bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4390: Metronomic maintenance chemotherapy of orally active pemetrexed for effective treatment of lung cancer
Authors: Mahmud Foyez , Kweon Seho , Chang Hyo Won , Nam Hae Yoon , Kim Mi Ra , Park Jung Je , Kim Sang Yoon , Byun Youngro 
Published: August 2015

Abstract
At present, most of the anticancer drugs are given parenterally, showing drug concentration above the maximum tolerable concentration (MTC) followed by rapid elimination from the plasma that causes enhanced side effects and lower efficacy. In contrast, low dose oral maintenance therapy may increase therapeutic efficacy by increasing the exposure time to cancer cells and also reduce the side effects by maintaining the drug concentration below MTC level. Pemetrexed is a folate antagonist approved for maintenance chemotherapy in lung cancer. However, a major limitation of Pemetrexed is the poor oral bioavailability which imposes IV administration. In this context, we have developed a physical complex of Pemetrexed with lysine conjugated deoxycholic acid (DCK) in water (mole ratio 1:2) for the purpose of oral delivery. The DSC thermogram of Pemetrexed/DCK complex showed the complex formation due to disappearance of exothermic and endothermic peaks from Pemetrexed. The pharmacokinetic studies of Pemetrexed/DCK were done in SD rats and analyzed by HPLC method. In antitumor study, low dose continuous oral therapy from 2.5 mg/kg to 20 mg/kg showed substantial tumor inhibition in SCC7 tumor bearing C3H mice. We also evaluated maintenance chemotherapy as oral Pemetrexed/DCK administration in A549 tumor bearing nude mice. We found that 5 mg/kg dose of oral Pemetrexed successfully inhibited tumor progression and also showed additional antitumor effects when given with Cisplatin as maintenance chemotherapy. In the context of oral anticancer drugs, we need to consider the toxicities in GI tracts (GIT). For this purpose, apoptosis in GI tracts and morphology of different organs were assessed by TUNEL and H&E staining. One month toxicity studies have been conducted in nude mice and we found that 5 mg/kg oral dose did not produce any abnormalities in hematological and serological parameters in mice having intact morphology of GI tracts. Our studies offer safe and effective oral maintenance chemotherapy of pemetrexed for cancer patients at home.
Citation Format: Foyez Mahmud, Seho Kweon, Hyo Won Chang, Hae Yoon Nam, Mi Ra Kim, Jung Je Park, Sang Yoon Kim, Youngro Byun. Metronomic maintenance chemotherapy of orally active pemetrexed for effective treatment of lung 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 4390. doi:10.1158/1538-7445.AM2015-4390
Abstract 4391: Evaluation of tumor targeting activity by elastin like polypeptide containing cell penetrating peptide and IL-4 receptor targeting peptide
Authors: Lee Young-Jin , Sarangthem Vijaya , Kim Yun-Jae , Hur Kuen , Lee Byung-Heon , Park Rang Woon 
Published: August 2015

Abstract
The tumor specific internalization of therapeutics drug is been a great importance for cancer therapy. Targeted macromolecular carrier has been used as drug cargos since it improve the cellular uptake of cytotoxic drug in the tumor, while preventing cellular uptake by healthy tissues. Because of favorable pharmokinetic profile, elastin like polypeptide (ELPs) has been used as macromolecular drug carrier for cancer therapy. Fusion with cell-penetrating peptides (CPPs) such as TAT, assist easy penetration and internalization of macromolecular drug conjugates into wide variety of tumor types. For therapeutic peptide to be more penetrable and more effective towards specific tumor tissue, here we have designed a chimeric polypeptide cargo, TAT-AP1-ELP containing TAT, IL-4 receptor (IL4R) targeting peptide AP-1and thermal sensitive elastin-like polypeptides (ELPs). Then it was successfully expressed and purified from E coli using inverse temperature cycling method. Cellular uptake and intracellular localization of TAT-AP1-ELP was monitored through flow cytometry and confocal microscopy. Flow cytometry analysis data shown that both TAT-AP1-ELP and TAT-ELP showed various extends of penetration ability to different cancer cells but not to normal cells. Further a greater cellular uptake was observed in IL4R highly expressing cancer cells when treated with TAT-AP1-ELP compared to TAT-ELP at 37°C in dose-dependent manner. Confocal imaging verified the better cellular accumulation of TAT-AP1-ELP than TAT-ELP in IL4R highly expressing cancer cells. Importantly, the FNR 675-labeled TAT-AP1-ELP polymer showed better tumor accumulation in MDA-MB 231 xenograft mouse model. Thus in this study we demonstrate the improved activity of CPP, fused with targeting modalities in order to enhance intra tumor accumulation of therapeutic peptides.
Citation Format: Young-Jin Lee, Vijaya Sarangthem, Yun-Jae Kim, Kuen Hur, Byung-Heon Lee, Rang Woon Park. Evaluation of tumor targeting activity by elastin like polypeptide containing cell penetrating peptide and IL-4 receptor targeting peptide. [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 4391. doi:10.1158/1538-7445.AM2015-4391
Abstract 4396: Nanocarrier for monoclonal antibody delivery
Authors: Gdowski Andrew , Ranjan Amalendu , Mukerjee Anindita , Vishwanatha Jamboor 
Published: August 2015

Abstract
Antibodies represent a large class of drugs that have a number of different therapeutic uses. The use of monoclonal antibodies against potential intracellular protein-protein interactions in cancer cells has remained largely unexplored. This lack of consideration is due largely to a number of factors that include poor intracellular uptake and rapid lysosomal degradation of monoclonal antibodies within cells. Encapsulating monoclonal antibodies within biodegradable nanoparticles is one strategy that can improve antibody cellular uptake and protect from lysosomal degradation so that the antibody can be released inside the cell and remain functional against the therapeutic target.
Purpose: The purpose of this study is to characterize a human monoclonal antibody encapsulated within poly(lactic-co-glycolytic) acid (PLGA) nanoparticles. We hypothesized that encapsulation of an antibody within PLGA nanoparticles is feasible and will release in a favorable manner.
Method: Anti-AnnexinA2 (AnxA2) monoclonal antibody was encapsulated within PLGA nanoparticles utilizing a water/oil/water double emulsion solvent evaporation method. Nanoparticles and released antibodies were characterized through a number of different modalities.
Results: Our results show encapsulation efficiency ranging from 16-22% with a mean of 18.725% (SEM 1.289) depending on initial concentration of antibody used in the nanoparticle formulation. Nanoparticles were formed in a favorable mono disperse manner as evidenced through dynamic light scattering. All of the formulations created maintained a hydrodynamic size below 250nm. Release kinetics revealed that at day 12 the cumulative release of the antibody is approximately 35%. In addition after release the antibody maintained functionality as evidenced through Western Blot analysis and immunocytochemistry.
Conclusions: Encapsulation of a monoclonal antibody within polymeric PLGA nanoparticles is feasible, exhibits sustained release kinetics, and maintains functionality upon release. This encapsulation technique may be used as a method to load antibodies in targeted nanoparticles and release the antibodies inside cancer cells to interfere with aberrantly expressed proteins. Future experiments will focus on utilizing this monoclonal antibody encapsulation approach to screen intracellular protein-protein interactions as potential new therapeutic cancer targets.
Note: This abstract was not presented at the meeting.
Citation Format: Andrew Gdowski, Amalendu Ranjan, Anindita Mukerjee, Jamboor Vishwanatha. Nanocarrier for monoclonal antibody delivery. [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 4396. doi:10.1158/1538-7445.AM2015-4396
Abstract 4403: Antitumor properties of ouabain in lipid double emulsion integrated with tumor cell membrane fractions
Authors: Wu Jun , Mondala Mariele , Hsieh Meng-Yin , Roberts Eugene , Ermel Richard 
Published: August 2015

Abstract
Cell membrane proteins such as integrins are crucial for cell-cell recognition, binding and communication, cell-stromal interaction and adhesion, tumor invasion and metastasis. It was reported that cell-size hydrophobic beads coated with tumor membrane molecules could stimulate the lymphokine activated killer (LAK) cells to release IFN-alpha and TNF-alpha, and interrupted the recognition between LAK cells and tumor cells (Chong AS, 1988, 1991). Lipid double emulsion is a convenient formulation method to integrate lipid materials, hydrophilic and hydrophobic drugs in uniformed particles to achieve combinational chemotherapy. However the nonspecific uptake of double emulsion particles in vivo limits its targeting therapeutic potential. In current study, we sought to coat double emulsion particles with tumor cell membrane fraction to mimic the tumor cell surface in order to enhance the interaction and uptake of emulsion particles into tumor cells. Canine osteosarcoma cells and lymphoma cells were chosen for this study because canine cancers develop in immunocompetent environments and share many similar features observed in human cancers, such as long periods of latency for initiation, progression and development, metastasis, acquired drug resistance and recurrence. We use ouabain as therapeutic warhead in the emulsion particles because ouabain is known to have extremely high anticancer potential at nanomolar concentration level from our previous studies. The major obstacle of applying ouabain in vivo therapy is that the therapeutic dose window of ouabain is very narrow. Therefore in an attempt to mitigate such narrow therapeutic margin of safety, ouabain was formulated in lipid double emulsion by using microfluidic synthesis method and membrane emulsification method. The double emulsion particles were further coated with osteosarcoma cell membrane fraction. Our preliminary results showed enhanced antitumor activities of ouabain in tumor cell mimic-double emulsion or nanoemulsion against canine osteosarcoma cells and lymphoma cells in vitro and in orthotopic xenograft models in vivo, suggesting a promising therapeutic benefit in canine cancer targeting therapy.
Citation Format: Jun Wu, Mariele Mondala, Meng-Yin Hsieh, Eugene Roberts, Richard Ermel. Antitumor properties of ouabain in lipid double emulsion integrated with tumor cell membrane fractions. [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 4403. doi:10.1158/1538-7445.AM2015-4403
Abstract 442: Decreased tumor progression by the knockdown of interleukin 17 receoptor A in the B16F10 melanoma model
Authors: Chen Ya-Shan , Liu Chao-Lin , Chen Hui-Shan , Wu Su-Ting , Shen Chia-Rui 
Published: August 2015

Abstract
Introduction: Interleukin 17 (IL-17), correlating with advanced stage or poor prognosis of cancer patients, appears to contribute to tumor progression. Here we demonstrated the presence of IL-17 receptor A (IL-17RA) on the tumor cells directly promoting tumor growth, angiogenesis and metastasis.
Methods: B16F10 and its derived IL-17RA deficient melanoma cells were stimulated with recombinant IL-17 (γmIL-17) or subcutaneously implanted into C57BL/6 mice. Cell proliferation, cell invasion, tumor growth, metastasis and angiogensis were monitored and anti-tumor immunity was also assessed.
Results: As compared with those in the control B16F10 cells, the γmIL-17 inducing cell proliferation, migration and invasion were significantly reduced in the derived IL-17RA-deficient cells. The tumor growth and metastasis were also apparently reduced in the mice bearing the IL-17RA deficient tumors. In fact, not ony the expression of MMP2 and MMP9 but also the production of VEGF and HGF were reduced both in vitro and in vivo. Additionally, the increased levels of IFNγ+ and Granzyme B+ immune cells as well as the reduced numbers of Tregs and MDSCs appeared in the mice bearing the IL-17RA deficient tumors, indicating the lack of IL-17 enhancing the CTL activity and other anti-tumor immunity.
Conclusion: These findings support the hypothesis that IL-17/IL-17RA signaling directly promotes tumor growth as well as recruits MDSCs and Treg cells, resulting in tumor progression. It suggests IL-17RA on tumors as a potential therapeutic target for cancer therapy.
Citation Format: Ya-Shan Chen, Chao-Lin Liu, Hui-Shan Chen, Su-Ting Wu, Chia-Rui Shen. Decreased tumor progression by the knockdown of interleukin 17 receoptor A in the B16F10 melanoma model. [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 442. doi:10.1158/1538-7445.AM2015-442
Abstract 4428: Metformin effects on ABCB1 expression and proliferation in pancreatic cancer cell lines with different ABCB1 genotypes/haplotypes
Authors: Lyn-Cook Beverly D. , Osborne Taylor , Joseph Stancy , Word Beverly , Pang Li , Hammons George 
Published: August 2015

Abstract
Pancreatic cancer carries a poor prognosis and survival rate. Developing effective agents or repurposing agents with low toxicity, such as metformin, an insulin-lowering drug, has recently been investigated for pancreatic cancer. Metformin has long been associated with decreased cancer risk, particularly in diabetic patients. Although its major action is inhibiting hepatic glucose production, it also improves insulin sensitivity in peripheral tissues. This study demonstrates that metformin modulates the ATP-binding cassette gene, ABCB1, expression in pancreatic cancer cell lines with different ABCB1 genotypes. Metformin (100μM or 200μM) alone (p = 0.0212 or p = 0.0161) or in combination with gemcitabine (15nM) (p = 0.0248 or p = 0.0174) significantly decreased ABCB1 expression in Mia pancreatic cells after 24 hr and/or 72 hr treatments. This correlated to increased cell death. Metformin in combination with indole-3-carbinol also significantly (p = 0.0317) decreased ABCB1 expression. However, a sex or genotype difference was noted when two female pancreatic cell lines, SU86.86 and AsPC1, were used. Metformin did not down-regulate ABCB1 expression and was chemoresistance in these two cell lines. AsPC1 and SU86.86 both carry the 2677GG-3435CC ABCB1 haplotype compared to MiaPaca-2 which carries the 2677TT-3134TT ABCB1 haplotype. The 2677TT and 3435TT genotypes/haplotypes are known to be associated with lower risk of developing pancreatic cancer but these data demonstrate that these genotypes are also more sensitive to metformin treatment compared to the 2677GG or 3435CC genotypes. Further research is needed to ascertain whether sex or genotype is contributing to different efficacy of metformin in pancreatic cancer cells with different genotypes.
Citation Format: Beverly D. Lyn-Cook, Taylor Osborne, Stancy Joseph, Beverly Word, Li Pang, George Hammons. Metformin effects on ABCB1 expression and proliferation in pancreatic cancer cell lines with different ABCB1 genotypes/haplotypes. [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 4428. doi:10.1158/1538-7445.AM2015-4428
Abstract 4431: Musashi enhances GS3K-beta and promotes stemness-related chemoresistance in glioblastoma
Authors: Chen Hsiao-Yun , Chiou Shih-Hwa 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM), one of the deadly malignant brain tumor, and is easily to recur and develop resistance to clinical chemotherapeutics. It has been demonstrated that cisplatin treatment select for resistance but also for a more oncogenic phenotype characterized by high self-renewal and oncogenic resistance. Musashi (MSI), a neural stem cell marker, is found to be elevated in several cancer tissues and positively regulates cancer progression. In this report, we found that MSI promoted tumourigenicity and enhances drug resistance of human GBM cells in response to cisplatin, a chemodrug. We further showed that MSI could activate and interact with phosphorylated-GS3K-β, and lead to a protective effect against mitigating cisplatin-induced cell death. Knockdown of MSI effectively suppressed the phosphorylation of GS3K-β and blocked β-catenin translocating into nucleus in cisplatin-resistant GBM cells, while overexpressing MSI reversed these effects. Notably, MSI could further upregulate β-catenin-driven stemness signature, and expression of Oct-4, Nanog, and ABCG2, thereby enhanced tumorigenicity and chemoresistance of GBM cells. Moreover, the result of in vivo animal study demonstrated that knockdown MSI effectively suppressed stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in GBM-transplanted immunocompromised mice. Taken together, our findings indicated that MSI-1 may provide a positive contribution to oncogenic resistance, in partly, through interplaying with GS3K-β and modulating WNT/stemness mechanism.
Note: This abstract was not presented at the meeting.
Citation Format: Hsiao-Yun Chen, Shih-Hwa Chiou. Musashi enhances GS3K-beta and promotes stemness-related chemoresistance in glioblastoma. [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 4431. doi:10.1158/1538-7445.AM2015-4431
Abstract 4458: The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo
Authors: Kuebler Jens , Kirschner Stefanie , Hartmann Linda , Welzel Grit , Engelhardt Maren , Herskind Carsten , Veldwijk Marlon R. , Schultz Christian , Felix Manuela , Glatting Gerhard , Maier Patrick , Wenz Frederik , Brockmann Marc A. , Giordano Frank A. 
Published: August 2015

Abstract
Background: Patients with actively replicating human immunodeficiency virus (HIV) are highly radiosensitive and exhibit adverse reactions even at low irradiation doses. A major underlying cause is high intra- and extracellular levels of a virus-encoded peptide termed viral protein R (Vpr). As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined whether it may be utilized as a drug in the treatment of glioblastoma multiforme (GBM).
Methods: Four glioblastoma-derived cell lines with and without lentivirus-mediated Methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2-6 Gy) or to combinations. Caspase assays were employed to detect apoptosis. Colony formation assays were used to analyse clonogenic survival. Dose escalation was performed using n = 12 NOD/SCID/γc−/− (NSG) mice in a classical 3+3 manner. This strain was also used as an orthotopic implant model of glioma using luciferase-expressing U87 cells (n = 18). Continuous Vpr administration was achieved using osmotic pumps, irradiation (3×5 Gy) was performed using a small-animal irradiation device and intracerebral tumor growth was monitored using repetitive contrast-enhanced micro CT scans.
Results: Vpr showed high rates of acute toxicities with a LD50 of 4.0±1.1 μM for U251 and a LD50 of 15.7±7.5 μM for U87 cells. Caspase assays revealed Vpr-induced apoptosis in U251 but not in U87 cells. Vpr also efficiently inhibited clonogenic survival both in U251 and U87 cells and showed additive effects with irradiation. In contrast to TMZ, Vpr acted independently of the MGMT expression status. Dose escalation in mice (n = 12) was feasible and resulted in no evident renal or liver toxicity. Similar to irradiation with 3 × 5 Gy (n = 8), Vpr treatment of orthotopically implanted NSG mice (n = 5) delayed tumor growth and significantly (p = 0.041; log-rank test) prolonged overall survival compared to untreated animals (n = 5).
Conclusion: The HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM.
Citation Format: Jens Kuebler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R. Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A. Brockmann, Frank A. Giordano. The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo. [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 4458. doi:10.1158/1538-7445.AM2015-4458
Abstract 446: Reciprocal paracrine signaling between epithelial and stromal cells alters the pancreatic tumor microenvironment
Authors: Stout Matthew C. , Cole Danielle R. , Campbell Paul M. 
Published: August 2015

Abstract
Despite considerable clinical and basic research efforts, the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) remains a dismal 6 percent in the United States. Much of the mortality of the disease is a result, in part, of the unique microenvironment of PDAC tumors. The stroma, a heterogeneous population including fibroblasts, immune cells, vasculature and extracellular matrix, comprises the bulk of the PDAC tumor volume. We and others hypothesize that disparate cell populations within this tumor microenvironment are receptive to paracrine signaling from one another to drive tumor survival and metastatic progression. Previous work has shown that the ELR+ CXC-chemokines and their CXCR2 receptor are upregulated in PDAC and can promote tumor-associated phenotypes such as angiogenesis. Our current research seeks to demonstrate that the ubiquitous PDAC oncogene, K-Ras, affects additional elements of the tumor microenvironment through paracrine CXCR2 chemokine signaling. In particular, we are interested on the interdependence of proliferation, migration, senescence, survival and death between fibroblasts and pancreatic epithelial cells. We show that activated epithelial K-Ras increases CXCL release and CXCR2 expression, but remarkably, paracrine signals from PDAC cells decrease the number of fibroblasts. These data suggest potentially both pro and antitumor effects of paracrine signaling in pancreatic cancer. Experiments are ongoing to further investigate how CXC chemokines modulate the tumor microenvironment in order to reveal novel therapeutic targets and diagnostic biomarkers.
Citation Format: Matthew C. Stout, Danielle R. Cole, Paul M. Campbell. Reciprocal paracrine signaling between epithelial and stromal cells alters the pancreatic tumor microenvironment. [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 446. doi:10.1158/1538-7445.AM2015-446