bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 581: Development of RNA interference-based therapeutics for bladder cancer and hepatocellular carcinoma
Authors: Fosnaugh Kathy L. , Seth Shaguna , Matsui Yoshiyuki , Adami Roger , Vaish Narendra , Chen Yan , Liu Yan , Harvie Pierrot , Johns Rachel , Severson Gregory , Bell Susan , Granger Brian , Zhu Tianying , Charmley Pat , So Alan , Templin Michael V. , Polisky Barry 
Published: February 2011

Abstract
Bladder cancer and hepatocellular carcinoma are two of many cancers refractory to current treatments. Small interfering RNAs (siRNAs) are a new therapeutic modality able to specifically silence expression of targets not accessible via current small molecule and antibody options. MDRNA is developing UsiRNAs, a novel siRNA construct containing unlocked nucleobase analogs, with improved specificity for RNA interference (RNAi). Delivery of UsiRNAs to target tissues is achieved using proprietary Di-alkylated Amino Acid (DiLA2)-based liposomes. Survivin, overexpressed in many cancers, is involved in cell division and inhibition of apoptosis. In orthotopic and xenograft models of liver cancer, systemic administration of survivin UsiRNA-DiLA2 liposomes resulted in approximately 60% and 70% reductions in survivin mRNA, respectively, and &gt; 50% decreases in tumor weight. Local intravesical administration in an orthotopic bladder cancer model resulted in 90% inhibition of mRNA expression and substantial tumor growth inhibition. Polo-like kinase 1 (PLK-1), also elevated in many tumors, regulates cell cycle progression and mitosis. Treatment of bladder cancer and liver cancer cell lines with PLK-1 UsiRNA/DiLA2 liposomes leads to significant caspase activation and corresponding apoptotic cell death. In vivo studies with PLK-1 UsiRNA are in progress. These UsiRNAs and UsiRNAs directed against additional targets are being evaluated in vitro and in orthotopic and xenograft models of cancer as single agents, in combinations of target-specific UsiRNAs, and with existing small molecule and antibody therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 581.
Abstract 583: Treatment of human liver cancer in nude mice with a tumor-targeting Salmonella typhimurium auxotroph
Authors: Zhang Yong , Zhao Ming , Liu Fang , Hoffman Robert M. 
Published: February 2011

Abstract
We have previously developed a tumor-targeting Salmonella typhimurium double-amino acid auxotrophic strain termed A1-R (Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007). In the present study, we evaluated the efficacy of A1-R against a nude mouse model of human liver cancer. GFP-expressing A1-R bacteria targeted, colonized, and replicated in the human liver tumor growing s.c. in transgenic nude mice expressing RFP as observed by fluorescence imaging on day 3 after i.v. injection of A1-R. Subsequently, the bacteria grew throughout most of the tumor by day 10 after i.v. injection. Bacterial growth within the tumor was observed by fluorescence imaging of the infected tumor tissue in transverse sections. For efficacy experiments, bacteria (5 × 107 CFU/100 μl) were inoculated i.v. in HepG2-bearing nude mice. Tumor growth was monitored by caliper measurement in two dimensions. Treatment with A1-R resulted in tumor shrinkage. The difference in tumor volume between the treated and control group was statistically significant. There were no obvious toxic effects on the host even with 5 × 107 A1-R injected i.v. The mice tolerated A1-R treatment and could survive as long as untreated mice. A1-R only replicated and persisted within the microenvironment of the tumor and not outside the tumor site. The results suggest the potential of bacterial therapy of liver cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 583.
Abstract 584: Identification of mutations in HSV-1 envelope glycoprotein B that enhance retargeted infection
Authors: Uchida Hiroaki , Chan Janet , Goins William F. , Grandi Paola , Kumagai Izumi , Cohen Justus B. , Glorioso Joseph C. 
Published: February 2011

Abstract
Conditionally-replicating herpes simplex virus type 1 (HSV-1) vectors, including mutants deleted for the neurovirulence factor ICP34.5 currently in clinical trials, are promising agents for oncolytic virotherapy. As an alternative strategy to accomplish cytocidal HSV replication exclusively in cancer cells, we have designed modified viral envelope glycoproteins to limit virus entry uniquely to EGF receptor (EGFR)-bearing cells. HSV-1 entry is initiated by the interaction of glycoprotein D (gD) with one of its receptors, herpesvirus entry mediator (HVEM) or nectin-1. Receptor binding results in a conformational change in gD triggering activation of gB and gH as the effectors of fusion between the viral envelope and cell membranes. To target virus entry solely to EGFR-expressing cells, we mutated or deleted gD residues essential for binding to the natural entry receptors and inserted an EGFR-specific single-chain antibody (scFv). Although ablation of virus entry through HVEM and nectin-1 was successful, entry through the EGFR was detectable but inefficient. To address this flaw, we carried out in vitro evolution experiments to isolate gain-of-function mutations that could compensate for defective gD-receptor interactions. We passaged a nectin-1-binding impaired HSV-1 mutant repeatedly through cells expressing a gD-binding impaired nectin-1 until visible plaques appeared. Plaque purification and sequence analysis revealed that each isolate contained the same double mutation in gB. We transferred the gB double mutation into wild-type virus and observed entry into cells that are normally resistant to HSV infection due to the absence of authentic gD receptors. In addition, we found that the mutant-gB virus was capable of entering cells through nectins other than nectin-1, and that entry into nectin-1-bearing cells was markedly accelerated compared to wild-type virus. We combined the gB double mutation with the EGFR-retargeted gD allele and found that this combination yielded increased entry into target cells without raising off-target infection. We are currently expanding this strategy to target other cancer-specific cell-surface markers. By enhancing the efficiency of retargeted infection, the gB double mutation is likely to reduce the need for strong mutations in current oncolytic vectors that not only prevent virus replication in normal cells, but also diminish replication in tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 584.
Abstract 59: Impact of omega-3 fatty acids on obesity-induced DNA oxidation and prostate cancer progression
Authors: Cavazos David A. , deGraffenried Linda A. 
Published: February 2011

Abstract
Obesity is associated with poor prognosis and contributes significantly to prostate cancer-related mortality. As the prevalence of obesity increases among young adult males, the contribution to prostate cancer progression and mortality are expected to rise dramatically. One potential mechanism by which obesity may promote worse outcome is through the induction of functional metabolic abnormalities known to promote inflammation and oxidative stress. Pre-clinical and clinical observations indicate that a BMI &gt;30 promotes oxidative DNA damage and is associated with shorter time to PSA failure and prostate cancer mortality. Growing evidence supports a beneficial role of omega-3 (ω-3) fatty acids in delaying time to PSA failure and reducing the aggressiveness of advanced prostate cancer, however, the mechanisms are multivariate and relatively unresolved. As oxidative burden is strongly implicated in the pathogenesis of age-related diseases, including prostate cancer tumor formation, and as omega-3 fatty acids possess known antioxidant and anti-inflammatory properties, we investigated the effects of docosahexaenoic acid (DHA-22:6n-3), one component of fish oil, in reducing the effects of obesity-induced oxidative DNA damage. Preliminary data demonstrates that prostate cancer cells (LNCaP) pretreated with ω-3 fatty acids and pulsed with physiologic levels of H2O2 were preferentially sensitive to induction of growth arrest compared to normal prostate epithelial cells (PrEC). LNCaP cells pulsed with 32 uM H2O2 exhibit DNA breaks associated with translocation of NF-κB into the nucleus, whereas pretreatment with DHA prior to H2O2 treatment prevented NF-κB translocation, selectively sensitizing LNCaP cells, but not PrEC, to cell death. Further, DHA attenuated H2O2-induced NF-κB transcriptional activity and diminished expression of the downstream target, survivin. NF-κB is heavily implicated in promoting prosurvival signaling and may be critical for resistance to the chronic oxidative stress and inflammation observed in the pathogenesis of prostate cancer. Here we describe one potential mechanism by which obesity may contribute to prostate cancer and the role of ω-3 fatty acids in mitigating these affects, ultimately setting the stage for Phase III clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 59.
Abstract 590: Preclinical biosafety test of oncolytic adenovirus-infected carrier cell for Phase I study
Authors: Hamada Katsuyuki 
Published: February 2011

Abstract
Although almost 1000 clinical trials of gene therapy have been tried in USA, any significant clinical effects have not yet been reported. This is due to the anti-viral neutralizing antibodies production after the induction of viral mediated gene delivery for clinical trials. To address this limitation, we developed a carrier cell system to deliver a replication-competent adenovirus. Carrier cells infected with oncolytic adenovirus were incubated with target ovarian cancer cells in high titer of antiadenovirus antibody. Carrier cells were injected into syngeneic subcutaneous ovarian tumors after immunization with adenovirus. Carrier cell-derived cell fragments containing viral particles were engulfed by proliferative target ovarian cancer cells. This engulfment-mediated transfer of adenovirus was not inhibited by antiadenovirus antibody and enabled repetitive infection. After the induction of antiadenoviral CTL responses by immunization of adenovirus, administration of carrier cells infected with a replication-competent adenovirus induced complete tumor regression. Short term toxicity and distribution test were carried out to inject carrier cells into ovarian tumor in nude mice at once and long term toxicity test was carried out to inject carrier cells into rabbits at 8 times for 4 weeks. Short term toxicity test did not show any lethal side effects in nude mice. In distribution test, single injection of carrier cells into ovarian tumor induced the peak levels of cells and oncolytic virus in tumors on the next day but did not show any significant levels of cells and oncolytic virus in tumors 14 days after injection. In long term toxicity test, 8 injections of carrier cells (1.25 × 107 cells/kg) did not show any significant toxicity in rabbits
This novel adenoviral receptor independent carrier cell-mediated viral transfection system might prove safe in this preclinical biosafety test and useful to treat solid tumors. Phase I clinical trial of this carrier cells infected with oncolytic adenovirus will be started soon to treat recurrent solid tumors which is resistant to the common treatment of surgery, radiation and chemotherapy.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 590.
Abstract 592: Downregulation of uPAR and uPA retards angiogenesis and proliferation and activates the extrinsic apoptotic pathway in pancreatic cancer cells
Authors: Gorantla Bharathi , Rao Jasti S. , Patel Jitendra , Gondi Christopher S. 
Published: February 2011

Abstract
Pancreatic cancer is one of the major causes of mortality in the United States. Despite well established chemotherapy and surgical resection strategies, the five-year mean survival rate is less than five percent. The activation of the uPAR/uPA system is an early event in the development of pancreatic ductal adenocarcinoma (PDAC), and uPAR gene amplification identifies a subgroup of particularly aggressive tumors. In the present study, we used two pancreatic cancer cell lines [MIA PaCa-2 (CRL1420) and PANC-1 (CRL1469)] to demonstrate the effect of uPA and uPAR downregulation. From the results, we observed that RNAi-expressing plasmids efficiently downregulated the expression of uPAR and uPA both at the mRNA and protein levels. In vitro and in vivo angiogenic assays revealed a significant decrease in angiogenic potential of CRL1420 (in vitro 26±3% and in vivo 13±2%) and CRL1469 (in vitro 23±1% and in vivo 10±2%) cells that were downregulated for both uPA and uPAR. From the antibody array analysis, we observed that the simultaneous downregulation of uPAR and uPA subsequently caused the downregulation of angiogenin and the overexpression of RANTES. The MTT proliferation assay results demonstrated that the downregulation of uPAR alone caused a decrease in proliferation (CRL1420: 24±3%; CRL1469: 38±2%) and downregulation of uPA alone caused a lesser decrease in proliferation (CRL1420: 19±2%; CRL1469: 26±1%) whereas the simultaneous downregulation of both uPA and uPAR caused the most significant decrease in proliferation in both cell lines (CRL1420: 84±4%; CRL1469: 93±3%). Further, FACS analysis demonstrated that the simultaneous downregulation of uPAR and uPA caused the accumulation of cells in the sub-G0/1 phase in both CRL1420 and CRL1469 cells. In addition, western blot analysis revealed that downregulation of uPA and uPAR caused the activation of caspase 8 and induced the cleavage of PARP, which is indicative of apoptosis; these results were confirmed by TUNEL assay. In conclusion, our results clearly demonstrate that the targeting of the uPAR-uPA system has potential clinical relevance for the treatment of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 592.
Abstract 593: Abusing oncogenic RAS to selectively target colorectal and pancreatic cancer cells
Authors: Naumov Inna , Lisiansky Victoria , Kazanov Dina , Shapira Shiran , Kraus Sarah , Arber Nadir 
Published: February 2011

Abstract
Background: RAS mutations are present in 40-60% of human colorectal (CRC) and 75-95% of pancreatic (PC) tumors leading to the activation of downstream target genes. The pro-apoptotic PUMA protein interacts with Bcl-XL and Bcl-2 to induce the release of mitochondrial cytochrome C and apoptosis.
Aim: To selectively kill RAS transformed cells by overexpressing the PUMA gene under the control of a RAS-responsive promoter.
Materials and methods: Four CRC and three PC cell lines were used. Six of them harboring KRAS mutations; SW480, HCT116, DLD1, Colo357, Panc1 and MiaPaca, whereas HT29 cells, harboring wt KRAS, served as control. In addition, normal rat enterocytes, IEC18 and RIE and their KRAS (R1), HRAS (RIE-RAS) transformed counterparts, were tested. We constructed two adenoviral vectors with the wt PUMA sequence, one containing RAS-responsive elements as an upstream promoter (PY4-PUMA) and a second lacking these elements which served as control (SV40-PUMA). Prior to the infections, RAS activity was determined by pull-down assay using GST-RBD. Inhibition of proliferation was determined on a Coulter counter; cell viability by MTT assay, apoptosis by FACS and protein expression by Western blotting. The effect of the adenoviruses was evaluated in vivo following injection of 106 cells into two flanks of nude mice (n=30).
Results: As expected, SW480, HCT116, DLD1, Colo357, Panc1, R1 and RIE-RAS showed increased RAS activity compared to HT29, IEC18 and RIE cells which had no activity. Infection with PY4-PUMA induced a marked inhibition of cell growth, up to 40-50% and spontaneous apoptosis, in all cells exhibiting high levels of RAS activity whereas HT29, IEC18 and RIE were unaffected by PY4-PUMA. The SV40-PUMA had no effect. Selective and high expression of PUMA was detected in PY4-PUMA affected cells.
In xenograft models of CRC in nude mice, PY4-PUMA injected i.p twice during a period of 4 weeks, suppressed de novo tumor formation and inhibited by ∼35% the growth of established tumors compared to the control virus.
Conclusions: Selective expression of PUMA in RAS transformed cells can induce cancer cell death. The minimal quantity of only two adenoviral injections in our in vivo model showed no toxicity and holds promise for its future application in humans that, unlike immunodeficient mice, are immunocompetent. Gene therapy may become a useful, effective and safe approach to target RAS mutated tumors while sparing the normal surrounding tissue. It might be applicable not only to GI tumors but to other tumors harboring KRAS or HRAS mutations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 593.
Abstract 596: Oncolytic vesicular stomatitis virus selectively kills bladder cancer cells which have a low level of type I interferon receptor
Authors: Zhang Kevin , Matsui Yoshiyuki , Hadaschik Boris A. , Lee Cleo , Jia William , Bell John C. , Fazli Ladan , So Alan I. , Rennie Paul S. 
Published: February 2011

Abstract
Bladder cancer is the second most common genitourinary malignancy. Current treatments options are of limited efficacy since approximately 80% of patients will develop recurrent tumors of which 20-30% evolve into more aggressive, potentially lethal cancers. A new strategy to treat bladder cancer is the intra-vesical application of vesicular stomatitis virus (VSV), which is a replication competent oncolytic virus that relies on an aberrant interferon signaling pathway within cancer cells.
Using a tissue microarray composed of human bladder cancer cores and by immunohistochemistry, we observed that expression of type I interferon (IFN) receptor (IFNAR) was decreased relative to normal bladder tissue. Advanced bladder cancers had even lower expression of IFNAR. We observed that VSV preferentially targeted high grade bladder cancer cells which were resistant to type I IFN treatment. We also found that these high grade bladder cancer cells susceptible to VSV-induced lysis had low expression of IFNAR. Furthermore, siRNA knockdown of IFNAR indeed facilitated replication of VSV in cells previously resistant to VSV treatment. Consequently, intra-vesicular instillation of wildtype VSV and the Delta51M strain, which has an impaired ability to shutdown innate immunity, significantly inhibited high grade tumor growth by 98% and 90% respectively as compared to controls treated with UV-inactivated VSV. No evidence of toxicity or systemic viral infection in either group was found.
In conclusion, down-regulation of IFNAR in bladder cancer may be one of the primary molecular mechanisms for clinical IFN resistance. However, this also facilitates VSV replication and oncolysis in high risk bladder cancers and provides a basis for selecting bladder cancer patients for IFN or oncolytic VSV therapy in future clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 596.
Abstract 597: Bacteria targeting and tumor vascular destruction by S. typhimurium A1-R depend on the vascularity of the tumor site
Authors: Liu Fang , Zhao Ming , Zhang Lei , Hoffman Robert M. 
Published: February 2011

Abstract
Our laboratory has previously developed a tumor-targeting double-auxotrophic mutant of S. typhimurium termed A1-1 (Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007). The A1-R mutant has high tumor virulence but requires leucine and argentine which disables the bacteria from growing in normal tissue. Our previous studies suggested that the rich vascularity of tumors may contribute to bacterial tumor targeting by A1-R. The goal of the present study was to determine the effect of A1-R on the tumors growing at different sites with different vascularity. In this study, we administered A1-R to Lewis lung carcinoma-bearing mice with tumor growing at three different sites. We observed that tumor location influences the efficacy of targeting of A1-R to the Lewis lung tumor. RFP-expressing Lewis lung cancer cells (1×107 cells/ml) were transplanted subcutaneously in the ear (50 µl), back skin (100 µl), and foot pad (25 µl) of nestin-GFP transgenic nude mice, which selectively express GFP in nascent blood vessels. The tumor-bearing mice were then treated with A1-R bacteria (5×107) via tail-vein injection. Bacteria tumor targeting and vascular damage were evaluated by fluorescence imaging with the Olympus IV100 and OV100 small-animal imaging systems designed for fluorescence imaging. Tumors in the ear had the fastest growth rate and were the most sensitive to bacteria targeting and hemorrhaged severely the day after A1-R injection. Tumors growing in the back were the second most sensitive to bacteria targeting and appeared necrotic 3 days after A1-R injection. Tumors growing in the food pad were the least sensitive to A1-R. Tumor vascularity correlated positively with A1-R targeting with the ear being the most vascular site and the foot pad the least vascular site. The present study suggests that bacteria tumor targeting and hemorrhage of the tumor depend on the vascularity of the tumor site.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 597.