bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 708: Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model
Authors: Rodriguez-Aguirre Maria E. , Espinoza Fernando Lopez , Martin Bryan , Yadiz Kader , Huang Tiffany T. , Ibanez Carlos E. , Ostertag Derek G. , Kasahara Noriyuki , Gruber Harry E. , Jolly Douglas J. , Robbins Joan M. 
Published: May 2015

Abstract
Despite advances in screening, colorectal cancer (CRC) remains the fourth most commonly diagnosed cancer and the second leading cause of cancer death for both men and women in the US. Approximately one half of patients with CRC develop liver metastases (mCRC). The standard treatment for mCRC is 5-fluorouracil (5-FU) based combination chemotherapy. 5-FU combination chemotherapy has extended the median survival of these patients from 6 to &gt;20 months.
We are pursuing a unique investigational approach to treat cancer via intratumoral production of 5-FU. Patients are first administered Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector (RRV) which selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) gene. In infected cells, the CD enzyme is expressed and converts 5-FC (flucytosine, an orally available anti-fungal drug) to the anti-cancer drug 5-FU in situ.
The combination of Toca 511 with oral extended release 5-FC (Toca FC) is currently in clinical trials for recurrent High Grade Glioma (NCT01156584, NCT01470794, and NCT01985256). We tested the suitability of this approach for the treatment of mCRC in a mouse syngeneic liver metastasis model. CT-26-luciferase colon carcinoma cells were delivered via intrasplenic injection producing multiple tumor foci within the liver. Toca 511 was then delivered either by intrasplenic or intravenous injection followed by courses of 5-FC. Vector delivery to tumor was monitored by PCR. 5-FC and 5-FU were detected using LC/MS. The effect of treatment with Toca 511 and 5-FC in this mouse model of mCRC will be presented.
Citation Format: Maria E. Rodriguez-Aguirre, Fernando Lopez Espinoza, Bryan Martin, Kader Yadiz, Tiffany T. Huang, Carlos E. Ibanez, Derek G. Ostertag, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins. Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model. [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 708. doi:10.1158/1538-7445.AM2014-708
Abstract 709: Efficacy of Salmonella typhimurium A1-R on experimental breast cancer brain metastasis
Authors: Zhang Yong , Miwa Shinji , Zhang Nan , Hoffman Robert M. , Zhao Ming 
Published: May 2015

Abstract
The aim of this study was to evaluate the efficacy of Salmonella typhimurium A1-R (A1-R) on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected into the left ventricle of transgenic nude mice expressing nestin-driven green fluorescent protein (ND-GFP). ND-GFP mice express GFP in nascent blood vessels. At various time points, the tumors and vasculature in the brain were imaged by laser-scanning confocal and stereo fluorescence microscopy. Eighty percent of the cells that reached the brain extravasated and grew perivascularly; twenty percent of the cells, however, proliferated within the vasculature which may lead to thrombosis-like infarction of the brain parenchyma. Compared to the control group, mice treated with Salmonella typhimurium A1-R (A1-R) had significant inhibition of brain metastasis and increased survival (p&lt;0.05). The results of the present study suggest the clinical potential of bacterial therapy of breast cancer brain metastasis.
Citation Format: Yong Zhang, Shinji Miwa, Nan Zhang, Robert M. Hoffman, Ming Zhao. Efficacy of Salmonella typhimurium A1-R on experimental breast cancer brain metastasis. [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 709. doi:10.1158/1538-7445.AM2014-709
Abstract 711: Salmonella typhimurium A1-R induces quiescent FUCCI-expressing cancer cells to cycle and become chemosensitive
Authors: Yano Shuya , Zhang Yong , Zhao Ming , Hiroshima Yukihiko , Miwa Shinji , Uehara Fuminari , Kishimoto Hiroyuki , Tazawa Hiroshi , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: May 2015

Abstract
Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Time-lapse imaging showed that Salmonella typhimurium A1-R (A1-R) encircled and invaded quiescent cancer cells in monolayer culture, thereby eliminating them. Moreover A1-R infected and killed quiescent fluorescent ubiquitination-based cell cycle indicator (FUCCI)-expressing cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill quiescent cancer cells in tumor spheres. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in killing quiescent cancer cells resistant to cytotoxic agents. Furthermore, the combination of A1-R and cisplatin reduced tumor size compared with A1-R monotherapy or cisplatin alone. This study demonstrates that A1-R can kill quiescent cancer cells and also sensitize them to conventional chemotherapy. These results suggest a new therapeutic paradigm potentially more effective than current therapeutics which are ineffective against quiescent cancer cells.
Citation Format: Shuya Yano, Yong Zhang, Ming Zhao, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara, Robert M. Hoffman. Salmonella typhimurium A1-R induces quiescent FUCCI-expressing cancer cells to cycle and become chemosensitive. [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 711. doi:10.1158/1538-7445.AM2014-711
Abstract 712: Salmonella typhimurium A1-R inhibits surgically induced breast cancer metastasis
Authors: Zhang Yong , Zhang Nan , Hoffman Robert M. , Zhao Ming 
Published: May 2015

Abstract
We investigated the efficacy of tumor-targeting Salmonella typhimurium A1-R in the perioperative period to eradicate micrometastatic disease. Fifty female BALB/c mice were inoculated in the mammary fat pad with metastatic murine mammary adenocarcinoma (4T1-RFP (3×105/mouse), and divided into five groups. Control group (n = 10) with no treatment; surgery group (n = 10) in which the tumor was completely resected at day 21 after cell inoculation; Salmonella typhimurium A1-R (A1-R) (n = 10) in which the primary tumor was treated with A1-R alone at day 10 after cell inoculation; postoperative-administration of A1-R (n = 10) in which A1-R was administrated only after the primary tumor was resected; perioperative administration of A1-R (n = 10) in which A1-R was administrated before and after the primary tumor was resected. Metastatic tumor burden was assessed by quantitative fluorescence imaging of metastasis. Efficacy was assessed by metastatic burden and survival. The study showed that excision of the primary tumor was associated with increased systemic metastatic burden, and postoperative metastases exhibited increased proliferation (p &lt; 0.05). A1-R alone treatment inhibited metastasis compared to untreated control and surgery only (p&lt;0.05). Post-operative A1-R treatment significantly inhabited surgically-induced metastases (p0.05). Perioperative administration of A1-R showed the best efficacy compared to all other treatments in inhibiting surgery-induced metastasis (p&lt;0.05) and prolonged survival (p&lt;0.05).
Citation Format: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao. Salmonella typhimurium A1-R inhibits surgically induced breast cancer metastasis. [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 712. doi:10.1158/1538-7445.AM2014-712
Abstract 717: Novel potent antisense oligonucleotides targeting transforming growth factor beta1 (TGF-β1)
Authors: Jaschinski Frank , Korhonen Hanna , Braun Stephan , Wosikowski Katja , Janicot Michel 
Published: May 2015

Abstract
Transforming growth factor beta (TGF-β) is a key member of a large family of cytokines, which play critical, pleiotropic roles in the pathophysiology of various human diseases, such as cancer, inflammation, autoimmune disease, and cirrhosis/fibrosis. TGF-β1, -2 and -3 isoforms are cytokines encoded by different genes but sharing strong sequence and structure homology. They function as the primary mediators of TGF-β signaling via both non-canonical and canonical signaling pathways. In Oncology, TGF-β isoforms are associated with a wide range of biological processes such as tumor cell invasion and migration, angiogenesis, immunosuppression, as well as regulation of tumor stem cell properties. Hence, blocking the TGF-β signaling pathway may have a multifold therapeutic benefit in Oncology, although therapeutic relevance of the respective TGF-β isoforms remains poorly documented.
In order to evaluate the specific biological relevance of TGF-β1 isoform in cancer, we have initiated an extensive discovery program for identification of antisense oligodeoxynucleotide constructs selectively inhibiting expression of the TGF-β1 ligand. Based on the sequence of the human TGF-β1 mRNA, more than 150 Locked Nucleic Acid (LNA)-modified gapmers were designed, synthesized and tested in cell-based assays. Highly potent and selective TGF-β1 constructs were identified and selected based on efficient suppression of TGF-β1 mRNA/protein expression in different human and rodent tumor cell lines, and in human Peripheral Blood Mononuclear Cells (PBMCs). Effective target downregulation was demonstrated after lipofectamine aided-transfection (sub-nM concentration range), but also in the absence of any transfection agent (gymnotic delivery) at sub-µM concentrations. Selected TGF-β1 specific oligonucleotides were further tested in relevant animal xenograft models and strong target inhibition was also observed following systemic administration. Further details of this discovery program will be discussed and pharmacology properties and features of potent and selective TGF-β1 antagonists will be presented.
Citation Format: Frank Jaschinski, Hanna Korhonen, Stephan Braun, Katja Wosikowski, Michel Janicot. Novel potent antisense oligonucleotides targeting transforming growth factor beta1 (TGF-β1). [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 717. doi:10.1158/1538-7445.AM2014-717
Abstract 718: Systemic delivery of therapeutic siRNA by multifunctional mesoporous silica-based nanocarrier inhibits lung cancer growth and metastasis
Authors: Chen Yijie , Gu Hongchen , Xia Weiliang 
Published: May 2015

Abstract
RNAi-based therapy by targeting dysregulated genes has shown great promise in biomedical research but still newer versions of effective and safe delivery systems are required. In this study, we developed a novel siRNA delivery vector based on our magnetic mesoporous silica nanoparticles (M-MSNs) platform. This nanocarrier was constructed by loading siRNAs into the mesopores of M-MSNs, followed by polyethylenimine (PEI) capping, PEGylation and fusogenic peptide KALA modification. The resultant functionalized delivery system exhibited prolonged half-life in bloodstream, enhanced cell membrane translocation and endosomal escapablity, and favorable tissue biocompatibility and biosafety. Systemic application of vascular endothelial growth factor (VEGF) siRNA via this nanocarrier resulted in remarkable tumor suppression, both in subdermal and orthotopic lung cancer models, while tumor metastasis was also significantly reduced, overall leading to improved survival. In addition, the magnetic core of the particles and the functionalized fluorescence markers conveniently enabled in vivo imaging of target tissues. Taken together, this M-MSNs-based siRNA delivery vehicle has shown very favorable applicability for cancer therapy.
Citation Format: Yijie Chen, Hongchen Gu, Weiliang Xia. Systemic delivery of therapeutic siRNA by multifunctional mesoporous silica-based nanocarrier inhibits lung cancer growth and metastasis. [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 718. doi:10.1158/1538-7445.AM2014-718
Abstract 719: Development of systemically-deliverable telomerase-specific oncolytic adenovirus
Authors: Aoyama Katsuyuki , Kuroda Shinji , Tazawa Hiroshi , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: May 2015

Abstract
Background: Oncolytic virotherapy is an emerging treatment strategy that allows to destroy cancer tissues only but not normal tissues. We previously developed a telomerase-specific oncolytic adenovirus (Telomelysin) whose replication is controlled by the human telomerase reverse tran¬scriptase (hTERT) promoter, and the clinical safety and pharmacokinetics of Telomelysin has been already evaluated in the phase I clinical trial conducted in the US. While oncolytic adenoviruses can produce promising treatment efficacy, their application is basically limited to locoregional administration because of nonspecific trapping in the liver and neutralization by immune response after systemic delivery. Nano-sized materials have been identified as effective and attractive drug carriers in the fields of cancer treatment and diagnosis. Liposome is one of the most popular and widely-used drug carriers. In this study, we investigated the possibility of systemic delivery of telomerase-specific oncolytic adenoviral plasmid DNA via lipid encapsulation as an alternative approach to overcome the shortcomings of oncolytic adenovirotherapy.
Methods: TelomeScan, a modified Telomelysin expressing the green fluorescence protein (GFP), is used in this study. Cytotoxic activity of TelomeScan plasmid DNAs encapsulated by liposomes (Lipo-TelomeScan-pDNA) against various types of human cancer cell lines including HCT 116, a human colorectal carcinoma cell line, and MKN1, a human gastric carcinoma cell line, were evaluated by XTT assay and compared with liposome complexes of GFP plasmid DNA controlled by the cytomegalovirus (CMV) promoter (Lipo-GFP-pDNA) as a control agent.
Results: Freeze-thaw procedure proved that viable oncolytic adenoviruses were successfully produced in H1299, a human lung cancer cell line, after Lipo-TelomeScan-pDNA transfection. Lipo-TelomeScan-pDNA showed cytotoxic activity on various types of cancer cell lines. Lipo-TelomeScan-pDNA killed HCT116 and MKN1 cells in a dose-dependent manner and produced more effective cytotoxic activity than Lipo-GFP-pDNA.
Conclusions: Lipo-TelomeScan-pDNA proved potent cytotoxic effects on cancer cells by producing viable oncolytic adenoviruses. In vivo examination is needed for the next step.
Citation Format: Katsuyuki Aoyama, Shinji Kuroda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara. Development of systemically-deliverable telomerase-specific oncolytic adenovirus. [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 719. doi:10.1158/1538-7445.AM2014-719
Abstract 74: Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice
Authors: Wu Yanyuan , Kim Juri , Elshimali Yayha , Vadgama Jaydutt V. 
Published: May 2015

Abstract
Introduction The data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. To explore oncogenic role of Akt1 in the development of mammary tumor, transgenic mice were created. Methods The transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used for inducing tumor formation. Results The MMTV driven myr-Akt1 transgene expression was detected primarily in mammary glands, uterus, and ovaries and the expression level increased significantly in lactating mice, suggesting the response was hormone dependent. The total expression level of Akt in the mammary gland was also high in these lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in ovary of transgenic mice caused significant increase in circulating estrogen levels, even at post-lactating stage. Expression of myr-Akt1 in mammary glands alone did not increase tumor formation frequency. However, an increased susceptibility to the induction of mammary tumors by DMBA was observed in transgenic mice, especially in post-lactating mice. DMBA induced 42.9% of mammary tumors in post-lactating transgenic mice within 34 weeks, but none in post-lactating wild-type mice. The myr-Akt1 driven mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and EGFR. Cyclin D1 was more frequently up-regulated in mammary tumors from transgenic mice compared to tumors from wild-type mice. Overexpression of Cyclin D1, however, was not completely dependent on activated Akt1. Interestingly, mammary tumors that had metastasized to secondary sites had increased expression of twist and slug, but showed low expression of Cyclin D1. Conclusions In summary, activation of Akt1 in mammary gland accelerated carcinogen-induced tumorigenesis, especially in post-lactating mice.
Citation Format: Yanyuan Wu, Juri Kim, Yayha Elshimali, Jaydutt V. Vadgama. Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice. [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 74. doi:10.1158/1538-7445.AM2014-74
Abstract 740: Phenotypic profiling and selectivity optimization of ERK inhibitors using a high-throughput imaged-based cell cycle assay
Authors: Chan Grace Ka-Yan , Kleinheinz Tracy , Martinson Matthew , Cheung Hok-Sum , Moffat John G. 
Published: May 2015

Abstract
The extracellular-signal-regulated kinases (ERK-1 and ERK-2) represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated due to oncogenic mutations in RAF or RAS or due to upstream oncogenic signaling, such as through receptor tyrosine kinase (RTK) signaling. We have discovered and developed potent and selective small molecule inhibitors of both ERK-1 and 2. Optimization of kinase selectivity was a critical goal in order for ATP-competitive ERK inhibitors to maintain parity with the safety profile of highly selective allosteric MEK inhibitors. As a complement to enzymatic kinase panel profiling, we employed an imaged-based cell cycle assay, based on the expected on-target phenotype of cytostatic G1 arrest in B-Raf-mutant cell lines. We were thus able to simultaneously measure on-target and off-target activities. Inhibition of Cdk2, one of the primary off-targets, was associated with a distinct G2 cell cycle arrest, which enabled us to quantify the functional selectivity margin between ERK and Cdk2 in a single assay, and select ERK inhibitors with acceptable selectivity margins for further development.
Note: This abstract was not presented at the meeting.
Citation Format: Grace Ka-Yan Chan, Tracy Kleinheinz, Matthew Martinson, Hok-Sum Cheung, John G. Moffat. Phenotypic profiling and selectivity optimization of ERK inhibitors using a high-throughput imaged-based cell cycle assay. [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 740. doi:10.1158/1538-7445.AM2014-740
Abstract 744: Effective use of MDK/Midkine and MEK inhibitor to treat KRas mutated pulmonary adenocarcinoma cells
Authors: Fukazawa Takuya , Maeda Yutaka , Ishida Naomasa , Yamatsuji Tomoki , Takaoka Munenori , Haisa Minoru , Takigawa Nagio , Whitsett Jeffery , Naomoto Yoshio 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. Although a platinum-doublet regimen has become the standard of care, the benefit is modest and the 5-year survival rate has remained essentially unchanged over the past 3 decades. Recently, several molecular alterations have been defined as “driver mutations,“ such as mutations in epidermal growth factor receptor (EGFR), KRas, chimeric tyrosine kinases involving ALK, RET, ROS1. And molecular targeting therapies for lung adenocarcinoma, targeting mutant EGFR or ALK, RET and ROS1 fusions, limit non-tumor toxicity and extend survival time compared to the conventional chemotherapies. However, there is no effective molecularly targeted therapy for mutant KRas-driven lung adenocarcinoma, the most frequent type of lung adenocarcinoma in the Caucasian population. Therefore, specific therapies that target various lung tumor types are desperately needed.
Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. We have previously reported that a MDK inhibitor: iMDK suppresses non-small cell lung cancer expressing MDK in vitro and in vivo without harming normal cells. Importantly, iMDK inhibits the PI3 kinase / Akt pathway and induces apoptosis in MDK expressing non-small cell lung cancer cells. In the present study, we have investigated the combination effect of iMDK and a mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD0325901. The combination treatment of iMDK and PD0325901 more effectively suppressed cell viability and colony formation, increased caspase-3 activity and induced apoptosis than those of single use in H441 and H2009 pulmonary adenocarcinoma cells harboring a G12 KRas mutation. Here, we describe the efficacy of the use of iMDK and PD0325901 for patients with inoperable advanced lung cancer including pulmonary adenocarcinoma harboring KRas mutations.
Citation Format: Takuya Fukazawa, Yutaka Maeda, Naomasa Ishida, Tomoki Yamatsuji, Munenori Takaoka, Minoru Haisa, Nagio Takigawa, Jeffery Whitsett, Yoshio Naomoto. Effective use of MDK/Midkine and MEK inhibitor to treat KRas mutated pulmonary adenocarcinoma cells. [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 744. doi:10.1158/1538-7445.AM2014-744