bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3908: miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells
Authors: Lulla Amriti R. , Einarson Margret B. , Zhou Yan , Lev Avital , Dicker David T. , El-Deiry Wafik S. 
Published: August 2018

Abstract
Tumor suppressor p53, guardian of the genome, is frequently mutated or functionally dysregulated in more than 50% of human tumors. p53 mutation is a later event in tumorigenesis and a number of p53 mutants have “Gain of Function” (GOF) properties that have been shown to promote invasive and more aggressive phenotypes in cancer cells. Mutant p53 has been an attractive and promising therapeutic target for advanced stages of tumors. Further understanding the GOF properties of mutant p53 may help with design of novel strategies to target mutant p53 and/or key GOF pathways. We developed a novel functional high throughput screening (HTS) assay to identify miRNAs that selectively target GOF in mutant p53-expressing cell lines. Of the 2754 miRNA mimics screened, we identified 56 miRNAs that selectively reduced cell viability in TP53 R175H (mutant) cells. The current study characterizes the role of our lead mimic, miR-3132 in mutant p53 cells. We found that expression of miR-3132 is lost in cancer cells and that miR-3132 expression is correlated to p53 status, with mutant p53 cells expressing lower levels of miR-3132 than those with wild-type p53. Restoring expression of miR-3132 via mimics induces anti-proliferative and pro-apoptotic effects in a broad panel of colorectal (CRC), breast and lung cancer cell lines. In addition, miR-3132 induces TRAIL-dependent cell death in mutant p53-expressing cells. All cell lines show potent upregulation of cleaved caspases -8, -9 and -3, at 72 hrs post transfection with miR-3132. DNA damaging agents and serum starvation endogenously increase mature miR-3132 levels in wild-type p53 cells. However, this increase is blunted in mutant p53 cells, indicating that p53 could have a role in modulating either the transcriptional or post-transcriptional levels of miR-3132. In summary, we have identified miR-3132 as a TRAIL and cell death-inducing miRNA whose regulation is dependent on p53. Our ongoing work aims at finding the key targets of miR-3132 that explain the cellular response, TRAIL induction and subsequent cell death. Our long-term goal is to develop miR-3132 as a novel single or combinatorial anti-cancer agent for mutant p53 cancer cells.
Citation Format: Amriti R. Lulla, Margret B. Einarson, Yan Zhou, Avital Lev, David T. Dicker, Wafik S. El-Deiry. miR-3132 induces TRAIL and cell death in mutant p53-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3908.
Abstract 3920: nfP2X7 mediates survival of cancer cells in the tumor microenvironment
Authors: Gilbert Simon Mark , Oliphant Christopher John , Peille Anne-Lise , Bronsert Peter , Virgilio Francesco Di , McNulty Shaun , Lara Romain 
Published: August 2018

Abstract
The purpose of this study was to demonstrate the effect of the tumor microenvironment (TME) on expression of nfP2X7, a cancer specific form of P2X7 involved in cancer cell survival. P2X7 is an ATP-gated receptor, involved in inflammation, cell death, cell proliferation and cell migration. Alterations in these cellular processes are associated with the development of cancer. P2X7 is characterized by its capacity to open a large molecular weight pore in response to prolonged ATP activation. A mechanism that triggers membrane depolarisation and cell death. The TME contains high concentrations of ATP sufficient to cause opening of the P2X7 pore, while ATP is almost undetectable in healthy tissue. Secretion by cancer cells and release of intracellular ATP from dying cells are thought to be the main source of extracellular ATP in the TME. Non-functional P2X7 (nfP2X7) is a cancer-specific receptor in which formation of the large molecular weight pore, has been abrogated. Acquisition of nfP2X7 enables tumor cells to survive in the presence of high ATP concentrations. Using antibodies raised against nfP2X7, we assessed the expression of the receptor in a panel of cancer types and analysed the effect of the high ATP concentrations on nfP2X7 expression. We further analyzed the effect of siRNA mediated nfP2X7 depletion on cancer cell lines' viability. Our data shows that nfP2X7 is broadly expressed at the surface of many cancer types and supports cancer cell survival. Furthermore, we demonstrate that exposure to a high ATP concentration, equivalent to those in the TME, drives nfP2X7 expression. These data demonstrate that nfP2X7 is a cancer therapeutic target, whose expression is driven by the TME.
Citation Format: Simon Mark Gilbert, Christopher John Oliphant, Anne-Lise Peille, Peter Bronsert, Francesco Di Virgilio, Shaun McNulty, Romain Lara. nfP2X7 mediates survival of cancer cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3920.
Abstract 3922: Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells
Authors: Kurihara Eisuke , Shien Kazuhiko , Torigoe Hidejiro , Takahashi Yuta , Ogoshi Yusuke , Yoshioka Takahiro , Namba Kei , Sato Hiroki , Yamamoto Hiromasa , Soh Junichi , Toyooka Shinichi 
Published: August 2018

Abstract
Purpose: Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) are the standard first-line treatment of advanced non-small cell lung cancer (NCSLC). However, almost all patients eventually acquire resistance to EGFR-TKIs, and novel therapeutic strategies to overcome the acquired resistance have been required. Heat-shock protein 90 (Hsp90) is a chaperon protein involved in folding and stabilization of client proteins essential for cancer cell growth and survival. Ganetespib (STA-9090) is one of the second-generation Hsp90 inhibitors with strong anti-tumor effect on NSCLC cells. In this study, we evaluated the anti-tumor effect of ganetespib in EGFR-TKI sensitive and acquired resistance NSCLC cell lines.
Materials and Methods: We treated 4 EGFR-mutant NSCLC cell lines (HCC827, HCC4006, PC-9 and HCC4011), and 14 experimentally established EGFR-TKIs (gefitinib or afatinib) resistance cell lines with ganetespib. The EGFR-TKI resistance mechanism consisted of EGFR T790M second mutation, MET amplification, epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like features. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathways.
Results: The IC50 values in parental NSCLC cell lines ranged from 1.3nM to 15nM, and those in acquired EGFR-TKI resistant cell lines ranged from 0.87nM to 25nM, which suggests strong anti-tumor effect of ganetespib. In addition, this effect was observed regardless of the resistant mechanisms, including EMT. Ganetespib suppressed EGFR activation in EGFR-TKI resistance cells harboring EGFR T790M second mutation. Also, ganetespib suppressed MET activation in EGFR-TKI resistance cells harboring MET amplification.
Conclusion: Ganetespib showed strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells regardless of the resistant mechanisms, suggesting that ganetespib could be a promising therapeutic option in the treatment of NSCLC with acquired EGFR-TKI resistance.
Citation Format: Eisuke Kurihara, Kazuhiko Shien, Hidejiro Torigoe, Yuta Takahashi, Yusuke Ogoshi, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka. Ganetespib demonstrates strong anti-tumor effect in acquired EGFR-TKI resistance NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3922.
Abstract 3927: Clinicopathologic features and immune microenvironment of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors
Authors: Takashima Yuta , Sakakibara-Konishi Jun , Hatanaka Yutaka , Hatanaka Kanako C. , Ohhara Yoshihito , Oizumi Satoshi , Hida Yasuhiro , Kaga Kichizo , Kinoshita Ichiro , Dosaka-Akita Hirotoshi , Matsuno Yoshihiro , Nishimura Masaharu 
Published: August 2018

Abstract
Background: Approximately 20-30% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations are not responsive to EGFR-tyrosine kinase inhibitors (TKIs). Although, primary resistance to EGFR-TKI is attributed to various genetic alterations, little is known about the clinical and immunopathological features of patients with primary resistance. The tumor immune microenvironment including tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) has been reported to play an important role in tumor progression in NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKI.
Materials and Methods: Characteristics of 124 NSCLC patients with EGFR mutations who received EGFR-TKI were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8, and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically.
Results: Primary resistance was observed in 13.7% (17/124) of patients. Smoking Tobacco correlated significantly with primary resistance compared to non-primary resistance. Lower density of total TILs and negative PD-L1 expression as per immunohistochemical analysis correlated significantly with primary resistance. Moreover, immune ignorant phenotype of tumor microenvironment, negative PD-L1 expression with low TIL density, was significantly observed in primary resistance.
Conclusions: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs.
Citation Format: Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C. Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura. Clinicopathologic features and immune microenvironment of non-small cell lung cancer with primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3927.
Abstract 3937: Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib
Authors: Kahraman Deniz C. , Kahraman Tamer , Atalay Rengul Cetin 
Published: August 2018

Abstract
Liver cancer stem cells (LCSCs) are derived from damaged and transformed hepatic progenitor cells (HPCs) during precancerous cirrhosis stage. Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are significantly deregulated in liver cancer. The activation of PI3K/AKT/mTOR pathway in LCSC population is one of the reasons for acquired resistance to sorafenib in advanced hepatocellular carcinoma (HCC) patients. Therefore, identifying novel inhibitors targeting this pathway acting on LCSCs is highly essential. We, therefore, elucidated the bioactivities of small-molecule kinase inhibitors on LCSCs acting through PI3K/Akt/mTOR pathway in comparison with DAPT (CSC inhibitor), DNA intercalators and sorafenib. For this purpose, CD133+/EpCAM+ cells originated from HCC cells were analyzed by flow cytometry and effective inhibitors on LCSCs were further tested for their potential combinatorial effects. Treatment of cells with sorafenib and DNA intercalators resulted in enrichment of CD133+/EpCAM+ cells. Yet, rapamycin, LY294002 and DAPT significantly reduced CD133/EpCAM positivity. Combination studies revealed that sequential treatment strategy decreased the ratio of LCSCs as opposed to sorafenib treatment alone. The effects of the inhibitors were also demonstrated with LCSC sphere formation. Additionally, a large panel of genes involved in cancer pathways was analyzed using Nanostring® nCounter® Technology to identify the differentially expressed genes in rapamycin, sorafenib or DAPT treated cells. Systematic pathway analysis using Cytoscape ScoreFlow algorithm application allowed us to identify differential response genes involved in stemness. While the stemness genes were downregulated in cells treated with rapamycin or DAPT, JAG1 gene was found to be upregulated in sorafenib-treated cells. Interleukin 8 (IL-8) was downregulated upon treatment with DAPT, yet upregulated upon sorafenib treatment. Following IL-8 inhibition with repaxirin, CD133/EpCAM positivity of cells decreased significantly, indicating that IL-8 signaling is crucial for the conservation of stemness features of cancer cells. The combination of sorafenib and reparixin resulted in lower levels of SOX2 and Nanog proteins. Conclusion: PI3K/Akt/mTOR pathway inhibitors alter hepatic CSC composition and gene expression in favor or to the detriment of cancer stem cell survival. Blockade of IL-8 signaling provides a promising therapeutic approach for prevention of LCSC enrichment.
Citation Format: Deniz C. Kahraman, Tamer Kahraman, Rengul Cetin Atalay. Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3937.
Abstract 3947: Glutaminolysis inhibitors benzo[d][1,2]selenazol -3(2H)-one dimers completely disrupt mitochondrial function and showed early promise as effective antitumor agents with little general toxicity
Authors: Ruan Benfang Helen , Yu Yan , Chen Zhao , Jin Yanhong , Fang Jinzhang , Zhao Han , Ruan Jennifer 
Published: August 2018

Abstract
Targeting glutaminolysis is an emerging approach to solve the imminent problems of drug resistance and drug toxicity in cancer therapeutics. Ebselen was identified in the KGA coupled assay as a potent KGA inhibitor but showed very low potency in inhibiting the growth of glutamine - dependent cancer cells. For rigorous characterization, we developed a direct kinetic binding assay for KGA using Bio-Layer Interferometry (BLI) as the detection method; Ebselen was identified as a GDH inhibitor but not a KGA inhibitor. Proteomic analysis demonstrated that the ebselen derivative could crosslink with KGA protein, but the binding site is at the N-terminal appendix domain outside of the catalytic domain, which might explain why ebselen is not a potent KGA enzyme inhibitor in functional assays. Furthermore, we designed and synthesized several benzo[d][1,2]selenazol -3(2H)-one dimers which were subjected to SAR analysis by several glutaminolysis specific biochemical and cell based assays. Novel dual KGA/GDH inhibitors were discovered from the synthetic compounds; the dual inhibitors completely disrupt mitochondrial function, depleted cellular NAD(P)H levels, induced ROS mediated cell death, and inhibited the growth of various cancer cells but not the normal cells. Importantly, in an aggressive liver cancer mouse model, a KGA/GDH inhibitor reduced the tumor size by 50-60% and lowered plasma lactate dehydrogenase (a biomarker of tumor metastasis) by 2-3 times. Thus, the novel dual-specific KGA/GDH inhibitors showed early promise as effective antitumor agents with little general toxicity.
Citation Format: Benfang Helen Ruan, Yan Yu, Zhao Chen, Yanhong Jin, Jinzhang Fang, Han Zhao, Jennifer Ruan. Glutaminolysis inhibitors benzo[d][1,2]selenazol -3(2H)-one dimers completely disrupt mitochondrial function and showed early promise as effective antitumor agents with little general toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3947.
Abstract 3950: Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in cancer cells
Authors: Zhang Shengliang , Zhou Lanlan , El-Deiry Wafik S. 
Published: August 2018

Abstract
NSC59984 is a small molecule with a duel capability to induce mutant p53 degradation and restore p53 pathway signaling in cancer cells. NSC59984 requires reactive oxygen species (ROS) to induce mutant p53 degradation via ERK2. ROS regulates cell growth and death with tumor cells having higher ROS levels than normal cells. Increasing ROS level is a promising therapeutic strategy applied in cancer clinical trials. However, the toxicity of high ROS levels is a limitation that needs to be solved urgently. We investigated the synergy between NSC59984 and ROS in cancer cells. To increase ROS, cells were treated with BSO, an ROS-generating agent. Our data reveal that ROS sensitizes cells to NSC59984 treatment including enhanced-p53 restoration and mutant p53 degradation induced by NSC59984. Combination of NSC59984 and BSO shows a synergy to induce cell death in cancer cells with an antagonism observed in normal cells at the tested doses. Consistent with the in vitro experiments, our in vivo experiments show that the combination of NSC59984 and BSO significantly suppresses tumor growth. Immunohistochemical staining shows a decrease in Ki67 and an increase in cleaved caspase 3 in xenografted tumors following combination treatment, suggesting that the tumor suppression is due to the induction of cell death and the inhibition of cell growth. Furthermore, the combination of NSC59984 and BSO shows a significant reduction in glutathione (GSH) levels in cancer cells, suggesting that the synergy between NSC59984 and BSO is due to the inhibition of the antioxidant system in mutant p53-expressing cancer cells. Our data indicate that a high level of ROS can be considered as a biomarker for NSC59984 administration in cancer therapy and supports further evaluation of the combination of NSC59984 and ROS-generating agents.
Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3950.
Abstract 3962: Antitumor effects of the antiparasitic agent ivermectin via inhibition of yes-associated protein 1 expression in gastric cancer
Authors: Kuramitsu Shotaro , Nanbara Sho , Hu Qingjiang , Kuroda Yousuke , Masuda Takaai , Ito Shuhei , Eguchi Hidetoshi , Mehara Yoshihiko , Mimori Koshi 
Published: August 2018

Abstract
[Background] Yes-associated protein 1 (YAP1) acts as an oncogene through dephosphorylation and nuclear translocation, and nuclear accumulation of YAP1 is associated with poor prognosis in gastric cancer (GC). We previously identified ivermectin, an antiparasitic drug, as a YAP1 inhibitor. Here, we aimed to clarify whether ivermectin had antitumor effects on GC through inhibition of YAP1.
[Result] First, we evaluated the antiproliferative effects of ivermectin on human GC cells using in vitro proliferation assays and a xenograft mouse model. YAP1-knockdown assays were performed to assess whether the sensitivity to ivermectin depended on YAP1 expression. Next, we explored the mechanism through which ivermectin regulated YAP1 expression or localization by immunoblotting and reverse transcription-quantitative polymerase chain reaction for YAP1 and the downstream gene CTGF. Finally, the clinical significance of YAP1 expression was examined using three independent GC datasets. We found that MKN1 GC cells were most sensitive to ivermectin, whereas MKN7 cells were most resistant. In MKN1 xenografts, ivermectin suppressed tumor growth, and the sensitivity of MKN1 cells to ivermectin was decreased by YAP1 knockdown. Ivermectin inhibited YAP1 nuclear expression and CTGF expression in MKN1 cells but not MKN7 cells. Moreover, ivermectin decreased YAP1 mRNA expression, thereby inhibiting nuclear accumulation of YAP1 in MKN1 cells. In survival analysis, low YAP1 mRNA expression was associated with a better prognosis in three independent GC datasets.
[Conclusion] Ivermectin suppressed the growth of GC in vitro and in vivo by inhibiting YAP1 expression. Furthermore, GC with low YAP1 expression had favorable clinicopathological features and good prognosis. These findings provided insights into the antiproliferative effects of ivermectin as a YAP1 inhibitor and established a theoretical basis for preclinical evaluations of ivermectin for management of GC.
Citation Format: Shotaro Kuramitsu, Sho Nanbara, Qingjiang Hu, Yousuke Kuroda, Takaai Masuda, Shuhei Ito, Hidetoshi Eguchi, Yoshihiko Mehara, Koshi Mimori. Antitumor effects of the antiparasitic agent ivermectin via inhibition of yes-associated protein 1 expression in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3962.