation Format: Elin Almstedt, Caroline Wärn, Ramy Elgendy, Neda Hekmati, Emil Rosén, Ida Larsson, Rebecka Jörnsten, Cecilia Crona, Sven Nelander. TargetTranslator: Big data identifies non-canonical targets for high risk neuroblastoma [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 3395.
Abstract 3425: Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy
Authors: Grant Michael , Snipes George , Halperin Rebecca , Heaton Paul , Kim Suwon 
Published: August 2019

Abstract
Up to 20% of breast cancer is clinically defined as triple-negative breast cancer (TNBC) lacking estrogen, progesterone, and HER2 receptors. Because no targeted therapy is available, cytotoxic chemotherapy is the primary mode of adjuvant TNBC therapy, but is effective in ~30% patients. In order to determine molecular underpinnings of chemotherapy resistance in TNBC, we analyzed 12 TNBC patient tumor samples collected post neoadjuvant chemotherapy using DNA/RNA sequencing. DNA analysis showed two tumors contained TP53 inactivating mutations and two tumors PIK3CA activating mutations. In addition, a number of mutations in the DNA repair pathway genes were identified including XRCC1, XRCC3, and ATXR, suggesting that DNA damaging nature of chemotherapy agents may have enriched these mutations. In addition, we found mutations in the genes involved in microtubule assembly including BUB3 and APC2, suggesting that these gene mutations may confer resistance to taxol, an anti-microtubule chemotherapy agent. RNA sequencing revealed a true heterogeneous nature of TNBE in that unsupervised clustering did not identify any distinct gene signature correlative of chemotherapy resistance. We are currently evaluating phenotypes related to chemotherapy resistance using cells genetically engineered with the BUB3 or APC2 mutations.
Citation Format: Michael Grant, George Snipes, Rebecca Halperin, Paul Heaton, Suwon Kim. Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy [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 3425.
Abstract 3426: Combining cell barcoding and CRISPR sgRNA libraries with targeted gene expression for single-cell genetic analysis of tumor metastasis
Authors: Chenchik Alex , Diehl Paul , Makhanov Mikhail 
Published: August 2019

Abstract
Pooled lentiviral libraries of CRISPR sgRNAs to mediate genome-wide gene knockout have become an invaluable tool for uncovering the functional genetic drivers required for a biological response. Another type of pooled lentiviral library designed with unique DNA sequence tags have also been used to label large populations of cells with unique cell-specific barcodes which allows monitoring changes in sub-populations of cells with distinct phenotypes over time. We have combined cell barcodes with CRISPR sgRNA to construct libraries that enable the identification of multiple occurrences of a common phenotypic response from independent transductions of the same sgRNA effector. Specifically, we demonstrate how this sort of library can be used to identify genes whose activation promotes metastasis of tumors derived from MDA-MB-231 cells engrafted into mice after transduction with a barcoded CRISPR-activation (CRISPRa) sgRNA library. By incorporating multiple barcodes with each sgRNA effector, it is possible to see that, not only are cells in metastatic tumors more likely to have a particular sgRNA targeted to a certain gene, but also that independent transductions of that sgRNA sequence lead to multiple independent metastatic events. With multiple independent clones producing the same phenotype, it is possible to confidently isolate the sgRNA, and by implication, the increased activation of its gene target, as the primary cause of the metastatic phenotype.
Citation Format: Alex Chenchik, Paul Diehl, Mikhail Makhanov. Combining cell barcoding and CRISPR sgRNA libraries with targeted gene expression for single-cell genetic analysis of tumor metastasis [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 3426.
Abstract 3444: Identification of Interleukin-1 (IL-1) induced gene expression pattern in breast cancer (BCa) cells
Authors: Nawas Afshan Fathima , Kanchwala Mohammed , Thomas-Jardin Shayna , Anunobi Vanessa , Wong Ally , Xing Chao , Delk Nikki 
Published: August 2019

Abstract
Breast cancer (BCa) and prostate cancer (PCa) are both hormone driven cancers with similar etiology and tumor microenvironment inflammation promotes BCa and PCa progression. Interleukin-1 (IL-1) is an inflammatory cytokine present in the tumor microenvironment and IL-1 is elevated in BCa and PCa patient tumor and/or blood serum and correlates with poor prognosis. We have shown that IL-1 represses the BCa and PCa therapeutic targets, Estrogen Receptor Alpha (ERa) and Androgen Receptor (AR), respectively, in PCa and BCa cell lines; yet the cells remain viable. Thus, IL-1 may promote treatment resistance and disease progression. The pro-survival protein Sequestome-1 (SQSMT1/p62) is also upregulated in both BCa and PCa cell lines exposed to IL-1, suggesting that BCa and PCa cells have evolved a shared response to IL-1 and hormone receptor loss. RNA sequencing of an IL-1-treated PCa cell line revealed an IL-1-modulated gene suite predicted to confer AR-independent tumorigenicity. We performed RT-qPCR in PCa cell lines for several select genes to confirm the RNA sequencing results and given the similar etiology and IL-1 regulation of ERa, AR, and p62 expression in BCa and PCa cell lines, we presumed that our select genes would be similarly regulated by IL-1 in BCa cells. However, outside of ERa, AR, and p62 expression, our select genes did not show similar IL-1 regulation in BCa cell lines, suggesting that IL-1 regulates a unique set of genes that could contribute to ERa-independent tumorigenicity in BCa cells. Therefore, to identify a BCa-specific IL-1-modulated gene suite, we performed RNA sequencing on an IL-1-treated ERα+ BCa cell line and compared gene expression changes with 1) basal gene expression in an ERa- BCa cell line and 2) our IL-1-modulated PCa-specific gene suite. Our bioinformatics analysis revealed pathways that are predicted to promote ERa-independent tumorigenicity in BCa cells and investigations are underway to demonstrate the functional significance of our gene expression data. Taken together, our studies provide insight into the mechanistic function of IL-1 in PCa and BCa resistance to hormone receptor-targeted therapies and tumor progression.
Citation Format: Afshan Fathima Nawas, Mohammed Kanchwala, Shayna Thomas-Jardin, Vanessa Anunobi, Ally Wong, Chao Xing, Nikki Delk. Identification of Interleukin-1 (IL-1) induced gene expression pattern in breast cancer (BCa) cells [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 3444.
Abstract 3446: STRAP is involved in mutated Apc-induced stemness and tumorigenesis in colon cancer
Authors: Vu Trung 
Published: August 2019

Abstract
Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Loss of its normal function leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and stemness. Here, we tested the effect of conditional deletion of Strap on intestinal tumor formation and growth by crossing ApcMin/+ mice with mice that are null for Strap in the intestinal epithelium, Strapfl/fl;Vil-Cre mice (StrapIEKO). We observed a dramatic decrease in the number of intestinal polyps in the ApcMin/+;Strapfl/fl;Vil-Cre mice (called StrapIEKO;ApcMin/+) compared to mice with intact Strap (Strapfl/fl;ApcMin/+). In an attempt to understand the mechanism of function of STRAP, we have observed that colon tumors from StrapIEKO;ApcMin/+ mice displayed a decrease in β-catenin nuclear localization and downregulation of Wnt targets such as c-Myc, AXIN2, and CCND1. Enteroids prepared from StrapIEKO;ApcMin/+ mice exhibited more budding compared to the ApcMin/+ enteroids, indicating the role of STRAP in stemness. STRAP knockdown in human CRC cells significantly diminished β-catenin/TCF4 transcriptional activity. Specifically, STRAP knockdown impaired the assembly of β-catenin/TCF4 complex and recruitment of the complex to the promoters of β-catenin target genes. Functional proteomic analyses of crypt cells from different genetic mice suggested that the MEK/ERK signaling pathway is suppressed in StrapIEKO;ApcMin/+ mice that is required for the effect of STRAP on Wnt/β-catenin signaling. We have shown that STRAP associates with MEK1/2 and promotes binding between MEK1/2 and ERK1/2 and subsequently induces the phosphorylation of ERK1/2. Given that MEK/ERK signaling is found to promote Wnt/β-catenin signaling, our results suggest that STRAP indirectly induce Wnt/β-catenin signaling through activating MEK/ERK pathway. Importantly, STRAP is found to be a novel target of Wnt/β-catenin
signaling as ChIP assays determined putative binding sites of β-catenin/TCF4 complex on Strap promoter. Finally, we showed that forced expression of STRAP in colon cancer organoids derived from patients with colon cancer can induce the growth of colon tumor organoids through promoting Wnt/β-catenin signaling. Altogether, these results suggest that STRAP is involved in mutated APC-induced tumor initiation through a novel feed-forward STRAP/MEK-ERK/β-catenin/STRAP regulatory axis.
Citation Format: Trung Vu. STRAP is involved in mutated Apc-induced stemness and tumorigenesis in colon 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 3446.
Abstract 3447: APC truncating mutations in Middle Eastern population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC to 5-FU chemotherapy
Authors: Parvathareddy Sandeep K. , Siraj Abdul K. , Bu Rong , Poyil Prateeshkumar , Masoodi Tariq , Padmaja Divya Sasidharan , Concepcion Rica , Begum Rafia , Sabido Maria A. , Melosantos Roxanne , Al-Sanea Nasser , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: August 2019

Abstract
Colorectal Cancer (CRC) is the leading cause of cancer related death and the most common cancer affecting Saudi males. Mutation of the adenomatous polyposis coli (APC) gene is considered as the initiating step of transformation in familial and sporadic CRC. The prevalence and prognostic role of APC mutation spectra are not well established in Middle Eastern CRC. Next generation sequencing of 412 CRC tumors was performed to determine mutations in APC. Association with protein expression and clinico-pathological correlation was performed. APC truncating mutation is found at a frequency of 58.2% (240/412) and is significantly associated with superior overall survival, whereas no difference in survival between short truncating and long truncating APC was noted. To test the hypothesis that APC mutations might influence 5- Fluorouracil (5-FU) therapy, which is the first line chemotherapy used in CRC, we compared CRC cell lines and showed that those expressing truncated APC exhibit limited response to 5-FU, unlike cells which were APC wild type. In COLO-320 DM and HCT-15, APC mutated CRC cells, we were able to increase sensitivity of APC truncated cells to 5-FU by inhibiting Tankyrase (TNKs) which are members of PARP family, using XAV939. In conclusion, the study identified the prognostic value of APC truncating mutation in Middle Eastern ethnicity. In vitro data further showed that APC mutation can be used as a molecular biomarker to predict response to 5-FU. Furthermore, Tankyrase inhibitor XAV939 selectively targeting APC-mutated CRC cells can be an effective strategy to overcome 5-FU resistance in these cells.
Note: This abstract was not presented at the meeting.
Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Prateeshkumar Poyil, Tariq Masoodi, Divya Sasidharan Padmaja, Rica Concepcion, Rafia Begum, Maria A. Sabido, Roxanne Melosantos, Nasser Al-Sanea, Fouad Al-Dayel, Khawla S. Al-Kuraya. APC truncating mutations in Middle Eastern population: Tankyrase inhibitor is an effective strategy to sensitize APC mutant CRC to 5-FU chemotherapy [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 3447.
Abstract 3457: Flubendazole targets STAT3 signaling and distant metasis in triple-negative breast cancer
Authors: Oh Eunhye , Kim Yoon-Jae , Jang Seojin , Cho Tae-Min , Park Soeun , Park Jung Min , Park Minsu , Kim Ji Young , Seo Jae Hong 
Published: August 2019

Abstract
Triple-negative breast cancers (TNBC) with higher cancer stem-like populations are reported to exhibit a more aggressive metastatic phenotype. In the present study, we investigated the effects of flubendazole, a candidate drug for repurposing and its novel mechanism of action with a focus on targeting STAT3 signaling and breast cancer stem-like traits in TNBC. The effect of FLU on TNBC cell lines in vitro was evaluated in terms of cell viability, breast cancer stem cells (BCSC)-like properties and expression of STAT3 signaling-related factors. An orthotopic injection model with BCSC-enriched population was used to examine the effect of flubendazole on tumor growth and metastasis in vivo. Our results showed that the BCSC-enriched populations harbored a higher Aldefluor-positive population and markedly elevated levels of CD49f and ALDH1A1 as well as higher STAT3 activation in vitro. Flubendazole attenuated STAT3 activation, as demonstrated by a significant reduction in phospho-STAT3 levels as well as subsequent downregulation of its downstream effector cyclin D1. Sphere-forming ability was significantly suppressed following two pharmacological STAT3 inhibitor, LLL12 or S3I-201 challenge. Treatment with interleukin-6 (IL-6) was observed to significantly increase the number and volume of mammospheres, while flubendazole abolished this effect. Bioluminescence in vivo imaging (BLI) revealed that the BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while flubendazole administration inhibited tumor growth and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. To our knowledge, these findings are the first to report that flubendazole reduces BCSC-enriched tumor burden and metastasis via STAT3 inactivation, implying that flubendazole treatment may have application in addressing metastasis.
Citation Format: Eunhye Oh, Yoon-Jae Kim, Seojin Jang, Tae-Min Cho, Soeun Park, Jung Min Park, Minsu Park, Ji Young Kim, Jae Hong Seo. Flubendazole targets STAT3 signaling and distant metasis in triple-negative breast 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 3457.