tbuckley/cabot-search huggingface dataset:
Abstract 539: MAEL promotes colorectal cancer cell growth and migration by activating EGFR pathway
Authors: Lulu Liu, Zhou Tong, Weiqin Jiang, Yi Zheng, Peng Zhao, Weijia Fang
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system. It is generally accepted that CRC pathogenesis is a long-term process involving accumulation of multiple genetic alterations. Herein, we aim to explore the molecular biological mechanisms of CRC initiation and progression. We have been committed to investigating MAEL function in digestive neoplasms and have found MAEL is a new candidate oncogene. Previously, overexpression of MAEL was frequently detected in CRC tissues and significantly associated with poor 5-year outcome. By MTT assay and transwell assay, functional study demonstrated that overexpression of MAEL promoted cell growth and cell migration in DLD1 and THC8307 cell lines. Furthermore overexpression of MAEL in DLD1 cell line could promote tumor formation in nude mice. Further study found that MAEL overexpression in DLD1 and THC8307 elevated the protein expression of p-EGFR, p-Raf-1, p-ERK 1/2, p-PI3K and p-AKT. These data indicated that MAEL enhanced the activity of EGFR/Ras/Raf/MEK/ERK1/2 and EGFR/PI3K/Akt pathways. However, more effort is needed to investigate MAEL function and how MAEL activate EGFR pathways. Citation Format: Lulu Liu, Zhou Tong, Weiqin Jiang, Yi Zheng, Peng Zhao, Weijia Fang. MAEL promotes colorectal cancer cell growth and migration by activating EGFR pathway [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 539. doi:10.1158/1538-7445.AM2017-539
Abstract 4083: Basic mechanisms ofVernonia amygdalinaexert antitumor activities in breast cancer cells
Authors: Clement G. Yedjou, Paul B. Tchounwou
Journal: Cancer Research (2017)

Abstract Breast cancer continues to represent the largest cause of mortality in the world especially among women. It is estimated that cancer kills more women in the USA than any other illness and it is also the leading cause of death among all Americans. Traditional medicine represents the first-choice of healthcare treatment for at least 80% of people living in developing countries. Preliminary studies from our laboratory have shown that a novel natural product, extracts of Vernonia amygdalina (VA) leaf exerts DNA-damaging anticancer activities against breast cancer. There is a need to develop targeted approaches for the treatment of human breast cancer. Therefore, the goal of this research was to determine the therapeutic mechanisms of V. amygdalina leaf extracts as anti-cancer agent in the management of breast cancer. To achieve our goal, cell viability, live and death cells were determined by trypan blue exclusion test. The extent of oxidative cell/tissue damage was determined by measuring malondialdehydes (MDA) levels. Expression of p53 tumor suppressor gene was assessed both by immunofluorescent and western blot analyses. Cell apoptosis was measured both by flow cytometry analysis and DNA laddering assay. Data obtained from the Trypan blue indicated that V. amygdalina significantly reduced the viability of MCF-7 cells in a dose-dependent response, showing gradual increase in the loss of viability in V. amygdalina-treated cells due to membrane damage. We observed an up-regulation of p53 tumor suppressor gene in V. amygdalina-treated cells compared to the control. Flow cytometry data showed a strong dose-response relationship between V. amygdalina exposure and caspase-3 positive cells. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in V. amygdalina-treated cells. Collectively, data generated from the present study demonstrated that V. amygdalina destroys breast cancer cells by reducing the percentage of cell viability and inducing apoptosis through up-regulation of p53 tumor suppressor gene, activation of caspase-3, and induction of nucleosomal DNA fragmentation associated with the formation of MDA, a by-product of lipid peroxidation and biomarker of oxidative stress. This result suggests that V. amygdalina treatment may be a good anti-cancer candidate for the treatment of breast cancer. Research supported by NIH Grant No. NIMHDG12MD007581) Citation Format: Clement G. Yedjou, Paul B. Tchounwou. Basic mechanisms of Vernonia amygdalina exert antitumor activities in breast cancer cells [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 4083. doi:10.1158/1538-7445.AM2017-4083
Abstract 2582: KIRnome: KIR genotyping for whole genome/exome sequencing data
Authors: Daeyoon Kim, Sung-Soo Yoon, Youngil Koh, Su Yeon Lee, Hongseok Yun, Sunghoon Cho, Hyung-Lae Kim
Journal: Cancer Research (2017)

Abstract In this study, we tried to develop valid KIR calling algorithm from WES/WGS data. As a consequence, here we suggest KIRnome (KIR typing for whole genome and exome sequencing) which is a KIR typing method for applying sequencing data such as WES/WGS. A total of 71 sequencing data (18 WES and 53 WGS data, respectively) and matched experimentally validated KIR genotype data are used to train and validate. Before developing this method, two types of allele references (genomic and coding, here after called gSeq and cSeq) are constructed by allele sequence of IPD/KIR. KIRnome consists of two part, first part is calculating normalized depth (here after called depth) of 16 KIR genes and considering allele reference length and second is estimating KIR type based on depth. In general, we get higher normalized depth when using genomic references for WGS data and using coding references for WES data. This coincides with scheme KIRnome and the characteristics of WGS and WES data. Given 71 samples of 3 data sets, we evaluated KIR genotyping performance of KIRnome per each KIR gene. For all 16 KIR genes, KIRnome shows &amp;gt;=98.5% accuracy. When KIRnome performance was tested only in 13 WES samples, the accuracy slightly drops to 94%. We assume this is attributable to relatively small number of the samples. In conclusion, we developed a novel and unique method named KIRnome for KIR typing from NGS data. KIRnome could determine KIR genotype accurately from WES and WGS data respectively. We expect KIRnome would facilitate revealation of immunogenetic facts in various disease. Moreover, future generation of KIR specific NGS data and improved reference sequence information of KIR would enable KIRnome to type KIR at allele level in a near future. Citation Format: Daeyoon Kim, Sung-Soo Yoon, Youngil Koh, Su Yeon Lee, Hongseok Yun, Sunghoon Cho, Hyung-Lae Kim. KIRnome: KIR genotyping for whole genome/exome sequencing 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 2582. doi:10.1158/1538-7445.AM2017-2582
Abstract 4728: Plasma interleukin-6 level predicts prognosis of patients who received sorafenib for advanced hepatocellular carcinoma
Authors: Yu-Yun Shao, Hang Lin, Yong-Shi Li, Ying-Hui Lee, Ho-Min Chen, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Cancer Research (2017)

Abstract Background: No biomarker has been proven to predict the treatment outcomes of sorafenib, the only approved first-line therapy for advanced hepatocellular carcinoma (HCC). We explored predictive and prognostic values of plasma interleukin (IL)-6 levels for patients who received sorafenib as first-line therapy for advanced HCC. Methods: This study had 2 patient cohorts. The exploration cohort consisted of patients who were previously enrolled in a phase 2 clinical trial that examined sorafenib with tegafur/uracil as first-line therapy for advanced HCC. The validation cohort consisted of patients who received sorafenib alone as first-line therapy for advanced HCC under reimbursement of National Health Insurance of Taiwan. Pretreatment plasma IL-6 levels were determined. We used the receiver operating characteristic (ROC) curve in the exploration cohort to determine the best cut point for IL-6 levels to predict overall survival (OS). We then confirmed the cut point in the validation cohort. Results: There were 55 and 73 patients in the exploration and validation cohort, respectively. In the exploration cohort, there was no complete response but 3 (6%) partial response. The median OS was 8.1 months. In the validation cohort, there was no complete response but 7 (10%) partial response. The median OS was 10.3 months. In the exploration cohort, we found 4.28 pg/ml was the best cut point in defining high and low IL-6 levels because it could differentiate OS (p = 0.042) with the best sensitivity and specificity. Applying the cut point on the validation cohort, patients with high pretreatment plasma IL-6 levels, compared with patients with low IL-6 levels, exhibited significantly poorer OS (median, 8.0 vs. 13.9 months, p = 0.031). After adjusting for age, gender, hepatitis etiology, tumor characteristics, α-fetoprotein level, performance status, and prior treatment, a high plasma IL-6 level remained an independent predictor for poor OS (hazard ratio 2.594, p = 0.005). By contrast, the plasma IL-6 level was not associated with progression-free survival, treatment response, disease control, or other patient characteristics. Conclusion: High pretreatment plasma IL-6 level predicted prognosis of patients who received sorafenib as first-line therapy for advanced HCC. Citation Format: Yu-Yun Shao, Hang Lin, Yong-Shi Li, Ying-Hui Lee, Ho-Min Chen, Ann-Lii Cheng, Chih-Hung Hsu. Plasma interleukin-6 level predicts prognosis of patients who received sorafenib for advanced hepatocellular carcinoma [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 4728. doi:10.1158/1538-7445.AM2017-4728
Abstract 3175: Context-dependent role of ARF for response to chemotherapy in muscle invasive bladder cancer
Authors: Lijie Rong, Tomasz Owczarek, Takashi Kobayashi, Cory Abate-Shen
Journal: Cancer Research (2017)

Abstract Muscle invasive bladder cancer (MIBC) is a significant cause of cancer death, in part because there are relatively few treatments and these have limited efficacy. Our studies show that expression of 14ARF (aka ARF), one of the major transcripts encoded by the CDKN2A tumor suppressor locus, is frequently up-regulated in MIBC, particularly in more aggressive disease subtypes. Our results further show that accumulation of ARF protein in the nucleolus is associated with poor outcome and reduced response to chemotherapy. Using both genetically-engineered mouse (GEM) models and human xenograft models of MIBC, we demonstrate that tumors expressing ARF display poor response to treatment with the platinum-based chemotherapy agent cisplatin. This is mediated in part by expression of the integrin-binding protein ITGB3BP (CENPR) and reflects ARF-dependent inhibition of protein translation, which is attenuated by drug treatment. Our findings reveal an unexpected context-dependent role for ARF in modulating drug response in bladder cancer through its ability to regulate protein translation. Citation Format: Lijie Rong, Tomasz Owczarek, Takashi Kobayashi, Cory Abate-Shen. Context-dependent role of ARF for response to chemotherapy in muscle invasive bladder 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 3175. doi:10.1158/1538-7445.AM2017-3175
Abstract 1138: The protein disulfide isomerase inhibitor XCE853 inhibits <i>in vitro</i>, <i>ex-vivo</i> and <i>in vivo</i> growth of human tumors
Authors: Gregoire Pierre Prevost, Anne Chauchereau, Patrick Ladam, Renaud Seigneuric, Denis Carniato, Marc-Henry Pitty, Paul Foster
Journal: Cancer Research (2017)

Abstract Protein disulfide isomerase (PDI) is a chaperone protein that regulates oxidative protein folding as well as cell viability. Increased PDI levels have been documented in a variety of human cancers associated with a poor overall survival, including ovarian, prostate, brain and lung cancers. Inhibition of PDI activity leads to apoptosis in cancer, suggesting that PDI is a promising druggable target. XCE853 is a synthetic small molecule displaying an excellent docking with the catalytic domain of the human PDI. XCE853 inhibits in vitro recombinant PDI enzymatic activity. In addition, the proliferation of a large panel of human tumor cells is blocked by XCE853 with IC50s in the nanomolar range through an irreversible cytolysis leading to a tumor cell death by autophagy and particles release (vesicles or protein aggregates). XCE853 is also active on a large panel of drug resistant human cancer cells. XCE853 induced an irreversible cytolysis of human tumor cells after a short in vitro exposure independently of efflux pumps. In addition, the ex-vivo approach using fresh human tumor explants cultivated in 3 dimensions with low concentrations of XCE853 has shown a strong decrease of the proliferation (KI-67 labeling) in several tumor types. Finally, XCE853 displayed excellent oral bioavailability in mice and was able to block the growth of several human cancers using in vivo xenograft models leading to a complete tumor growth arrest even after the cessation of the treatment. Altogether, these data strongly support further efforts to move this drug candidate to the preclinical studies to access advanced cancer patients. Citation Format: Gregoire Pierre Prevost, Anne Chauchereau, Patrick Ladam, Renaud Seigneuric, Denis Carniato, Marc-Henry Pitty, Paul Foster. The protein disulfide isomerase inhibitor XCE853 inhibits in vitro, ex-vivo and in vivo growth of human tumors [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 1138. doi:10.1158/1538-7445.AM2017-1138
Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation
Authors: H. Takamatsu, N. Takezako, J. Zheng, M. Moorhead, V.E.H. Carlton, K.A. Kong, R. Murata, S. Ito, T. Miyamoto, K. Yokoyama, K. Matsue, T. Sato, T. Kurokawa, H. Yagi, Y. Terasaki, K. Ohata, M. Matsumoto, T. Yoshida, M. Faham, S. Nakao
Journal: Annals of Oncology (2017)

Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required.We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR).NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(-)] (defined as <10-6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(-) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(-) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10-7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33).Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.
Abstract 797: Glioblastoma animal model using CRISPR-Cas9 technology
Authors: Da Eun Jeong, Kee Hang Lee, Sung Soo Kim, Yoon Kyung Bae, Hyun Nam, Ji Yoon Hwang, Hee Jang Pyeon, Hye Jin Song, Kyeung Min Joo
Journal: Cancer Research (2017)

Abstract Current in vivo model system poses limitation on fully recapitulating genomic characteristics of a tumor due to high complexity and poor understanding of the heterogeneous microenvironment conditions in cancer pathogenesis. In an effort to address such issues, strategic models are required. In present study, we propose that the most representative cancer models have consistent tumor microenvironments and genomic mutations. The Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system is a powerful genome editing tool for efficient and precise genome engineering. Here, we employed CRISPR-Cas9 system in vivo to generate Cre-dependent Cas9 knock-in mouse (B6;129-Gt(ROSA)26Sortm1(CAG-cas9*,-EGFP)Fezh/J, Jackson lab.). The Cre-dependent Cas9 mouse models harbor combinations of genomic alterations including well-established oncogenes such as EGFRviii, c-MET, PDGFRa, IDH1 R132H and KRAS, EGFR, ALK, BRAF in Brain and Lung cancer models, respectively. While, they also consist of tumor suppressor genes including PTEN, NF1, Ink4a/ARF, Rb, TP53 and TP53, PTEN, NKx-1, APC in both Brain and Lung models, respectively. Cre-dependent model allows us to study in-depth into the tumor initiation and progression, while able to follow up in the role of tumor microenvironment in cancer maintenance. A better understanding of cancer models for preclinical research including their uses, as well as their limitations, may aid future potential studies regarding the development and implementation of new immune targeted therapies and potential validation of novel therapeutic biomarkers. Citation Format: Da Eun Jeong, Kee Hang Lee, Sung Soo Kim, Yoon Kyung Bae, Hyun Nam, Ji Yoon Hwang, Hee Jang Pyeon, Hye Jin Song, Kyeung Min Joo. Glioblastoma animal model using CRISPR-Cas9 technology [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 797. doi:10.1158/1538-7445.AM2017-797
Abstract 4777: Cancer stemness and resistance: Napabucasin (BBI-608) sensitizes stemness-high cancer cells to Paclitaxel by inhibiting the STAT3-MUC1 pathway
Authors: Harry A. Rogoff, Juying Li, Chiang Li
Journal: Cancer Research (2017)

Abstract Stemness-high cancer cells, or cancer stem cells (CSC) represent a subpopulation of cancer cells with enhanced tumorigenic capacity, metastasis-forming potential, and resistance to conventional chemotherapy and radiation. One such key CSC pathway is regulated by STAT3, a transcription factor that is downstream of several cytokines and growth factor receptors which controls the expression of a broad range of target genes and plays essential roles in CSC biology in many tumor types. Cancer stemness inhibitor Napabucasin (BBI-608), a small molecule that inhibits gene transcription driven by STAT3, can inhibit stemness gene expression, block spherogenesis, and kill CSCs. In vivo, BBI-608 effectively blocks cancer relapse and metastasis in xenograft models while sparing normal hematopoietic stem cells, suggesting that targeting stemness-high cancer cells is a feasible approach for developing next-generation cancer therapeutics to combat cancer recurrence. SOX2 (sex-determining region Y-box protein 2), a transcription factor that is essential for self-renewal and pluripotency, is amplified in various cancer types and has been shown to be required for CSC self-renewal and maintenance. Mucin 1 (MUC1), a glycoprotein normally expressed at the apical surface of epithelial cells, is overexpressed in most human epithelial cancers. MUC1 has been implicated in regulating tumor proliferation, metabolism, invasion, angiogenesis, chemoresistance, and inflammation. Here, we generated a stemness-high culture system based on the reporter activity of a SOX2-regulatory region construct in MKN28 gastric cancer cells (MKN28 SOX2-reporter GFP+ cells). BBI-608 treatment inhibited the STAT3-MUC1 pathway in stemness-high cells. High MUC1 status in stemness-high cells was associated with Paclitaxel resistance. Down-regulation of MUC1 sensitized stemness-high cells to Paclitaxel. Moreover, BBI-608 synergized with Paclitaxel in inhibiting spherogenesis of stemness-high cells. This study provides a new mechanism for the association of cancer stemness with drug resistance. Our findings support this combination therapy, which pairs a conventional chemotherapy (Paclitaxel) with a cancer stemness inhibitor (BBI-608), as a promising strategy to combat cancer. Citation Format: Harry A. Rogoff, Juying Li, Chiang Li. Cancer stemness and resistance: Napabucasin (BBI-608) sensitizes stemness-high cancer cells to Paclitaxel by inhibiting the STAT3-MUC1 pathway [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 4777. doi:10.1158/1538-7445.AM2017-4777
Abstract 5513: Notch directly represses transcription by recruitment of PRC2 to the ternary complex
Authors: Xiaoqing Han, Prathibha Ranganathan, Anthony Capobianco
Journal: Cancer Research (2017)

Abstract It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. In this study, we report that the Notch ternary complex can also serve to direct the formation of a repressor complex to terminate genes expression of select target genes. Herein we demonstrate that p19Arf and Klf4 are transcriptionally repressed directly by Notch. Data indicate that Notch recruits PRC2 and Lsd1 to these promoters, which leads to changes in the state of the epigenetic landscape and repression of transcription. The demethylase activity of Lsd1 is a pre-requisite for Notch-mediate transcriptional repression. Furthermore, we identified a stable Notch transcriptional repressor complex containing Lsd1, PRC2 and the Notch ternary complex. This study demonstrates proof of concept for a novel function of Notch and provides further insight into the mechanisms of Notch mediated tumorigenesis. This finding provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Note: This abstract was not presented at the meeting. Citation Format: Xiaoqing Han, Prathibha Ranganathan, Anthony Capobianco. Notch directly represses transcription by recruitment of PRC2 to the ternary complex [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 5513. doi:10.1158/1538-7445.AM2017-5513