bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5394: A high-throughput screening platform for the identification of small molecule inhibitors of MAP2K4
Authors: Krishna Sankar Narayan , Luan Chi-Hao , Clutter Matthew R. , Mishra Rama K. , Scheidt Karl A. , Anderson Wayne F. , Bergan Raymond C. 
Published: May 2015

Abstract
Prostate cancer (PCa) is the second highest cause of cancer death in United States males. If the metastatic movement of PCa cells could be inhibited, then mortality from PCa could be greatly reduced. Mitogen-activated protein kinase kinase 4 (MAP2K4) has previously been shown to activate pro-invasion signaling pathways in human PCa. Recognizing that MAP2K4 represents a novel and validated therapeutic target, we sought to develop and characterize an efficient process for the identification of small molecules that target MAP2K4. Using a fluorescence-based thermal shift assay (FTS) assay, we first evaluated an 80 compound library of known kinase inhibitors, thereby identifying 8 hits that thermally stabilized MAP2K4 in a concentration dependent manner. We then developed two in vitro MAP2K4 kinase assays to evaluate kinase inhibitory function, one a western-blot based assay employing the biologically relevant downstream substrates, JNK1 and p38 MAPK, and the other an Alphascreen based activity assay. In this manner, we validated the performance of our initial FTS screen. Finally, by coupling our structure-activity relationship data to MAP2K4's crystal structure, we constructed a model for inhibitor binding. It predicted binding of our identified inhibitors to MAP2K4's ATP pocket. We next applied this approach in a high-throughput fashion to over 2200 chemically diverse compounds and identified new inhibitors of MAP2K4. Herein we report the creation of a robust inhibitor-screening platform with the ability to inform the discovery and design of new and potent MAP2K4 inhibitors.
Citation Format: Sankar Narayan Krishna, Chi-Hao Luan, Matthew R. Clutter, Rama K. Mishra, Karl A. Scheidt, Wayne F. Anderson, Raymond C. Bergan. A high-throughput screening platform for the identification of small molecule inhibitors of MAP2K4. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2014-5394
Abstract 5398: Nanoparticles for image guided focused ultrasound drug delivery
Authors: Thanou Maya , Wright Michael , Centelles Miguel 
Published: May 2015

Abstract
Thermally triggered, PEGylated drug- liposomes are currently in clinical trials. Conventional thermosensitive liposomes (TSLs) lack the labels that would allow tumor imaging upon intravenous injection and a better mark for tissue specific applied hyperthermia (image guidance). We suggest dual- labelled thermosensitive liposomes for focused ultrasound (FUS) induced hyperthermia, triggered-release and functional delivery of the therapeutic anti-cancer drugs to xenograft tumors in response to thermal stimuli in vivo. In addition to labeling for MR Imaging we introduce the use of near infrared (NIR) fluorophores that allow for real time imaging of nanoparticle behavior in the absence of any significant intrinsic tissue background fluorescence, with good to excellent transmission and reduced scattering throughout tissues. We have synthesized these labels as lipid-probe conjugates and using these labels and thermosensitive lipids we have prepared TSL nanoparticles. N`-XenoLight750-N,N-distearylamidomethylamine (XLA750.DSA) and Gadolinium(III) 2-{4,7-Bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amidomethyl]-1,4,7,10-tetraazacyclododec-1-yl}acetic Acid (Gd.DOTA.DSA) were synthesized and characterized. Both lipids were used to prepare TSL nanoparticles carrying the anticancer drugs at substantial encapsulation efficiency. Nanoparticles were tested for their biophysical characteristics (thermal drug release, stability in plasma, size) in vitro. MRI contrast enhancement ability and Near-IR signal were tested in vitro and in vivo. Nanoparticles carrying drugs were injected intravenously in mice bearing tumors. Nanoparticle kinetics in tumors were assessed with optical imaging and at defined time intervals (post injection), FUS (TIPS Phillips: 1.4MHz) was applied for 3-5 min to induce a small increase in temperature from 37°C to 41°C. Optical imaging revealed both substantial nanoparticle accumulation and drug release immediately after and only in tumors treated with focused ultrasound induced (focal) hyperthermia. Tumors treated with both nanoparticles and FUS post injection showed substantial growth inhibition compared to tumors treated with nanoparticles only. The applications of these multifunctional nanoparticles with short and mild hyperthermia could have a transformative effect on cancer chemotherapy.
Citation Format: Maya Thanou, Michael Wright, Miguel Centelles. Nanoparticles for image guided focused ultrasound drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2014-5398
Abstract 5401: Investigation of sub-tumor accumulation of PRINT nanoparticles reveals dose and route of administration dependence on particle association
Authors: Roode Luke , Bo Tao , Perry Jillian , Luft J. Chris , Bear James E. , Davis Ian J. , DeSimone Joseph M. 
Published: May 2015

Abstract
The assessment of nanoparticle accumulation in tumors and other organs uses a whole organ-based approach. These techniques, however, neglect the complex composition of tumors which multiple types of cells other than cancer cells(e.g. endothelial cells, macrophages). For delivery of certain therapeutics, identification of precisely which cells are associating with particles is critical. Using an orthotopic model of melanoma and fluorescently labeled 80x320nm PRINT nanoparticles, we assessed nanoparticle distribution in a cell-type specific manner by flow cytometry. We found that although cancer cells make up 90% of the tumor cells, only a small fraction (1-7%) associate the nanoparticles following intravenous dosing. The fractional association was dependent on the dose used and a plateau is seemingly reached, suggesting a limited number of cells are able to associate with 80x320nm particles. In addition, particle-positive tumor-associated macrophages associated with 4-fold more particles than cancer cells despite constituting approximately 1% of all cells in the tumor. When particles were administered intratumorally, cancer cell association doubles as compared to intravenous dosing. Fluoresence intensity suggests that when dosed intratumorally cancer cells associated with a greater amount of particles, similar to macrophages. Together, these data suggest a biological limitation on the ability of intravenous administration of nanoparticles for nucleic acid delivery and reveal the potential for therapeutic targeting of macrophages.
Citation Format: Luke Roode, Tao Bo, Jillian Perry, J. Chris Luft, James E. Bear, Ian J. Davis, Joseph M. DeSimone. Investigation of sub-tumor accumulation of PRINT nanoparticles reveals dose and route of administration dependence on particle association. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5401. doi:10.1158/1538-7445.AM2014-5401
Abstract 5403: Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer
Authors: Gharpure Kshipra M. , Chu Kevin S. , Bowerman Charles , Miyake Takahito , Pradeep Sunila , Mangala Lingegowda S. , Han Hee-Dong , Rupaimoole Rajesha , Wu Sherry Y. , Dalton Heather J. , Napier Mary E. , Lopez-Berestein Gabriel , DeSimone Joseph M. , Sood Anil K. 
Published: May 2015

Abstract
Purpose: The purpose of this study was to investigate the combined antitumor effects of metronomic docetaxel-containing PLGA-PRINT nanoparticles and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles (CH-mEZH2 siRNA). Method: In vivo dose-finding studies and therapeutic experiments with PLGA-PRINT-docetaxel and CH-mEZH2 siRNA were conducted in well-established orthotopic mouse models of ovarian cancer (HeyA8 and SKOV3ip1). Antitumor effects were quantified through mean tumor weight and tumor nodule counts. Tumor tissues from these studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase-3), and microvessel density (CD31). Result: Dose-finding studies for PLGA-PRINT-docetaxel revealed all doses (0.5, 1.5, 2 mg/kg for metronomic and 20mg/kg for MTD) significantly reduced tumor burden (p&lt;0.05 for MTD; p&lt;0.01 for metronomic doses). The lowest dose (0.5 mg/kg) reduced tumor weight by ∼80% and was selected for subsequent therapeutic studies. We then tested whether combining PLGA-PRINT-docetaxel particles with CH-mEZH2 siRNA would enhance antitumor effect. CH-mEZH2 siRNA alone reduced tumor weight by ∼70% in both models (p&lt;0.01 for HeyA8; p&lt;0.05 for SKOV3ip1). PLGA-PRINT-docetaxel treatment reduced tumor weight by ∼80% (p&lt;0.01). Combination therapy showed the greatest therapeutic benefit with ∼95% reduction in tumor weight in both models (p&lt;0.001 in HeyA8; p&lt;0.01 in SKOV3ip1). In both the models, the combination therapy resulted in the greatest reduction of tumor nodules. Individual as well as combination therapies showed a significant reduction in proliferation (p&lt;0.001). Metronomic PLGA-PRINT-docetaxel and CH-mEZH2 siRNA monotherapy increased the apoptotic index significantly (p&lt;0.05), whereas the combination therapy had an additive effect (p&lt;0.001). CH-mEZH2 siRNA as well as metronomic PLGA-PRINT-docetaxel therapy resulted in significant reduction in MVD (p&lt;0.01). Conclusion: Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA is an attractive therapeutic strategy.
Citation Format: Kshipra M. Gharpure, Kevin S. Chu, Charles Bowerman, Takahito Miyake, Sunila Pradeep, Lingegowda S. Mangala, Hee-Dong Han, Rajesha Rupaimoole, Sherry Y. Wu, Heather J. Dalton, Mary E. Napier, Gabriel Lopez-Berestein, Joseph M. DeSimone, Anil K. Sood. Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5403. doi:10.1158/1538-7445.AM2014-5403
Abstract 5415: Targeted nanoparticle based therapy for the treatment of glioblastoma multiforme: Unprecedented anti-cancer activity in highly drug resistant/refractory mouse models of glioblastoma with novel apoptotic nanoparticles which hone to a cell-surface protein f
Authors: Hudson Sarah , Agemy Lilach , Kotamraju Venkata Ramana , Sharma Shweta , Ruoslahti Erkki , Brunel Florence , MacLaren Ann , Muraski John , Slee Deborah 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) or “glioblastoma,” is the most common and aggressive malignant primary brain tumor in humans. An effective treatment that increases patient survival would represent a significant advance in the field, and provide a desperately needed new therapy for this deadly disease. Herein we disclose the identification of the target of the tumor homing peptide which, when conjugated to ‘nanoworms’, deliver and carry the pro-apoptotic nanoparticle system selectively to the tumor target tissue. This nanosystem has shown unprecedented anti-cancer activity in highly drug resistant/refractory mouse models of glioblastoma, which closely mimic the human disease and thus provide an exciting new opportunity for the treatment of GBM. Plans for further development of this Nanosystem will also be discussed.
Citation Format: Sarah Hudson, Lilach Agemy, Venkata Ramana Kotamraju, Shweta Sharma, Erkki Ruoslahti, Florence Brunel, Ann MacLaren, John Muraski, Deborah Slee. Targeted nanoparticle based therapy for the treatment of glioblastoma multiforme: Unprecedented anti-cancer activity in highly drug resistant/refractory mouse models of glioblastoma with novel apoptotic nanoparticles which hone to a cell-surface protein f [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5415. doi:10.1158/1538-7445.AM2014-5415
Abstract 5417: Improved tumor targeting by BLD1-ELP
Authors: Cho Eun-A , Sarangthem Vijaya Devi , Lee Byung-Heon , Kim In-San , Park Rang-Woon 
Published: May 2015

Abstract
Elastin-like polypeptide (ELP) is a promising class of recombinant biopolymers for drug delivery to solid tumors. It is a thermally responsive
polypeptide derived from mammalian elastin and consists of repeating pentapeptide sequence, Val-Pro-Gly-X-Gly, where X can be any amino acid except proline. ELPs conjugated to targeting peptide and drugs would enable enhanced targeting for drug delivery to solid tumors. BLD1 is a peptide which can selectively bind to bladder tumor cells. Not only for overcoming its rapid elimination from circulation and short half-life, but also enhancing tumor targeting efficiency, we introduced multiple BLD1 into the ELP (BLD1-ELP). Transition temperature (Tt) of BLD1-ELP was approximately 39 °C. BLD1-ELP showed superior cell binding ability than BLD1 peptide alone with 5637 and HT-1376 bladder tumor cell lines. The confocal microscopic imaging further confirmed that BLD1-ELP polymer efficiently bound to 5637 cells and HT-1376 cells compare to HEK293 embryonic kidney epithelial cells. The cellular uptake of BLD1-ELP was also much higher in 5637 cells and HT-1376 cells than in HT-29 colon cancer cells and HEK293 cells. In in vivo imaging analysis, tumor targeting of intravenously injected BLD1-ELP was observed in 5637 tumor xenograft model. These data suggest that BLD1-ELP can be developed as an effective tumor targeting, drug delivery system for diagnosis and therapy.
Citation Format: Eun-A Cho, Vijaya Devi Sarangthem, Byung-Heon Lee, In-San Kim, Rang-Woon Park. Improved tumor targeting by BLD1-ELP. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5417. doi:10.1158/1538-7445.AM2014-5417
Abstract 5424: Development of selective therapy of childhood ALL and Ewing's sarcoma using targeted-hybrid polymerized liposomal nanoparticles (HPLN)
Authors: Kang Hyunggyoo , Shahbazian Violette , Schafenacker Amanda , Nagy Jon , Triche Timothy 
Published: May 2015

Abstract
Until now a lot of understanding and research of cancer biology can make it possible to develop many anticancer drugs which can inhibit the specific pathways required for growth, proliferation, and survival of cancer cells. The current success in cancer therapy using these drugs improves the survival rate of patients but unfortunately it is not the case of all cancers and still many different kinds of cancers continue to have a poor prognosis. Furthermore the incompleteness of cancer therapies causes a variety of side effects such as secondary cancers, heart or lung damage, infertility or chronic hepatitis. Therefore a reliable tumor specific therapy is urgently needed to treat cancer patients. It is widely recognized that the recent chemotherapy could be far more effective if higher doses could be specifically delivered to the tumor and not to normal tissues. Targeted nanoparticles have shown the potential to deliver the anticancer drugs to cancer cells selectively and to overcome unexpected cytotoxicity and limited efficacy of the chemotherapy caused by the unselective delivery to the normal cells. In our study a novel nanoparticle (HPLN) was used for the treatment of childhood ALL and Ewing's sarcoma. AntiCD19 and antiCD99 antibodies were used for targeting of ALL and Ewing tumor, respectively. These tumor specific HPLNs effectively inhibit tumor growth in a murine model. Removal of targeting antibody or drug eliminates the antitumor effects, which proves this anticancer effect of HPLN is very specific to the target cancer cells and dependent upon drug. No abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. Theses targeted HPLNs showed much better cytotoxicity over a conventional untargeted PEG-liposomal Doxorubicin formulation (Doxil®). Additionally the targeted HPLN could be found in the tumor cells in a murine model. In conclusion, we have found the safe and efficient targeted HPLN delivery system of anticancer drugs to childhood ALL and Ewing's Sarcoma.
Citation Format: Hyunggyoo Kang, Violette Shahbazian, Amanda Schafenacker, Jon Nagy, Timothy Triche. Development of selective therapy of childhood ALL and Ewing's sarcoma using targeted-hybrid polymerized liposomal nanoparticles (HPLN). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5424. doi:10.1158/1538-7445.AM2014-5424
Abstract 5450: Screening more than 60 human SCLC lines with approved and investigational agents indicates complex patterns of response: Identification of HSP90 and HDACs as potential targets
Authors: Evans David M. , Delosh Rene , Laudeman Julie , Ogle Chad , Reinhart Russell , Selby Michael , Silvers Thomas , Connelly John , Monks Anne , Polley Eric , Kaur Gurmeet , Morris Joel , Teicher Beverly 
Published: May 2015

Abstract
Small cell lung cancer (SCLC) is an aggressive cancer with a 5-year survival rate of &lt;5%. While initially responsive to treatments with platinum agents, topoisomerase inhibitors or methotrexate, the tumors frequently recur after chemotherapy. To identify whether approved small molecule drugs or investigational agents may have unexpected effects in SCLC lines, we undertook a systematic large-scale screen with &gt;500 compounds against &gt; 60 well characterized SCLC cell lines in culture. Cells were exposed to 101 Approved Oncology Drugs (AOD) and 433 Investigational Agents. By evaluating compounds at 9 concentrations (10uM to 1.5nM), using cell viability 96h post drug exposure as the endpoint (Cell Titer Glo), we were able to obtain concentration response curves and IC50 values for the compounds and rank activity of these agents. In parallel studies, using Affymetrix exon ST1 arrays and miRNA profiling, we examined these same cell lines for differences in gene expression patterns that may correlate with sensitivity or resistance to select agents in the screen. The Myc oncogene (cMyc, LMyc, or nMyc) is over-expressed in about 40% of SCLC lines. Surprisingly, early analyses of the SCLC screen data have been unable to correlate high Myc expression with response to drugs or investigational agents (there is a trend with bromodomain inhibitors). The large majority of SCLC lines were sensitive to compounds against select target classes (e.g. HSP90 inhibitors and HDAC inhibitors). Examining HSP70 and HSP90 levels by Western blot suggested a slight reduction in HSP90 levels in cells resistant to the HSP90 inhibitor Ganetespib with no change in HSP70 levels. Some inhibitors against these targets showed broader cell activity than others. We are currently determining whether such differential drug sensitivity is correlated with specific changes in gene expression patterns in these cells. Further data analyses from the screen combined with genomic profiling of the cells will be presented.
Funded by NCI Contract No. HHSN261200800001E.
Citation Format: David M. Evans, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Thomas Silvers, John Connelly, Anne Monks, Eric Polley, Gurmeet Kaur, Joel Morris, Beverly Teicher. Screening more than 60 human SCLC lines with approved and investigational agents indicates complex patterns of response: Identification of HSP90 and HDACs as potential targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2014-5450
Abstract 5461: The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide
Authors: Moen Erika L. , Stark Amy L. , Zhang Wei , Dolan M. Eileen , Godley Lucy A. 
Published: May 2015

Abstract
The goal of precision medicine is to use patient-specific markers to design individualized treatment strategies. Promoter methylation of O6-methylguanine-DNA methyltransferase (MGMT), which encodes for the DNA repair protein MGMT, has been shown to predict glioblastoma patient survival after treatment with temozolomide. Unfortunately, there is no approved therapeutic alternative for patients whose tumors have an unmethylated MGMT promoter and are unlikely to respond to temozolomide treatment. Promoter methylation status of MGMT is used to predict expression levels of MGMT, despite some observed discordance between promoter methylation and protein levels. We hypothesized that incorporation of MGMT gene body cytosine modification levels in models of temozolomide response may lead to better prediction of MGMT expression levels and, more importantly, improved methods of prediction for glioblastoma patient response to temozolomide. Using 91 human glioblastoma samples from The Cancer Genome Atlas, we observed significant variation in MGMT expression levels in patients with an unmethylated promoter, with higher levels of gene body cytosine modification correlating with higher gene expression levels. Furthermore, inducing hypomethylation across the MGMT gene body with decitabine resulted in decreased levels of MGMT gene expression in lymphoblastoid and glioblastoma cell lines. These data indicate an important functional role for gene body cytosine modifications in maintaining gene expression levels. We reasoned that the decrease in MGMT expression induced by decitabine might render resistant glioblastoma cell lines more sensitive to temozolomide. Indeed, MGMT-expressing glioblastoma cell lines pre-treated with decitabine became significantly more sensitive to temozolomide-induced cytotoxicity. Overall, our results demonstrate a functional role for gene body cytosine modification in regulating gene expression of MGMT and suggest that patients with an unmethylated MGMT promoter could benefit from pre-treatment with decitabine to increase tumor sensitivity to temozolomide.
Citation Format: Erika L. Moen, Amy L. Stark, Wei Zhang, M. Eileen Dolan, Lucy A. Godley. The role of gene body cytosine modifications in MGMT expression and sensitivity to temozolomide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5461. doi:10.1158/1538-7445.AM2014-5461