bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3501: EGFR tyrosine kinase inhibitors combined with cytotoxic drugs for treatment of NSCLC with EGFR gene mutations: Efficacy and mechanisms
Authors: Yoshida Ryohei , Okumura Synsuke , Sasaki Takaaki , Ohsaki Yoshinobu 
Published: August 2015

Abstract
Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved overall survival in non-small-cell lung cancer (NSCLC) patients whose tumors have EGFR activating mutations. After treatment with EGFR-TKIs, NSCLC tumors with EGFR activating mutations become resistant to EGFR-TKIs, and development of novel treatment strategies is needed to improve survival in such patients.Next-generation EGFR-TKIs have been developed, and a clinical trial showed clinical activity of 3rd generation EGFR-TKIs in patients with acquired resistance, especially secondary mutation T790M to EGFR-TKIs. Moreover, clinical trials demonstrated survival benefit of combination with cytotoxic agents and EGFR-TKIs in patients with EGFR-mutated NSCLC. In contrast, the IMPRESS study showed that continuation of gefitinib in addition to cisplatin and pemetrexed didn't show survival benefit in patients with acquired resistance to gefitinib.Several basic studies reported that efficacy of targeted therapy combined with chemotherapy is schedule dependent. We, therefore, conducted an in vitro study to develop a novel therapeutic strategy for NSCLC with EGFR mutations. Methods: In vitro effects of docetaxel and an EGFR-TKI, gefitinib (AstraZeneca) or AZD9291 (Selleckchem), were examined in five lung cancer cell lines (PC9, PC9GR, HCC827, HCC827GR, and H1975) using a 3D culture model (PrimeSurface 96, SUMITOMO BAKELITE CO.). The NSCLC cells were treated with the combinationeither concurrently or sequentially (EGFR-TKIs after docetaxel or docetaxel after EGFR-TKIs). Combination Index (CI) values were calculated at various levels of cytotoxicity (the Chou-Talalay method). We evaluated changes in MAPK pathway activation and in expressions of Bcl2 family proteins and cleaved PARP (Cell Signaling) by western blot analysis. Results: Docetaxel followed by EGFR-TKIs weremore effective at CI, compared with EGFR-TKIs followed by docetaxel in two of the five cell lines with EGFR activating mutations, PC9GR (EGFR19del+T790M) and HCC827GR (EGFR19del+METamp) cells. The HCC827GR cells were likely to be more sensitive than PC9GR to the combination with docetaxel and gefitinib. The combo led to inactivation of the MAPK pathway and alteration of the Bcl2 family proteins. d) Conclusion: In conclusion, our results suggest that the sequential combination of docetaxel followed by EGFR-TKIs was effective against NSCLC with acquired resistance to EGFR-TKIs.
Citation Format: Ryohei Yoshida, Synsuke Okumura, Takaaki Sasaki, Yoshinobu Ohsaki. EGFR tyrosine kinase inhibitors combined with cytotoxic drugs for treatment of NSCLC with EGFR gene mutations: Efficacy and mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3501. doi:10.1158/1538-7445.AM2015-3501
Abstract 3510: Novel lysine demethylase LSD1 inhibitors promote differentiation and apoptosis of glioma stem cells
Authors: Sareddy Gangadhara R. , Suzuki Takayoshi , Brenner Andrew J. , Vadlamdui Ratna K. 
Published: August 2015

Abstract
Glioblastoma (GBM) is the most common and devastating primary tumor of the central nervous system with dismal prognosis. GBM development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in GBM are urgently needed to identify novel therapeutic targets. Recent studies demonstrated that Glioma Stem Cells (GSCs) play central roles in GBM development and responsible for tumor propagation, invasion and chemo/radiation resistance. GSCs elimination is critical for development of efficient therapeutic strategies for GBM. Recently, we showed that lysine demethylase LSD1 is overexpressed in GBM and its inhibition reduces proliferation of GBM cells. In this study, we tested whether, LSD1 modulates GSCs differentiation and novel LSD1 inhibitors (NCL-1 and NCD-38) promote differentiation and apoptosis of GSCs. We have isolated GSCs using well established stem markers (CD133 and CD15) from two established and two patient derived GBM cells. Functionality of GSCs was established using self-renewal assays, and by profiling stem cell marker expression. Western analysis of purified GSCs showed that LSD1 is highly expressed in purified GSCs. Differentiation of GSCs resulted in decreased expression of LSD1. Down regulation of LSD1 expression using lentiviral LSD1-shRNA or by pharmacological inhibition (NCL-1 and NCD-38) significantly reduced the proliferation, neurosphere formation and self-renewal ability of GSCs with little or no effect on normal astrocytes and differentiated cells. Accordingly, treatment of GSCs with LSD1 inhibitors resulted in a dramatic reduction in the expression of stemness markers and promoted induction of differentiation markers. RNA sequencing analysis of GSCs treated with or without LSD1 inhibitors, revealed that LSD1 inhibitors modulate several pathways related to stem ness, differentiation and apoptosis. The expression of top five genes and three pathways were validated using q-RT-PCR, and western blot analysis. Chromatin Immunoprecipitation assays confirmed significant alternations in epigenetic markers at LSD1 target genes. Further, LSD1 inhibitors significantly reduced the growth of GSC driven tumors in vivo. Taken together, these results provided the evidence that induction of GSCs differentiation and apoptosis following LSD1 inhibition as a promising approach to eradicate GSCs.
Citation Format: Gangadhara R. Sareddy, Takayoshi Suzuki, Andrew J. Brenner, Ratna K. Vadlamdui. Novel lysine demethylase LSD1 inhibitors promote differentiation and apoptosis of glioma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3510. doi:10.1158/1538-7445.AM2015-3510
Abstract 3514: A novel inhibitor of IDH1 abrogates 2-HG production and reverses aberrant epigenetic alterations in IDH1 mutant cells
Authors: Rominger Cynthia , Quinn Chad , Gao Enoch , Pietrak Beth , Rendina Alan , Smallwood Angela , Groy Arthur , Korenchuk Susan , McHugh Charles , Wiggall Ken , Reif Alexander , Schmidt Stanley , Qi Hongwei , Zhao Huizhen , Concha Nestor , Carpenter Christopher , Luengo Juan , Kruger Ryan , Schwartz Benjamin , Adams Nicholas , McCabe Michael T. 
Published: August 2015

Abstract
The isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are mutated in acute myelogenous leukemia, low-grade glioma, intrahepatic cholangiocarcinoma, and chondrosarcomas. IDH1 and IDH2 normally function to convert isocitrate into alpha-ketoglutarate. However, when these enzymes are mutated at select residues the mutant enzymes now convert α-KG into 2-hydroxyglutarate (2-HG). In normal cells, 2-HG levels are typically extremely low, but IDH1/2 mutant cells can accumulate up to 10 mM 2-HG. In an effort to counteract the neomorphic activity of mutant IDH enzymes, we identified and developed potent inhibitors of IDH1. The compounds inhibit IDH1 catalytic activity in biochemical assays and reduce 2-HG production in IDH1-mutant cell lines. Consistent with the fact that 2-HG inhibits α-KG dependent enzymes including histone demethylases and Tet family hydroxylases, these IDH1 inhibitors induce a decrease in several histone methylation marks and also DNA methylation. These data demonstrate that small molecule inhibitors can reverse many of the epigenetic effects of mutant IDH1.
Note: This abstract was not presented at the meeting.
Citation Format: Cynthia Rominger, Chad Quinn, Enoch Gao, Beth Pietrak, Alan Rendina, Angela Smallwood, Arthur Groy, Susan Korenchuk, Charles McHugh, Ken Wiggall, Alexander Reif, Stanley Schmidt, Hongwei Qi, Huizhen Zhao, Nestor Concha, Christopher Carpenter, Juan Luengo, Ryan Kruger, Benjamin Schwartz, Nicholas Adams, Michael T. McCabe. A novel inhibitor of IDH1 abrogates 2-HG production and reverses aberrant epigenetic alterations in IDH1 mutant cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3514. doi:10.1158/1538-7445.AM2015-3514
Abstract 3517: Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis
Authors: Yan Jun , Zhang Qing , Zhao Wei , Ye Changxiao , Chang Cunjie , Huang Xiaojing , Zhuang Junlong , Song Jiannan , Cui Yangyan , Eliaz Isaac , Shen Bing , Huang Ruimin , Ying Hao , Guo Hongqian 
Published: August 2015

Abstract
EZH2, a histone H3K27 methyltransferase, plays an essential role in regulation of cell proliferation, survival, invasiveness and cancer stem cell (CSC) maintenance. The upregulation of the histone methyltransferase EZH2 is frequently detected in various cancer types, including urinary bladder cancer (UBC). However, the mechanisms underlying its role in cancer cell are not yet fully understood. Honokiol, a biologically active biphenolic compound isolated from the Magnolia spp, has been linked with anticancer activities; however, its mechanisms is poorly understood. In this study, we investigated the in vitro and in vivo effects of honokiol on UBC cells and whether honokiol can modulate EZH2 mediated network. By employing MTT, colony formation, wound healing, transwell invasion, Western blot, and Aldofluor stem cell detection assays, honokiol was shown to inhibit human UBC cell proliferation, survival, CSC maintenance, migration and invasion. Immunoblotting assay showed that the reduction of EZH2 expression level by honokiol was correlated with the decreases of MMP9, CD44, Sox2, Notch1. Forced expression of EZH2 reversed honokiol induced cell growth arrest and low clonogenicity, indicating that EZH2 is a major downstream target for honokiol in UBC cells. Since EZH2 is essential for gene expression repression, we screened 24 cancer related miRNAs and found that tumor suppressor miR-143 was the most induced miRNA by honokiol treatment. Further quantitative RT-PCR, chromatin immunoprecipitation (ChIP) and functional analysis revealed that EZH2 directly inhibited the expression of miR-143, whereas the inhibition of miR-143 partially rescued the EZH2 knockdown-induced cell growth arrest and reduced clonogenicity. Moreover, in vivo investigation using xenograft analysis in athymic nude mice indicated that honokiol treatment inhibited tumor progression, which was associated with reduced EZH2, CD44, Sox2, Notch1 and MMP9, and increased expression of miR-143. Altogether, our data indicated that honokiol inhibited human UBC tumor growth and aggressiveness through suppression of EZH2 function and induction of its target, miR-143, and that honokiol is promising candidate for chemoprevention and/or therapeutic treatment for bladder cancer.
Citation Format: Jun Yan, Qing Zhang, Wei Zhao, Changxiao Ye, Cunjie Chang, Xiaojing Huang, Junlong Zhuang, Jiannan Song, Yangyan Cui, Isaac Eliaz, Bing Shen, Ruimin Huang, Hao Ying, Hongqian Guo. Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3517. doi:10.1158/1538-7445.AM2015-3517
Abstract 3518: Growth inhibition of SCLC cell lines by treatment with LSD1 inhibitors is associated with modulation of neuroendocrine pathways
Authors: Paul Thomas A. , Sharma Shikhar , Hallin Jill , Xie Tao , Nichols Timothy , Greig Mike , Hardwick James , Wythes Martin , Verhelle Dominique 
Published: August 2015

Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early metastasis. Response rates to first-line chemotherapy are typically high, but short lived. We describe an epigenetic-based mechanism for targeting SCLC using inhibitors for the LSD1 histone lysine demethylase. Mechanistically reversible and irreversible LSD1 inhibitors (GSK690 and OG-86) demonstrate induction of either cell cycle arrest or apoptosis in 54% of SCLC cell lines (12/22) that becomes apparent upon continuous treatment for 7-to-10 days. Maximal rates of growth inhibition in sensitive cell lines vary from 50-to-95% and plateaus between 18-to-21 days of LSD1 inhibitor treatment. Thus, heterogeneous sensitivity to LSD1 inhibitors exists between cell line models as well as within subpopulations of cells in the same cell line.
To understand the mechanisms underlying LSD1 inhibitor activity in SCLC we have performed RNA-seq and ChIP-seq experiments coupled with bioinformatic analysis of expression signatures in sensitive and resistant models. Our data indicate that although LSD1 is over-expressed in SCLC cell lines and patient samples relative to non-small cell lung cancers, high LSD1 expression does not predict sensitivity to LSD1 inhibitors. Pathway analysis demonstrates that LSD1 inhibition modulates the expression of genes involved in cell adhesion and axon guidance including members of the Ephrin and Semaphorins families. At LSD1 target genes, we demonstrate site-specific H3K4me2 histone methylation changes overlapping LSD1 binding sites, however no global changes in H3K4me2 were observed. Interestingly we find morphological and cell adhesion changes in sensitive cell lines that coincide with expression changes in markers of neuroendocrine differentiation of SCLC such as GRP, NCAM, and NEUROD1. Based on these data, we propose a model that LSD1 inhibition modulates the neuroendocrine differentiation program of SCLC cells promoting tumor inhibition in sensitive SCLC models.
Citation Format: Thomas A. Paul, Shikhar Sharma, Jill Hallin, Tao Xie, Timothy Nichols, Mike Greig, James Hardwick, Martin Wythes, Dominique Verhelle. Growth inhibition of SCLC cell lines by treatment with LSD1 inhibitors is associated with modulation of neuroendocrine pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3518. doi:10.1158/1538-7445.AM2015-3518
Abstract 3535: A novel tumor-specific oncolytic biological therapy against invasive pancreatic cancer
Authors: Koujima Takeshi , Tazawa Hiroshi , Hori Naoto , Tamura Shuta , Kuroda Shinji , Kishimoto Hiroyuki , Nishizaki Masahiko , Urata Yasuo , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: August 2015

Abstract
Pancreatic cancer is one of the worst prognosis disease all over the world and has an overall 5-year survival rate of less than 5%. At the time of diagnosis, more than 80% of patients are not eligible for curative surgical resection due to extensive local tumor invasion and early systemic metastasis. Moreover, even after curative surgery, pancreatic cancers still show poor prognosis due to local recurrence and systemic metastasis. Gemcitabine is the standard chemotherapeutic agent to treat advanced pancreatic cancers, but median overall survival ranged from 5.0 to 7.2 months, suggesting that standard chemotherapy is less effective to most of pancreatic cancer patients. Therefore, the development of novel therapeutic strategy is needed for the treatment of pancreatic cancers. We developed a novel oncolytic adenovirus, OBP-702, in which a human telomerase reverse transcriptase gene promoter drives viral E1 gene for virus replication, and armed with the wild-type tumor suppressor p53 gene. Precise antitumor effects of OBP-702 have been evaluated in human pancreatic cancer cells. We used four pancreatic cancer cell lines with different invasion ability, including non-invasive type (MIA PaCa-2, Panc-1) and invasive type (BxPC-3, Capan-1). The antitumor effect of OBP-702 for each cell line was assessed using XTT assay. OBP-702 induced profound anti-tumor effect in all human pancreatic cancer cells, whereas OBP-301 lacking the p53 tumor suppressor gene showed differential effects among the cell types. OBP-301 induced moderate anti-tumor effect in MIA Paca-2, BxPC-3 and Capan-1 cells and strong anti-tumor effect in Panc-1 cells in a dose-dependent manner, suggesting the broad spectrum of OBP-702's efficacy. The molecular mechanism of anti-tumor effect was assessed by Western blot analysis. OBP-301 induced autophagy-related cell death, whereas OBP-702 induced autophagy- and apoptosis-related cell deaths. These results suggest that an oncolytic adenovirus, OBP-702, is a promising antitumor agent to induce profound cell death in invasive human pancreatic cancer cells. The clinical trial of intratumoral administration of OBP-702 in patients with invasive pancreatic cancer is warranted.
Citation Format: Takeshi Koujima, Hiroshi Tazawa, Naoto Hori, Shuta Tamura, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara. A novel tumor-specific oncolytic biological therapy against invasive pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3535. doi:10.1158/1538-7445.AM2015-3535
Abstract 3537: Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer
Authors: Ranjan Manish , Abd Elmageed Zakaria , Kim Hogyoung , Datta Amrita , Bhasin Nobel , Braun Steven E. , Mondal Debasis , Abdel-Mageed Asim B. 
Published: August 2015

Abstract
The twice as high incidence and mortality among African Americans (AA) compared to Caucasian Americans and other ethnic minorities remains elusive. The de novo synthesis of androgens by prostate tumors provides a significant survival advantage leading to outgrowth of castration resistant tumors. The “intracrine” production of androgens in the tumor microenvironment is greatly influenced by the synthesis of androgen metabolizing enzymes (AMEs) and the level of circulating hormones. Currently, targeting de novo synthesis of androgens in tumor microenvironment is singularly the toughest challenge presented to oncologists. Our present research attempts to identify and exploit the key players among the AMEs for targeting the backdoor pathway of DHT synthesis in castration resistant prostate cancer (CRPC). Comparative analysis of gene expression of AMEs in microdissected cells versus the adjacent normal tissue revealed AKR1C4 to be the most promising candidate for targeting the backdoor pathway in DHT synthesis. Existing literature supports this view since Type 1 3a-HSD enzyme has been shown to readily oxidize testosterone to Δ4-androstene-3, 17-dione in a substrate dependent reaction. Our analysis using recombinant AKR1C4 induced cytotoxicity and apoptosis in androgen dependent PC cells in vitro. Next, using a lentivirus construct, we genetically engineered tumor-tropic adipose-derived stem cells (ASCs) to express and secreted AKR1C14 (mouse homolog of AKR1C4). The results showed that ASCs are capable of expressing the enzyme, which can catabolize DHT in vitro and induce apoptosis in androgen dependent prostate cancer cells as shown by DHT Elisa, psPSA reporter assays and cytotoxicity and survival assays. Our current research plan is to examine the efficacy of tumor-tropic AKR1C14-expressing ASCs in targeting and inhibiting prostate metastatic growth in an animal model system.
Citation Format: Manish Ranjan, Zakaria Abd Elmageed, Hogyoung Kim, Amrita Datta, Nobel Bhasin, Steven E. Braun, Debasis Mondal, Asim B. Abdel-Mageed. Stem-cell based selective delivery of alpha keto reductases for therapeutic targeting of residual androgens in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3537. doi:10.1158/1538-7445.AM2015-3537
Abstract 3538: Quorum-sensing Salmonella selectively trigger protein expression within tumors
Authors: Swofford Charles A. , Van Dessel Nele , Forbes Neil S. 
Published: August 2015

Abstract
Salmonella that secrete anti-cancer proteins have the potential to eliminate tumors, but nonspecific expression causes damage to healthy tissue. Salmonella, integrated with a density-dependent switch, would only express proteins in tightly packed colonies within tumors, reducing side-effects after the initial bacterial administration. To test this, we cloned the lux quorum-sensing (QS) system and a GFP reporter into the attenuated Salmonella strain VNP20009. Fluorescence and bacterial density were measured in culture and a tumor-on-a-chip device to determine the critical density necessary to initiate expression. QS Salmonella were injected into 4T1 tumor-bearing mice to quantify GFP expression in vivo. At densities below 0.6×1010 CFU/g in tumors, less than 3% of QS Salmonella expressed GFP. Above densities of 4.2×1010 CFU/g, QS Salmonella had similar expression levels to constitutive controls. GFP expression by QS colonies was dependent upon the distance to neighboring bacteria. No colonies expressed GFP when the average distance to neighbors was greater than 155 μm. Calculations of autoinducer concentrations showed that expression was sigmoidally dependent on density and inversely dependent on average radial distance. Based on bacterial counts from excised tissue, the liver density (0.0079×1010 CFU/g) was less than the critical density (0.11×1010 CFU/g) necessary to initiate expression, indicating that expression of a therapeutic protein would not be induced in healthy organs. Inserting the bacterial toxin S. Aureus α-hemolysin (SAH) under the control of the QS system resulted in the expression of SAH only at high bacterial dosage. In vitro, supernatant from cultures of QS-SAH Salmonella reduced cancer cell viability by 70%. When administered to the microfluidic tumor-on-a-chip, QS-SAH Salmonella killed 43% of the tissue, 12 times greater (P&lt;0.05) than induced by control bacteria. QS Salmonella are a promising tool for cancer treatment that will target drugs to tumors, while preventing damage to healthy tissue.
Citation Format: Charles A. Swofford, Nele Van Dessel, Neil S. Forbes. Quorum-sensing Salmonella selectively trigger protein expression within tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2015-3538