tbuckley/cabot-search huggingface dataset:
Abstract 4103: IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance <i>EGFR</i> mutant lung cancer cells
Authors: Shang-Yin Wu, Hsuan-Heng Yeh, Chun-Hua Hung, Chien-Chung Lin, Wen-Pin Su, Wu-Chou Su
Journal: Cancer Research (2017)

Abstract Transformation to small-cell lung cancer (SCLC, one of aggressive neuroendocrine [NE] tumor) is reported when activating epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer acquired resistance to tyrosine kinase inhibitors (TKI, such as gefitinib). IL-6 activation confers to acquire TKI resistance and associates with p53 and RB inactivation those are SCLC hallmark changes. Whether NE transformation could phenocopy in isogenic acquired resistance cell line and the role of IL-6 in this process remain unknown. We established 827GRs (including 827GR, 827GR+ and 827GR.M6) acquired resistance to gefitinib from HCC827 cells by long term stepwise treated with gefitinib and they still had EGFR exon 19 deletion without acquired T790M. 827GR was parental resistance line with unstable gefitinib resistance in drug-free medium by passage. We maintained 827GR in medium with or without 1μM gefitinib over 6 months to generate stable clones: 827GR+ and 827GR.M6. 827GRs had SCLC hallmark changes, i.e., inactivation of p53, RB and Notch by western blot and gene set enrichment analysis. Compared to HCC827, 827GRs were more sensitive to cisplatin and etoposide but not paclitaxel. IL-6 level was positive correlated with gefitinib resistance among 827GRs by cytokine array and ELISA. Interestingly, among 827GRs, 827GR.M6 harbored low IL-6 secretion had obviously NOTCH-ASCL1-DLL3 alteration, high NE marker expression and significant inter-rater agreement with selected Byers’ SCLC gene signature than high IL-6 secretion 827GR+, suggesting IL-6 dynamics might regulate NE marker expression. IL-6 genetic manipulation in HCC827 and 827GR+ also demonstrated this phenomenon. Moreover, IL-6 dynamics correlate with NE expression also showed in patient derived lung cancer cell line in published microarray dataset (GSE64322). In conclusion, our work demonstrated activating EGFR mutant lung cancer acquired resistance to TKI with NE transformation could phenocopy in isogenic cell line model and IL-6 dynamics might regulate this process. Citation Format: Shang-Yin Wu, Hsuan-Heng Yeh, Chun-Hua Hung, Chien-Chung Lin, Wen-Pin Su, Wu-Chou Su. IL-6 dynamics regulate neuroendocrine transformation in gefitinib acquired resistance EGFR mutant lung 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 4103. doi:10.1158/1538-7445.AM2017-4103
Abstract 1460: miRNome analyses reveal that activity of CAF expressed podoplanin in tumor microenvironment is modulated by exosome miRNAs involved in the PTEN-PI3K-AKT-mTOR signaling
Authors: Anna Tejchman, Eric Mennesson, Isabelle Fixe, Alexandra Foucher, Simon Perera, Laura Artigas, Jose Manuel Mas, Catherine Grillon, Maciej Ugorski, Nadia Normand, Claudine Kieda
Journal: Cancer Research (2017)

Abstract In breast cancer, cancer associated fibroblasts (CAF) express podoplanin but little is known about its mechanism of expression and modulation. This might be crucial for cancer cell movements and for the ability to escape from the tumor site. Podoplanin showed anti-adhesive activity towards tumor and immune cells. A key control of tumor microenvironment is exerted by microRNAs on gene expression. Therefore miRNAs profiling was performed with 3D-Gene microarray technology on a breast CAF model, on cell lysates and on secreted exosomes, in hypoxia versus normoxia culture conditions. Systems biology enrichment analyses were carried out through bioinformatics using mathematical models that simulate in silico the behaviour of human physiology. Targets linked to the set of differential miRNAs, both up-regulated and down-regulated, have been analyzed with various methods including a hypergeometric distribution method. Processes linked to hypoxia, glycosylation, angiogenesis, extracellular matrix and pathways associated with PI3K-AKT, mTOR, P53 and chemokines signaling were studied. We showed that podoplanin expression strongly affected miRNAs involved in these processes. Hypoxia increased expression of miR-210, miR-21 and miR-29b in cells over-expressing podoplanin. miR-21 is an oncogenic regulator in most cancer cells through its downstream target proteins among which stands the tumor suppressor PTEN, a candidate to alleviate hypoxia in tumors, regulating tumor angiogenesis and modulating tumor hypoxia. miR-29b is a tumor suppressor, it also correlates with PTEN repression. We highlighted miRNA regulation of podoplanin expression through downregulation of upstream genes for tumor suppressor PTEN. The combination of miRNome analysis and systems biology bioinformatics uncovered potential miRNAs involved in the regulation of podoplanin activity in CAF. Such data analysis may be applied to protein and mRNA biomarkers and extended to other pathology pathways. Citation Format: Anna Tejchman, Eric Mennesson, Isabelle Fixe, Alexandra Foucher, Simon Perera, Laura Artigas, Jose Manuel Mas, Catherine Grillon, Maciej Ugorski, Nadia Normand, Claudine Kieda. miRNome analyses reveal that activity of CAF expressed podoplanin in tumor microenvironment is modulated by exosome miRNAs involved in the PTEN-PI3K-AKT-mTOR signaling [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 1460. doi:10.1158/1538-7445.AM2017-1460
Abstract 1097: Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects
Authors: Vilas Desai, Aditi Jain, Maryna Perepelyuk, Annie Chhun, Christopher Farrell, James C. K. Lai, Alok Bhushan
Journal: Cancer Research (2017)

Abstract Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and Metabolic effects Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM is characterized by aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. Furthermore, the current standard therapy of surgical resection followed by radiotherapy and chemotherapy with Temozolomide is not very effective. The inefficacy of the currently available chemotherapeutic agents for GBM can be attributed to the challenges of drug delivery to the tumor. Our laboratory has previously reported the anticancer potential of isoflavones like Biochanin A against oral, pancreatic, breast and brain cancers. In this study, we tested our hypothesis that, Biochanin A sensitizes the GBM cells to Temozolomide, thereby increasing its efficacy in combination treatment. We used the MTT assay to determine the effects of Biochanin A alone and in combination with Temozolomide on survival of U-87 MG cells. Furthermore, two different nanoformulations of Single Walled Carbon Nanotubes (SWCNTs) functionalized with Biochanin A and Atorvastatin and SWCNTs functionalized with Temozolomide were synthesized and their effects on cell viability of U-87 MG glioblastoma cells tested. The cell viability results indicate a decrease in cell proliferation with the combination treatment as compared to the individual drug treatment. Similarly, the flow cytometry analysis showed an increased induction of apoptosis with combination treatment as compared to the drugs alone. Western-blot analysis and Immunofluorescence imaging methods were used to elucidate some of the cell survival/proliferation mechanisms involving EGFR, p-AKT, MMP-2, MT-MMP1. The effects of the drugs on U-87 MG cell metabolism (parameters like ECAR &amp; OCR) studied using Seahorse XFp analyser, suggest an increase in the mitochondrial respiration. Our results provide support for our hypothesis and the data shows that it may have implications in increasing the efficacy of the conventional treatments for GBM. These results will potentially aid in designing new therapies that can improve the outcome of GBM. Citation Format: Vilas Desai, Aditi Jain, Maryna Perepelyuk, Annie Chhun, Christopher Farrell, James C. K. Lai, Alok Bhushan. Enhancing the efficacy of Temozolomide with Biochanin A: Mechanistic and metabolic effects [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 1097. doi:10.1158/1538-7445.AM2017-1097
Abstract 5476: CIP2A can be a therapeutic target of rapamycin in radioresistant head and neck cancer with P53 mutation
Authors: Song Hee Kim, Won hyeok Lee, Myung Jin Lee, Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Jung Je Park, Myung Woul Han, Sang Yoon Kim
Journal: Cancer Research (2017)

Abstract The presence of p53 mutation was associated with poor survival in various tumors. The involvement of p53 in apoptosis and cell-cycle control makes it a plausible biomarker of prognosis . Classifying TP53 mutations in HNSCC described disruptive TP53 mutation in either the L2 or L3 loop of the DNA binding domain, resulting in polarity change within the protein, or stop cordon. Disruptive TP53 mutation in HNSCC tumors predicts for locoregional recurrence, due to increased radioresistance via the inhibition of senescence. Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we found that overexpression CIP2A (cancerous inhibitor of protein phosphatase 2A) positively correlated with presence of p53 mutation in head and neck cancer and mediates radioresistance through suppression of radiation induced senescence. And we demonstrated that rapamycin could induce senescence via CIP2A downregulation and increase radiosensitivity in p53 disruptive mutation cell line. This is the first investigation to analyze the role of CI2A in resistance to the radiotherapy of head and neck cancer. As a consequence, a greater understanding of radioresistance mechanisms through our results in head and neck cancer with p53 mutation will enable the rational design of combination regimens and sequential treatment algorithms to improve clinical outcomes and points to the usefulness of CIP2A as a biomarker to predict clinical response to rapamycin in head and neck cancer. Citation Format: Song Hee Kim, Won hyeok Lee, Myung Jin Lee, Hyo Won Chang, Ji Won Kim, Mi Ra Kim, Jung Je Park, Myung Woul Han, Sang Yoon Kim. CIP2A can be a therapeutic target of rapamycin in radioresistant head and neck cancer with P53 mutation [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 5476. doi:10.1158/1538-7445.AM2017-5476
Abstract 513: The link between polyploidy and replication stress in melanoma
Authors: Anna E. Vilgelm, C. Andrew Johnson, Kiran Malikayil, Dayanidhi Raman, David Flaherty, Brian Higgins, Ann Richmond
Journal: Cancer Research (2017)

Abstract Genomic instability is a hallmark of cancer implicated in tumor evolution and resistance to therapy. However, the molecular mechanisms that underlie genomic instability are still poorly understood. One common feature of cancer cells is an elevated genomic content (polyploidy) which is also associated with the acquisition of therapy resistance. Here we demonstrate a link between genomic instability and polyploidization in melanoma cells. We show that polyploidy induced by treatment with small molecule inhibitors of various mitotic kinases, such as AURKA, AURKB and PLK1, leads to DNA damage in cells with elevated (&amp;gt;4n) DNA content. This DNA damage results from replication stress exacerbated by limited activation of p53 in malignant melanocytes. Pharmacological induction of p53 in polyploid cells using an MDM2 antagonist reduced DNA damage by blocking re-replication of the polyploid genome as a result of p53-mediated p21 activation and transactivation of DNA repair genes. Notably we found that p21 blockade using siRNA knockdown or genetic knockout shifted polypoid cell response to p53 activation from cytostatic to cytotoxic. As a result, p21-deficient cells exhibited enhanced sensitivity to mitotic blockade combined with p53 induction. Furthermore, TCGA dataset analysis showed poor progression free survival in melanoma patients with high p21 protein expression. These data argue for administering mitotic inhibitors and MDM2 antagonists, which are currently in clinical development, in conjunction with agents that target p21. In summary, our data here reveal that polyploidization can be a mechanism for induction of DNA damage and genomic instability associated with drug resistance in cancer and suggest a novel strategy for targeting these pathways to improve melanoma therapy. Citation Format: Anna E. Vilgelm, C. Andrew Johnson, Kiran Malikayil, Dayanidhi Raman, David Flaherty, Brian Higgins, Ann Richmond. The link between polyploidy and replication stress in melanoma [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 513. doi:10.1158/1538-7445.AM2017-513
Abstract 1333: Cross talk between mitogen-activated protein kinase signaling cascades and Wnt/β-catenin in HER2+ overexpressing breast cancer cells
Authors: Miguel Nava, Nwamaka A. Amobi, Yanyuan Wu, Robin Farias-Eisner, Jay Vadgama
Journal: Cancer Research (2017)

Abstract Introduction: The HER2-positive breast cancer is characterized by an amplification of the HER2 gene, resulting in an increase in HER2 presence on the surface of cells and magnification of downstream intracellular signaling. Treatment of HER2+ breast cancer with trastuzumab decreases tumor volume, reduces metastasis and increases overall survival. Unfortunately, HER2-positive breast cancers develop resistance to trastuzumab. The mechanism of resistance may involve the activation of compensatory networks of different cell signaling pathways. The purpose of the study is to examine the crosstalk between HER2/EGFR and Wnt signaling in HER2-positive breast cancer cells. Methods: In order to address this, a HER2-positive breast cancer cell line (SKBR3) was used and induced with EGF. The phosphorylation of p38 and ERK1/2 was determined by Western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis. Results: Our data demonstrated an early and transient peak of phospho-p38 at 30min post EGF treatment. Interestingly, both phospho-p38 and phospo-ERK1/2 were detected in the nuclear compartment at this time. β-catenin, the major effector molecule in Wnt signaling, was stabilized 30min post EGF treatment. β-catenin protein levels remained higher in EGF treated cells than untreated cells up to 4h post EGF treatment. It is likely that a stabilized β-catenin following EGF treatment potently modulates a subset of Wnt targets. We are assessing this possibility using chromatin immunoprecipitation based experiments for H3K18ac, H3K27ac, pol2 and β-catenin. Taken together, our data suggests that EGFR signaling promotes Wnt signaling in HER2-positive breast cancer cells. We hypothesize that this promotes cancer stem cell niche maintenance and an EMT phenotype. Citation Format: Miguel Nava, Nwamaka A. Amobi, Yanyuan Wu, Robin Farias-Eisner, Jay Vadgama. Cross talk between mitogen-activated protein kinase signaling cascades and Wnt/β-catenin in HER2+ overexpressing 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 1333. doi:10.1158/1538-7445.AM2017-1333
Abstract 5106: <i>In vitro</i> and <i>in vivo</i> evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy
Authors: Taichi Ueshima, Tomonori Yamaguchi, Kenji Itoh, Naoki Kashimoto, Tatsuya Hirano, Rumiko Shimabara, Yohei Kawakubo, Masayuki Sato, Junpei Yamashita, Akira Yazaki, Koichi Tamura
Journal: Cancer Research (2017)

Abstract Introduction: DNA topoisomerases (Topo) are classical but still attractive targets for drug therapy in multiple types of cancers. Topo inhibitors, such as Etoposide and Daunorubicin, have been effectively used; however, their clinical use is often limited by drug resistance in cancer cell population. Therefore, the development of a novel chemical class of Topo inhibitors has been desired to overcome drug resistance. Recently, Vosaroxin (QINPREZO) is identified as a first-in-class anti-cancer quinolone derivative targeting Topo II, which is under development for relapsed or refractory acute myeloid leukemia (AML). In this study, we evaluated the in vitro and in vivo activities of WAC-224, a novel quinolone derivative for Topo II inhibition, for various cancer cell lines including multi-drug resistant cells and in mouse xenograft models, respectively. Materials and Methods: In vitro anti-proliferative activities against over 20 cell lines were determined using WST cell proliferation reagent. Apoptosis was measured by Annexin-V staining. In vivo anti-tumor activity was determined in immunodeficient mice bearing multi-drug resistant human uterine sarcoma MES-SA/DX5. Results: WAC-224 accomplished extensive anti-proliferative activities for cancer cell lines including multi-drug resistant ones with the EC50 range of 0.001 to 1 microM. Especially, in MV4-11 AML cell line, WAC-224 showed a potent and superior anti-proliferative activity compared with Doxorubicin (EC50: 1.4 nM for WAC-224 v.s. 2.5 nM for Doxorubicin). Molecular and cellular mechanisms of WAC-224 were defined as inhibition of human Topo II, induction of G2/M phase cell cycle arrest and apoptosis. Additionally, significant antitumor effects of WAC-224 were confirmed in mouse xenograft models. Furthermore, WAC-224 showed no toxic effect on small intestinal crypts in mice. Conclusion: This study demonstrated that WAC-224 has strong in vitro activities against broad cancer cell types along with the potent in vivo efficacy and well tolerability, without gastrointestinal toxicity. These results indicate that WAC-224 is promised to provide a new therapeutic option for various cancers including multi-drug resistant and hematological ones. Citation Format: Taichi Ueshima, Tomonori Yamaguchi, Kenji Itoh, Naoki Kashimoto, Tatsuya Hirano, Rumiko Shimabara, Yohei Kawakubo, Masayuki Sato, Junpei Yamashita, Akira Yazaki, Koichi Tamura. In vitro and in vivo evaluation of WAC-224, a novel quinolone class of topoisomerase II inhibitor for cancer therapy [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 5106. doi:10.1158/1538-7445.AM2017-5106
Abstract 4300: Thymoquinone Inhibits Proliferation and induces apoptosis in leukemic cells
Authors: Steve Harakeh, Josiane Semaan, Marwan El Sabban, Soad K. Al Jaouni, Mona Diab-Assaf, Rania Azar
Journal: Cancer Research (2017)

Abstract Introduction: Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus 1 (HTLV-1) and is an aggressive form of malignancy. So far, there is no effective treatment for ATL. Thymoquinone has been reported to exhibit many useful effects including anti-cancerous properties. Objective: The aim of this study is to investigated the effects of TQ on proliferation, apoptosis induction and the underlying mechanism of action in both HTLV-1 positive (C91-PL and HuT-102) and HTLV-1 negative (CEM and Jurkat) malignant T-lymphocytes. Materials and methods: Cells were treated with various concentrations of thymoquinone for 24h. Cell cytotoxicity was assayed using the CytoTox 96® Non-Radioactive Cytotoxicity Assay Kit. Cell proliferation was determined using CellTiter 96® Non-Radioactive Cell Proliferation. Cell cycle analysis was performed using staining with propidium iodide. Apoptosis was assessed using cell death ELISA kit. The effect of TQ on p53, p21, Bcl-2 protein expression was determined using Western blot analysis while TGF mRNA expression was determined by RT-PCR. Results: At non-cytotoxic concentrations of TQ, it resulted in inhibition of proliferation in a dose dependant manner. Flow cytometric analysis revealed a shift in the cell cycle distribution to the PreG1 phase which is a marker of apoptosis. Also TQ increased DNA fragmentation. TQ mediated its anti-proliferative effect and apoptosis induction by an up-regulation of TGFβ1, p53 and p21 and a down-regulation of TGF-α and Bcl-2α. Conclusion: Thymoquinone showed antiproliferative and proapoptotic potentials in ATL cells. For this reason, further research is required to investigate its possible application in the treatment of ATL. Citation Format: Steve Harakeh, Josiane Semaan, Marwan El Sabban, Soad K. Al Jaouni, Mona Diab-Assaf, Rania Azar. Thymoquinone Inhibits Proliferation and induces apoptosis in leukemic 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 4300. doi:10.1158/1538-7445.AM2017-4300
Abstract 3303: Survivin negatively-regulates autophagy through interference with the formation of Atg5-Atg12-Atg16L complex in breast cancer cells
Authors: Hsiu-Han Chan, Mohane Selvaraj Coumar, Siao-Muk Cheng, Shing-Ling Tsai, Chun-Hui Lin, Shang-Hung Chen, Euphemia Leung, Chun Hei Antonio Cheung
Journal: Cancer Research (2017)

Abstract Survivin, a member of the inhibitors-of-apoptosis proteins family, is highly expressed in different cancers and its expression is correlated with tumorigenesis and tumor metastasis. At the cellular and molecular levels, Survivin is a dual functions protein that promotes mitosis and also inhibits apoptosis. In this study, we found that Survivin is a novel negative-regulator of autophagy. Molecular analysis and computational modeling revealed that Survivin negatively regulates the formation of Atg5-Atg12 conjugates, which plays important roles in the process of autophagosome elongation, in breast cancer cells. It also negatively regulates the expression and activity of cathepsin L in cells. Interestingly, we found that Survivin binds to p62/SQSTM1 and LC3B and is also an autophagic substrate protein, in which its expression is in part directly regulated by autophagy at the protein level. Finally, mechanistic study revealed YM155, a Survivin inhibitor that was originally developed to inhibit Survivin gene transcription, downregulates Survivin expression in part through autophagic protein degradation. Taken together, findings of this study provide new mechanistic insights into both molecular functions and regulations of Survivin and the molecular mechanism of actions of YM155, a drug currently undergoing clinical trials for cancer treatment. Citation Format: Hsiu-Han Chan, Mohane Selvaraj Coumar, Siao-Muk Cheng, Shing-Ling Tsai, Chun-Hui Lin, Shang-Hung Chen, Euphemia Leung, Chun Hei Antonio Cheung. Survivin negatively-regulates autophagy through interference with the formation of Atg5-Atg12-Atg16L complex 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 3303. doi:10.1158/1538-7445.AM2017-3303