bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5617: A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin.
Authors: Curnis Flavio , Sacchi Angelina , Longhi Renato , Colombo Barbara , Gasparri Anna , Corti Angelo 
Published: August 2014

Abstract
Albumin is emerging as a versatile drug carrier in a number of applications in cancer therapy and diagnosis. Basically, albumin can be exploited to enhance the tumor uptake of peptides and low molecular-weight compounds, owing its tendency to accumulate in tumors, and for the preparation of nanoparticles that encapsulate anti-cancer drugs or diagnostic agents.
We have addressed the hypothesis that coupling albumin with a peptide containing the isoAsp-Gly-Arg (isoDGR) sequence, a tumor-vasculature targeting motif discovered by our group, might enhance its tumor-homing properties. IsoDGR is a mimetic of Arg-Gly-Asp (RGD), an integrin-recognition motif. Accordingly, isoDGR can recognize RGD-dependent integrins with different affinity and selectivity depending on isoDGR conformation and molecular scaffold. To have at hand isoDGR peptides that can be easily coupled to albumin we designed various head-to-tail-cyclized exapeptides containing free thiol groups, to enable chemical coupling to proteins, and analyzed their integrin binding properties before and after coupling to albumin. We have identified a peptide (c(CGisoDGRG)) that, after coupling to human serum albumin, has a very good selectivity for alphaV/beta3 and alphaV/beta5, two integrins overexpressed in the tumor vasculature. In vitro and in vivo studies showed that isoDGR-tagged albumin binds to endothelial cells, inhibits their adhesion properties, homes in on tumor vessels and inhibits tumor growth, with no evidence of toxicity. IsoDGR-tagged albumin was exploited as a carrier for the preparation of a new nano-gold systems capable of delivering tumor necrosis factor α (TNF), a well known vascular damaging agent, to tumor vessels. In vivo studies, performed with mice bearing WEHI-fibrosarcomas, showed that intravenous administration of gold nanoparticles loaded with isoDGR-tagged albumin and TNF (equivalent 5 pg of bioactive TNF/mouse) could induce stronger anti-tumor effects than nanoparticles loaded with albumin and TNF. These findings support the concept that isoDGR-tagged albumin is superior to albumin as a vector system for targeted delivery of nanomedicines to tumor vessels. Because of its good selectivity for tumor vessels and its inherent anticancer activity isoDGR-tagged albumin might be exploited as a novel and versatile material for the preparation of a wide range of tumor vasculature-selective drugs and nanoparticles for cancer therapy and diagnosis.
Citation Format: Flavio Curnis, Angelina Sacchi, Renato Longhi, Barbara Colombo, Anna Gasparri, Angelo Corti. A new alphaV/beta3 integrin selective carrier for nanodrug delivery to tumors based on isoDGR-tagged albumin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5617. doi:10.1158/1538-7445.AM2013-5617
Abstract 5619: Preclinical development of anti-SLC34A2 antibody drug conjugate as a therapeutic for non-small cell lung and ovarian cancers.
Authors: Lin Kedan , Zhang Crystal , Harstad Eric , Hiraragi Hajime , Solis Willy , Tsai Siao Ping , Xu Keyang , Hristopoulos Maria , Venook Rayna , Rubinfeld Bonnee , Polakis Paul 
Published: August 2014

Abstract
SLC34A2, also known as type II Na/Pi co-transporters NaPi2b or NaPi3b, is a member of solute carrier protein family SLC34. SLC34A2 is highly expressed on cancers of the lung, ovary and thyroid as well as on normal lung pneumocytes, and is a promising target for antigen-directed therapy. Antibody drug conjugates (ADCs) specify the delivery of a cytotoxic drug to cells expressing an accessible antigenic target. Here we have appended monomethyl auristatin E (MMAE) to an antibody recognizing SLC34A2. Anti-SLC34A2-vc-MMAE inhibits tumor growth in multiple ovarian and non-small cell lung cancer xenograft models that express SLC34A2. Anti-SLC34A2 antibody and its conjugate cross-react with both human and monkey, and toxicity studies in monkeys are conducted to identify both target- and MMAE-related effects. Anti-SLC34A2-vc-MMAE was well tolerated in monkeys at efficacious doses and produced dose-related bone marrow suppression and increased apoptosis and mitotic figures consistent with MMAE-related pharmacology. Despite high levels of expression in normal lung of non-human primate, the cross-reactive ADC exhibited an acceptable safety profile with a dose-limiting toxicity unrelated to normal tissue expression. Overall, our preclinical results suggest that the antibody drug conjugate targeting the SLC34A2 may provide an effective new therapy for the treatment of NSCLC and ovarian cancer.
Citation Format: Kedan Lin, Crystal Zhang, Eric Harstad, Hajime Hiraragi, Willy Solis, Siao Ping Tsai, Keyang Xu, Maria Hristopoulos, Rayna Venook, Bonnee Rubinfeld, Paul Polakis. Preclinical development of anti-SLC34A2 antibody drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5619. doi:10.1158/1538-7445.AM2013-5619
Abstract 5626: EBP50: Novel biomarker for resistance to endocrine and HER-2 targeted therapies in breast cancer. .
Authors: Gu Guowei , Corona-Rodriguez Arnoldo , Covington Kyle , Fernandez Natalie , Zhou Jianling , Cai Weiyan , Ando’ Sebastiano , Fuqua Suzanne A.W. 
Published: August 2014

Abstract
Backgroud: Na+/H+ Exchanger Regulatory Factor (NHERF1) also named ERM Binding Protein 50 (EBP50) functions as a molecular scaffold to coordinate ion transport and second messenger signal transduciton. Recently, a number of studies suggest a role for EBP50 expression in cancer progression.
Methods: Microarray profiling. Stable transfection. Soft agar and MTT growth assays. Immunoblot and immunoprecipitation assays. Confocal microscopy. Duolink in situ.
Results: The mean levels of EBP50 were reduced in tamoxifen (Tam)-resistant, metastatic breast tumors compared to Tam-sensitive tumors. Knockdown of EBP50 decreased Tam sensitivity in MCF-7 and ZR-75B cells. EBP50 knockdown cells showed higher levels of phosphorylated HER2 and EGFR, as well as their downstream signalling pathways. PI3K/AKT inhibitors were able to restore Tam sensitivity in knockdown cells. Similarly, knockdown EBP50 in ERα/HER2 positive BT-474 cells increased constitutive pHER2 and these cells were resistant not only to Tam, but also to Trastuzumab (Tras) treatment. An EGFR inhibitor or Lapatinib were able to restore Tras sensitivity. Overexpression of EBP50 restored Tam sensitivity in BT-474 cells. We demonstrate that EBP50 is capable of binding to HER2 and ERα using immunoprecipitation and PLA assay, suggesting that EBP50 interacts directly with both. Overexpression of EBP50 decreased pHER2 and pEGFR levels suggesting that EBP50 can downregulate its activity. EBP50 overexpression upregulated ERα transcriptional activity. ERα transcriptional activity in cells overexpressing EBP50 was costitutively higher and more sensitive to Tam. We previously published that Dicer overexpression and loss of RhoGDIα were associated with Tam resistance. Interestingly, EBP50 knockdown was associated with higher Dicer and lower RhoGDIα levels suggesting that Tam resistance is associated with inter-related mechanisms. We performed microarray analysis and identified kinase signiture in EBP50 knockdown cells. This kinase signature predicts Tam resistance. Our data suggest that EBP50 is a novel negative regulator of HER2 signaling, and its loss confers resistance to both Tam and Tras. We hypothesize that EBP50 levels might be a new predictive biomarker for targeted therapy.
Citation Format: Guowei Gu, Arnoldo Corona-Rodriguez, Kyle Covington, Natalie Fernandez, Jianling Zhou, Weiyan Cai, Sebastiano Ando’, Suzanne A.W. Fuqua. EBP50: Novel biomarker for resistance to endocrine and HER-2 targeted therapies in breast cancer. . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5626. doi:10.1158/1538-7445.AM2013-5626
Abstract 5635: Development of a high-throughput cell and fluorescent image-based ABCB1-mediated efflux assay for screening inhibitors of ABCB1.
Authors: Ansbro Megan R. , Shukla Suneet , Ambudkar Suresh V. , Yuspa Stuart H. , Li Luowei 
Published: August 2014

Abstract
ABCB1, also known as P-glycoprotein (P-gp) or multidrug resistance protein 1 (MDR1), is a membrane-associated multidrug transporter of the ATP-binding cassette (ABC) transporter family. It is one of the most widely studied transporters that enable cancer cells to develop drug resistance. Reliable high-throughput assays that can identify compounds that interact with ABCB1 are crucial for developing new therapeutic drugs. A high-throughput assay for measuring ABCB1-mediated calcein AM efflux was developed using the IncuCyteFLR technology. Time- and dose-dependent accumulation of fluorescent calcein in ABCB1-overexpressing KB-V1 cells was recorded using the IncuCyteFLR. Validation of the assay was performed with known ABCB1 inhibitors, XR9576, verapamil, and cyclosporin A, all of which displayed dose-dependent inhibition of ABCB1-mediated calcein AM efflux in this assay. A kinase inhibitor library and other compounds with known therapeutic targets were screened. The assay is highly reproducible and inhibitors for ABCB1-mediated efflux were identified from the kinase inhibitor library. Among compounds with known targets, BEZ235, BI 2536, IKK 16, and Ispinesib (SB-715992) inhibited calcein AM efflux in a dose-dependent manner and were also active in the flow cytometry based efflux assay. BEZ235, BI 2536, and IKK 16 also successfully competed with radiolabeled photoaffinity substrate [125I]iodoarylazidoprazosin (IAAP) for binding to ABCB1. Inhibition of ABCB1 lowered the IC50 value of BI 2536 treated ABCB1-overexpressing cancer cells. Phase and fluorescent images taken by the IncuCyteFLR provided additional opportunities for evaluating compounds that are cytotoxic or produce false positive signals. This high-throughput assay provides an efficient, reliable, and simple technique for screening libraries of natural and synthetic compounds to identify ABCB1 inhibitors. The same approach may be applied to screen inhibitors of other ABC transporters when suitable cell lines and fluorescent substrates are used.
Citation Format: Megan R. Ansbro, Suneet Shukla, Suresh V. Ambudkar, Stuart H. Yuspa, Luowei Li. Development of a high-throughput cell and fluorescent image-based ABCB1-mediated efflux assay for screening inhibitors of ABCB1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5635. doi:10.1158/1538-7445.AM2013-5635
Abstract 5636: Different characteristics of drug resistance in AML cell lines between a dual Flt3/CDK4 kinase inhibitor AMG 925 and Flt3 inhibitors.
Authors: Li Cong , Liang Lingming , Beaupre Darrin , Newhall Katie , Li Zhihong , Wang Queenie , Xia Zhen , Liu Qiang , McGee Larry , Wickramasinghe Dineli , Dai Kang 
Published: August 2014

Abstract
Objectives: Flt3 inhibitors have shown clinical responses in Flt3 mutant acute myeloid leukemia (AML) but resistance develops rapidly. In order to improve the durability of clinical response of AMLFlt3 MUT, a small molecule inhibitor of Flt3 and CDK4/6 kinases, AMG 925, was developed. The primary purpose of this study is to compare the ability of AML cell lines to become resistant to AMG 925 and to other Flt3 inhibitors, and to elucidate the underlying molecular mechanisms.
Methods: Drug resistant MOLM13 and Mv4-11 cell clones were isolated by prolonged exposure to increasing concentrations of AMG 925 and other Flt3 inhibitors. Cell proliferation was determined by CellTiter Glo. Protein expression levels were assessed by Western Blotting, IP Western Blotting and MSD assays. Flt3 mRNA levels were measured by RT-PCR.
Results and Conclusions: Both MOLM13 and Mv4-11 cells developed resistance to all the inhibitors tested within 3-4 months. In contrast to AML cells resistant to other Flt3 inhibitors (IC50 increased by about 1000 fold), cells resistant to AMG 925 were only at much lower drug concentrations (IC50 increased by 3-5 fold). Mutations in the Flt3 kinase domains were found in cells resistant to the other Flt3 inhibitors but not in those resistant to AMG 925. P-Flt3 and P-STAT5 in AMG 925 resistant cells were less inhibited than in the sensitive parental cells, apparently as a result of an increased total Flt3 (2-3 fold) in the resistant cells. These results are consistent with the hypothesis that it is more challenging for AML cells to develop drug resistance against combined inhibition of Flt3 and CDK4/6 (AMG 925) than against inhibition of Flt3 alone.
Citation Format: Cong Li, Lingming Liang, Darrin Beaupre, Katie Newhall, Zhihong Li, Queenie Wang, Zhen Xia, Qiang Liu, Larry McGee, Dineli Wickramasinghe, Kang Dai. Different characteristics of drug resistance in AML cell lines between a dual Flt3/CDK4 kinase inhibitor AMG 925 and Flt3 inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5636. doi:10.1158/1538-7445.AM2013-5636
Abstract 565: An investigation into the potential therapeutic benefit of targeting Skp2 in neuroblastoma.
Authors: Evans Laura , Willmore Elaine , Tweddle Deborah A. , Newell David R. 
Published: August 2014

Abstract
Background: S-phase kinase-associated protein 2 (Skp2) is a component of an E3 ubiquitin ligase complex which targets several key regulators of the G1/S transition of the cell cycle. Skp2 is overexpressed in many cancers and has been implicated in tumourigenesis due to its ability to degrade the cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1, promote S phase entry and induce growth. We identified Skp2 as a possible MYCN target gene in neuroblastoma (Bell et al, Cell Cycle, 2007), and other groups have reported an increase in Skp2 transcript levels in aggressive MYCN- amplified neuroblastoma (Westermann et al, Clinical Cancer Res 2007). As MYCN amplification is a well-established poor prognostic marker we hypothesise that targeting Skp2 may be a potential therapeutic approach for neuroblastoma, especially the MYCN-amplified subtype.
Methods: The relationship between MYCN and Skp2 was investigated using the SHEP Tet21N-regulatable MYCN expression system and Skp2 siRNA. The effects of Skp2 knockdown on downstream proteins (p21, p27), cell cycle arrest and cell apoptosis were analysed using western blotting, flow cytometry, and the caspase-3/7 glow assay, respectively.
Results: A decrease in Skp2 and subsequent increase in p27 and p21 levels was seen in SHEP Tet21N cells when MYCN expression was suppressed. A G1 arrest was also induced by MYCN removal, an effect mirrored after Skp2 knockdown in Tet21N MYCN+ cells. Skp2 knockdown increased both p27 and p21 levels in non-MYCN amplified SHSY5Y cells and MYCN amplified IMR-32 cells. Both cell lines had ∼20% reduction (p&lt;0.01) in growth after 72 hours knockdown compared to the scrambled control. However, only SHSY5Y cells showed a G1 arrest (p&lt;0.05) and increase in caspase activity (p&lt;0.05).
Conclusions: These data further establish the relationship between MYCN and Skp2. The effect of Skp2 knockdown on growth arrest and apoptosis suggest it would be a valid therapeutic target in neuroblastoma.
Citation Format: Laura Evans, Elaine Willmore, Deborah A. Tweddle, David R. Newell. An investigation into the potential therapeutic benefit of targeting Skp2 in neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 565. doi:10.1158/1538-7445.AM2013-565
Abstract 5650: Determinants of acquired resistance to PI3K/mTOR inhibition in cells refractory to EGFR inhibition.
Authors: Koh King Xin , Bhattacharya Bhaskar , Loh Joanne , Ng Hong Kiat , Soo Ross , Iacopetta Barry , Soong Richie 
Published: August 2014

Abstract
Acquired resistance to EGFR inhibitors can be mediated through PI3K/mTOR pathway activation. This has prompted the consideration of PI3K/mTOR inhibitors for treatment of EGFR inhibitor-refractory non-small cell lung cancer (NSCLC). This study aimed to generate and elucidate mechanisms of acquired resistance to BEZ235, a PI3K/mTOR inhibitor, in H1975 NSCLC cells containing the EGFR T790M resistance mutant. IC50 values of compounds were determined at 72 hours using the MTS assay. Acquired resistant clones of H1975 were generated by continual exposure of H1975 cells to parental IC50 concentrations of BEZ235, followed by monoclonal selection. Protein levels, cell invasion/migration, and cell cycle analysis were evaluated using standard techniques. Apoptosis was measured using Roche Cell Death kit. Two resistant clones were generated with stably higher IC50 values (Clone 5 2.29uM, Clone 6 1.94uM) to parental H1975 cells (0.32uM) after 6 months. The clones were resistant to other PI3K/mTOR inhibitors but not other cytotoxic compounds or targeted agents such as EGFR/MEK inhibitors. Following BEZ235 treatment, acquired resistant clones underwent less cell cycle G1 arrest and displayed greater invasion and migration compared to parental cells. No significant differences were seen in basal levels of pRTKs, pAKT, pmTOR, pS6 and p4EBP1, and apoptosis. In summary, EGFR inhibitor-refractory cells with acquired resistance to PI3K/mTOR inhibition have been generated and characterized with phenotypes suggestive of a class-mediated mechanism of acquired resistance. Possible mediators of acquired resistance have emerged following RNA-sequencing and reverse phase protein array analyses and are currently being validated.
Citation Format: King Xin Koh, Bhaskar Bhattacharya, Joanne Loh, Hong Kiat Ng, Ross Soo, Barry Iacopetta, Richie Soong. Determinants of acquired resistance to PI3K/mTOR inhibition in cells refractory to EGFR inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5650. doi:10.1158/1538-7445.AM2013-5650
Abstract 5658: Development and optimization of CZ48-loaded microbubbles for controlled drug delivery .
Authors: Wang Yang , Li Siyang , Zheng Jian , Yan Xiufeng , Cao Zhisong , Vardeman Dana , Giovanella Beppino 
Published: August 2014

Abstract
CZ48, the 20-O-propionate ester of camptothecin, is a prodrug requiring activation by converting to parental CPT in vivo. To circumvent the problems of low water solubility, lack of absorption, and poor bioavailability, novel CZ48-loaded microbubbles were investigated in this study. CZ48-loaded microbubbles were prepared at particle sizes ranging from 0.5 μm to 6.7 μm using a double emulsion technique (W/O/W). The satisfactory encapsulation efficiency and drug-loading content were 85.73±2.41% and 26.07±0.76%, respectively. The successful encapsulation of the microbubbles was confirmed by confocal laser scanning microscope (CLSM) observations and X-ray diffraction (XRD) patterns. The comparison between the controlled drug release from CZ48-loaded microbubbles and the free drug release from plain CZ48 crystals was performed in vitro, showing that 55% of the CZ48 was steadily released by the CZ48-loaded microbubbles in the first 48 hrs while more than 90% of the CZ48 was rapidly released by CZ48 crystals within the first 5 hrs. In vivo pharmacokinetic studies indicated that the bioavailabilities of CZ48 and CPT from CZ48-loaded microbubbles raised 121% and 517%, respectively, after intravenous administration compared to the plain CZ48. Compared to the plain CZ48, CZ48-loaded microbubbles also showed a higher mean residence time (MRT) and a longer elimination half-life (T1/2), indicating that CZ48-loaded microbubbles were indeed able to release CZ48 drug in a finely controlled manner. These results demonstrated that such microbubbles could be a promising approach for the construction of an effectively controlled drug delivery system for CZ48 as well as for other drugs with lower water solubility.
Citation Format: Yang Wang, Siyang Li, Jian Zheng, Xiufeng Yan, Zhisong Cao, Dana Vardeman, Beppino Giovanella. Development and optimization of CZ48-loaded microbubbles for controlled drug delivery . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5658. doi:10.1158/1538-7445.AM2013-5658
Abstract 5665: New alternatives to photodynamic therapy based on light-enabled drug delivery.
Authors: Dcona M. Michael , Mitra Deboleena , Goehe Rachel W. , Gewirtz David A. , Lebman Deborah A. , Hartman Matthew C.T. 
Published: August 2014

Abstract
Conventional photodynamic therapy (PDT) aims to achieve tumor drug targeting by selectively killing cells upon illumination. PDT serves as a non-invasive treatment option for many types of non-metastatic, light-accessible cancers such as those involving the head and neck, lung, bladder, prostate, or esophagus. The various types of PDT all use the same basic strategy for killing cells; photosensitizing molecules are taken up by cancer cells, and, upon illumination, singlet oxygen is generated in the vicinity of the photosensitizer, killing the cell. A new alternative to PDT is photochemical internalization, in which singlet oxygen generated by a photosensitizer disrupts endosomes containing a toxin, releasing it into the cytoplasm and killing the cell. A drawback to both of these approaches is that moderate levels of oxygen are required, yet tumors are often hypoxic environments. Moreover, during PDT treatment, oxygen levels drop even further as the singlet oxygen is consumed; this can compromise treatment effectiveness. We have sought to address these challenges by developing new strategies for light-based treatment of cancer that are oxygen independent. In the first approach, which we call photocaged permeability, we have attached the anticancer drug doxorubicin to a cell impermeable small molecule via a light-cleavable linker. We show using flow cytometry and confocal microscopy that this conjugate is cell impermeable in the dark, yet upon illumination, doxorubicin is released and enters the cells. The IC50 for our conjugate in JH-EsoAd1 cells using non-cytotoxic doses of light is 1.6 μM, identical to that of doxorubicin alone. No cytotoxicity is observed at doses 30-fold higher in the dark. In a second approach, we have attached doxorubicin to folate receptor and PSMA ligands via a light cleavable linker in order to enable dual cancer cell targeting with both light and ligand specificity. The ability of the resulting conjugates to selectively kill cells expressing the requisite receptors with light will be described.
Citation Format: M. Michael Dcona, Deboleena Mitra, Rachel W. Goehe, David A. Gewirtz, Deborah A. Lebman, Matthew C.T. Hartman. New alternatives to photodynamic therapy based on light-enabled drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5665. doi:10.1158/1538-7445.AM2013-5665