bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4819: High-throughput screening of glioma stem-like cells (GSCs) identifies synergistic therapeutic combination of FGFR inhibitor and CDK4/6 inhibitor
Authors: Dong Jianwen , Martinez-Ledesma Emmanuel , Nguyen Nghi , Wu Shaofang , Piao Yuji , Tiao Ningyi , Park Soon Young , Brunell David , Stephan Clifford , Verhaak Roel , Sulman Erik , Balasubramaniyan Veerakumar , Groot John F. de 
Published: August 2018

Abstract
High-grade gliomas are challenging tumors to treat. The lack of efficacy of single-agent therapy emphasizes the importance of developing combination strategies to overcome acquired resistance. Quantitative high-throughput screening (HTS) of 2 and 3 drug combinations at 5 concentrations (maximal concentration of 1 uM) of each agent were evaluated in a panel of GSCs to identify potentially novel combination therapy. Genomic, proteiomic (reverse protein lysate array, RPPA) and GSC subtype were correlated with drug IC50 to find biomarkers of drug sensitivity. GSCs were classified as sensitive (IC50 ≤ 1µM) or resistant (IC50 &gt;1µM) for single-agent screening. The Bliss independence model and combination index (CI) criteria were used to quantify the synergy of compound combinations. Evaluation of drug combination data for synergistic combination identified FGFR inhibitor LY2874455 and CDK4/6 inhibitor LY2835219 as the most effective combinations for multiple drug sets. Abnormal activation of FGFR and alterations in the CDKN2A-CDK4/6-Retinoblastoma 1 (RB1) pathway have been implicated in glioblastoma pathogenesis. We further investigated the in vitro combination efficacy of FGFR inhibitor and CDK4/6 inhibitor. Compared to single agent, combination of FGFR inhibitor and CDK4/6 inhibitor induced prominent cleaved poly ADP ribose polymerase (c-PARP), an index of apoptosis, which was further confirmed by Annexin V staining. Combination therapy significantly inhibited p-RB, p-STAT3, p-Akt, p-Erk and p-c-Jun expression compared to single agent. Genomic data demonstrated that high PDGFRα expression and low methylation correlated to sensitivity to the FGFR and CDK4/6 inhibitor combination. These findings were validated by demonstrating that this synergistic sensitivity was decreased by knocking out PDGFRα by CRISP/Cas9 system with the combination index (CI) at IC50 increased from 0.964 to 2.247. In addition, Western blotting showed that expression of PDGFRα and Notch1 was significantly inhibited by combination treatment. However, this combination failed to show any survival and tumor inhibition benefits in intracranial xenograft mouse models.
Citation Format: Jianwen Dong, Emmanuel Martinez-Ledesma, Nghi Nguyen, Shaofang Wu, Yuji Piao, Ningyi Tiao, Soon Young Park, David Brunell, Clifford Stephan, Roel Verhaak, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. High-throughput screening of glioma stem-like cells (GSCs) identifies synergistic therapeutic combination of FGFR inhibitor and CDK4/6 inhibitor [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 4819.
Abstract 4824: Rac1b overexpression confers resistance to chemotherapy treatment in colorectal cancer
Authors: Chaturvedi Pallavi , Goka Erik , Garza Adriana De La , Lopez Dayrelis Mesa , Lippman Marc E. 
Published: August 2018

Abstract
Acquired resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. New strategies to circumvent this problem are critical to prolonging patient survival. Previous studies have shown that Rac1b, a constitutively activate isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NFκB signaling. In the present study, we show that Rac1b overexpression correlates with colorectal cancer stage with the highest levels identified in metastatic cancer. We show that Rac1b expression is associated with increased growth of colon adenocarcinoma cells and that modulation of Rac1b expression in colon adenocarcinoma cells reduces NFκB activity. The use of a Rac inhibitor in colon cancer cells reduces the 2D and 3D colony formation of colon adenocarcinoma cells, reduces the migratory capacity of these cells, and suppresses NFκB signaling. Rac inhibition also reduces tumor growth in a xenograft model of colon adenocarcinoma cells. Surprisingly, Rac1b expression and NFκB activity was upregulated in colon carcinoma cells treated with 5-FU and oxaliplatin (two components of the standard of care FOLFOX chemotherapy regimen), suggesting that Rac1b facilitates chemo-resistance by activation of NFκB signaling. Knock down of Rac1b in colon cancer cells or Rac inhibitor increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac in the colon cancer cells prevents the increase in NFκB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. Moreover, while Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in significant further reduction of tumor growth than either single agent alone. Thus, we provide the first evidence that Rac1b expression confers resistance to standard of care chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NFκB signaling providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.
Citation Format: Pallavi Chaturvedi, Erik Goka, Adriana De La Garza, Dayrelis Mesa Lopez, Marc E. Lippman. Rac1b overexpression confers resistance to chemotherapy treatment in colorectal 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 4824.
Abstract 4827: Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB signaling
Authors: Kojima Kanako , Takahashi Sanai , Saito Shungo , Nittami Tadashi , Usugi Eri , Ishii Kenichiro , HIrokawa Yoshifumi , Watanabe Masatoshi 
Published: August 2018

Abstract
Patients with metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis. Docetaxel (DTX)-based therapy is one of current standard treatments for mCRPC since 2004 although cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC. Although DTX-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. We have investigated usefulness of magnetic iron oxide nanoparticles (MNPs- Fe3O4) for cancer diagnosis and therapy, showing that MNPs- Fe3O4 may modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and MNPs- Fe3O4 on prostate cancer cell lines, DU145 and PC-3 and clarify their mechanisms. Electron microscopy, flow cytometry and Western blotting were used to study apoptosis and autophagic cell death with/without an autophagic inhibitor. Our results showed that MNPs- Fe3O4 produced reactive oxygen species (ROS) and 8-OHdG, and the combination of docetaxel and MNPs- Fe3O4 inhibited cancer cell growth and induced apoptosis and autophagic cell death. Although docetaxel induced nuclear factor-kappaB (NF-KB) expression, combination of docetaxel and MNPs inhibited NF-KB expression. These results suggest that MNPs- Fe3O4 may enhance effect of docetaxel on prostate cancer cells via ROS generation and inhibition of NF-KB signaling, leading to new tumor ablation therapies.&lt;!–EndFragment–&gt;
Citation Format: Kanako Kojima, Sanai Takahashi, Shungo Saito, Tadashi Nittami, Eri Usugi, Kenichiro Ishii, Yoshifumi HIrokawa, Masatoshi Watanabe. Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB signaling [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 4827.
Abstract 4830: Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy
Authors: Haines Eric , Zimmermann Astrid , Zenke Frank , Blaukat Andree , Vassilev Lyubomir T. 
Published: August 2018

Abstract
M3814 is a selective inhibitor of DNA-PK in clinical development. It effectively blocks non-homologous end joining repair of DNA double strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By inhibiting DNA-PK catalytic activity in the presence of DSB damage, M3814 disrupts a previously unrecognized negative regulatory loop between DNA-PK and ATM, leading to increased activation of the ATM pathway, including its downstream targets, CHK2 and p53. As a result, in cancer cells expressing wild-type p53, DNA-PK inhibitor strongly activates the p53 response to DSB DNA damage and its two main functions- cell cycle arrest and apoptosis. While p53 activation in p53 wild-type epithelial cancer cells causes effective cell cycle arrest, the majority of the epithelial tumors lose their ability to undergo p53 dependent apoptosis. In contrast, tumor cells from patients with acute leukemia express wild-type p53 in with preserved p53 apoptotic function, making them amenable to p53 activation approaches. Here, we investigate the therapeutic potential of M3814 in combination with DSB-inducing agents in acute leukemia cells. M3814 strongly potentiated the activity of IR in three p53 wild-type leukemia cell lines (MOLM-13, MOLT-4, MV4-11) but had minimal effect on the p53-null HL-60 and THP-1 lines. This potentiation was due to enhanced activation of the p53 pathway as demonstrated by substantially increased expression of p53 transcriptional targets, p21 and PUMA, and induction of apoptosis only in p53 wild-type cells. M3814 showed synergism in p53-dependent cell killing with the topoisomerase inhibitors, daunorubicin and idarubicin, and 2-3 fold increase in the potency of daunorubicin/cytarabine combination in p53 wild-type acute myeloid leukemia (AML) cells. Daunorubicin/cytarabine/M3814 combinations were better tolerated by CD34+ bone marrow cells harvested from healthy volunteers and tested in vitro. These results support further exploration of M3814 as a novel combination partner in the treatment of p53 wild-type AML.
Citation Format: Eric Haines, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Lyubomir T. Vassilev. Selective DNA-PK inhibitor, M3814, boosts p53 apoptotic response to DNA double strand breaks and effectively kills acute leukemia cells: Implications for AML therapy [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 4830.
Abstract 4847: Evaluation of the combination of olaparib and cediranib in small-cell lung cancer cells
Authors: Morikawa Naoto , Nilsson Monique B. , Guijarro Irene , Fan You-Hong , Poteete Alissa , Heymach John V. 
Published: August 2018

Abstract
Metastatic Small cell lung cancer (SCLC) is exceptionally lethal, having a median survival of 9-10 months from the time of diagnosis and a 5 year survival rate of less than 2 percent. More effective treatment approaches to SCLC are desperately needed. Poly ADP-ribose polymerase (PARP) inhibitor such as olaparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. Preclinical data indicates that SCLC cell lines overexpress PARP and are sensitive to PARP inhibition, and PARP inhibitors show promise in the clinical setting of SCLC. The identification of combination regimens that potentiate the efficacy of PARP inhibition would be of great clinical value. Recent findings indicate that olaparib and the vascular endothelial growth factor receptor (VEGFR) inhibitor, cediranib, is an effective therapeutic combination in patients with BRCA wild-type ovarian cancer. Therefore, we evaluated the efficacy of the olaparib and cediranib combinations in SCLC models. Human SCLC cell lines, NCI-H841, H526, COR-L24 and murine SCLC cell line TKOmTmG were sensitive to olaparib or cediranib therapy in vitro as determined by Cell Titer Glo® assay. Moreover, a significantly greater effect on cell viability was observed when olaparib and cediranib were used in combination. Likewise, in H841 xenograft models, single agent treatment of olaparib or cediranib inhibited tumor growth, and combination treatment of olaparib plus cediranib induced tumor regression. Western blot analysis indicated that treatment with cediranib or the combination of olaparib and cediranib induced PD-L1 protein expression both in vivo and in vitro. In TKOmTmG xenograft model in syngeneic mice, programmed death-ligand 1 (PD-L1) inhibitor plus olaparib or olaparib/cediranib combination resulted in superior combined efficacy compared to the respective single agent therapies in terms of tumor growth inhibition. These data indicate that olaparib plus cediranib may be an effective therapeutic strategy for the treatment of SCLC. Further study is warranted to understand the mechanism of action and clinical activity.
Citation Format: Naoto Morikawa, Monique B. Nilsson, Irene Guijarro, You-Hong Fan, Alissa Poteete, John V. Heymach. Evaluation of the combination of olaparib and cediranib in small-cell lung 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 4847.
Abstract 4852: Induction of HRD by targeting G9a and MTDH in DNA repair proficient endometrial cancer cells
Authors: Meng Xiangbing , Yang Shujie , Bi Jianling , Li Yiyang , Zhang Yuping , Areecheewaku Sudartip , Li Mary , Wang Zihan , Salem Aliasger K. , Leslie Kimberly K. 
Published: August 2018

Abstract
The homologous recombination repair (HRR) pathway is required for high-fidelity repair of double-strand DNA breaks. Cancer cells with HRR deficiency due to somatic BRCA1 or BRCA2 mutations are sensitive to platinum agents and targeted therapy with PARP inhibitors. Endometrial cancer is the most common cancer of the female reproductive system. DNA damage agents are commonly used in treatment but tumors often develop resistance. Metadherin (MTDH) has been shown to be amplified in a wide range of solid tumors as well as in leukemia and lymphoma. Overexpression of MTDH is correlated with angiogenesis, metastasis, and chemoresistance. Histone lysine N-methyl-transferase G9a catalyzes the demethylation of histone H3 at lysine residue 9 (H3K9) resulting in a repressive histone modification. The objective of this study is to validate the function of MTDH and G9a in HRR and test the potential to target MTDH or G9a to increase drug sensitivity. p21 expression was induced when G9a was depleted. DNA damage induced MTDH expression at 4 hours after 8Gy γ-irradiation in the well validated endometrial adenocarcinoma cell line Ishikawa H. However, induction of MTDH protein expression by the same radiation dosage was reduced when G9a was depleted. The G9a inhibitor UNC0642 itself can also induce the expression of MTDH after 24 hours treatment. Ishikawa parental cells and two Ishikawa sub-cell lines in which G9a was depleted by CRISPR were tested for the DNA damage biomarker γH2Ax and Rad51 foci formation at 4 hours following 8Gy irradiation. G9a depletion was shown to decrease Rad51 foci formation and to increase the formation of γH2Ax foci. Two natural products, Celastrol and Pristimerim were found to inhibit MTDH, FANCD2 and FANCI protein levels, which may be used to induce BRCA-ness in homologous recombination repair proficient cancer cells. G9a depletion results in the reduction of irradiation-induced Rad51 foci formation and an increase of irradiation-induced γH2Ax foci formation. We suggest that G9a depletion can increase cancer cell sensitivity to DNA damage agents. MTDH is induced by DNA damage and is a G9a inhibitor. MTDH depletion causes reduction of irradiation-induced Rad51 foci. This study is supported by the University of Iowa Department of Obstetrics and Gynecology Research Development Fund, NIH grant R01CA99908 and R01CA184101.
Citation Format: Xiangbing Meng, Shujie Yang, Jianling Bi, Yiyang Li, Yuping Zhang, Sudartip Areecheewaku, Mary Li, Zihan Wang, Aliasger K. Salem, Kimberly K. Leslie. Induction of HRD by targeting G9a and MTDH in DNA repair proficient endometrial 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 4852.
Abstract 4858: Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like cells
Authors: Shaw Vikram , Piao Yuji , Park Soon Young , Dong Jianwen , Martinez-Ledesma Emmanuel , Carrillo Caroline , Henry Verlene , Ezhilarasan Ravesanker , Sulman Erik , Balasubramaniyan Veerakumar , Groot John F. de 
Published: August 2018

Abstract
Protein arginine methyltransferase (PRMTs) function as epigenetic regulators of transcription and play a major role in gene regulation. PRMTs are upregulated in gastric, colorectal and lung cancer, and lymphoma and leukemia. PRMT5 is capable of forming symmetric dimethylarginine (SDMA) residues, and has been reported as a therapeutic target in glioblastoma, as its expression has been correlated with tumor grade and progression. In this study, the in vitro therapeutic efficacy of PRMT5 inhibitor GSK591 was investigated in a panel of gliomas stem-like cell (GSC) lines with specific molecular subtypes. Genomic, proteiomic (reverse protein lysate array, RPPA), methylation status and GSC subtype were correlated with drug IC50 to find predictors of drug sensitivity. The efficacy of inhibiting PRMT5 activity was retained at low dose of GSK591 in a small number of GSCs. Western blotting data showed high expression of PRMT5 and multiple bands of SDMAs in most GSCs tested (n=31), indicating PRMT5 enzymatic activity in GSC cell lines. Evidence of PRMT5 inhibition was demonstrated at low doses (&lt; 1.5 uM) in 4 GSC lines (13%) as shown by the total inhibition of SDMA expression in a dose- and time-dependent fashion after GSK591 treatment. The sensitivity of GSK591 correlated with low methylation of multiple genes pretreatment, including MAGI2, EGR2, and DUSP16. In addition, upregulated genes in sensitive GSCs correlated with proliferation signatures using gene set enrichment analyses (GSEA). Together, our study demonstrated that inhibition of PRMT5 activity and its substrate product SDMA correlated with inhibition of tumor growth. These promising in vitro results have led to ongoing experiments to evaluate the efficacy of GSK591 in intracranial xenograft models and the underlying mechanism of sensitivity and resistance to PRMT5 inhibition.
Citation Format: Vikram Shaw, Yuji Piao, Soon Young Park, Jianwen Dong, Emmanuel Martinez-Ledesma, Caroline Carrillo, Verlene Henry, Ravesanker Ezhilarasan, Erik Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Efficacy of the protein arginine methyltransferase PRMT5 inhibitor GSK591 in glioma stem-like 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 4858.
Abstract 4864: Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype
Authors: Schaum Nicholas , Wiley Christopher , Almirah Fatouma , Lopez-Dominguez Jose A. , Scott Gary , Benz Christopher , Campisi Judith , Davalos Albert R. 
Published: August 2018

Abstract
Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous cytokines, growth factors and proteases, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1A by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.
Citation Format: Nicholas Schaum, Christopher Wiley, Fatouma Almirah, Jose A. Lopez-Dominguez, Gary Scott, Christopher Benz, Judith Campisi, Albert R. Davalos. Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype [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 4864.