bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4326: Phosphatidylserine-targeting ‘betabodies’ for the treatment of cancer.
Authors: Huang Xianming , Ye Dan , Luster Troy , Ward E Sally , Thorpe Philip 
Published: August 2014

Abstract
Bavituximab is a chimeric monoclonal antibody that is being combined with chemotherapy to treat patients with lung or pancreatic cancer in randomized Phase II clinical trials. Bavituximab targets the immunosuppressive lipid, phosphatidylserine (PS), which becomes exposed on the outer membrane surface of tumor blood vessels and tumor cells in tumors responding to therapy. The antibody acts by destroying tumor vasculature and by reactivating tumor immunity. Here, we generated new PS-targeting therapeutics by fusing domains of the PS-binding plasma protein, mouse β2-glycoprotein I (β2GP1), to the Fc region of mouse IgG2a. Such ‘betabodies’ potentially have the following advantages: they bind directly to PS, and do not require a cofactor protein (β2GP1) for binding; they can be made fully human; they are smaller in size (100 KDa); and they have slower blood clearance rates. A construct was generated that bound strongly to PS-expressing cells and plates, localized to tumor vascular endothelium in vivo, and had a β-phase blood half-life of approximately five days after intravenous injection into mice as compared with one day for a murine version of bavituximab, 2aG4. Betabodies could potentially be the next generation of PS-targeting cancer therapeutics.
Citation Format: Xianming Huang, Dan Ye, Troy Luster, E Sally Ward, Philip Thorpe. Phosphatidylserine-targeting ‘betabodies’ for the treatment of 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 4326. doi:10.1158/1538-7445.AM2013-4326
Abstract 4338: Tumor reversion: From bench to potential clinical applications using sertraline and thioridazine.
Authors: Amson Robert , Pece Salvatore , Di Fiore Pier Paolo , Karp Judith , Marine Jean-Christophe , Telerman Adam 
Published: August 2014

Abstract
This presentation aims at summarizing today's knowledge on tumor reversion (ref.1) with recent applications and new findings for potential cancer treatment. In order to study the molecular program of tumor reversion we have provided with a series of biological models. In this approach, we derived revertant cells from tumor cell lines ranging from leukemia to solid tumors such as breast, colon, lung cancer and melanoma. Using differential gene profiling, between the parental tumor cells and the revertants, over 300 genes were identified, as implicated in reversion such as Siah-1, TSAP6, PS1 and most importantly Translationally Controlled Tumor Protein (TPT1/TCTP) (ref. 2). Notably TPT1/TCTP is highly expressed in the tumor cells and almost undetectable in the revertants. Knocking down TPT1/TCTP reorganized breast cancer cells into ductal structures reminiscent of normal breast morphology. More recently, we identified a strong reciprocal repressive feedback loop between TPT1/TCTP and p53 (ref.3). P53 represses the transcription of TPT1/TCTP by binding to the promoter of TPT1/TCTP. Conversely, TPT1/TCTP interacts directly with p53, Numb and MDM2. TPT1/TCTP competes with Numb. Importantly, TPT1/TCTP stabilizes MDM2, promoting hereby MDM2-dependent ubiquitination and proteasomal degradation of p53. Screening of a large cohort of breast cancer patients (508) shows high expression of TPT1/TCTP in the most aggressive G3 tumors, predicting poor prognosis. TPT1/TCTP is also highly expressed in normal and cancer breast stem cells. Decreasing TPT1/TCTP by siRNA in a mammosphere assay significantly reduces the colony forming efficiency. Thus, TPT1/TCTP also regulates the stem cell compartment. We found two drugs, Sertraline and Thioridazine, which bind and inactivate TPT1/TCTP, restoring elevated levels of wild type p53. Pilot studies on ex vivo cells derived from AML-patients indicate that Sertraline and Ara-C act synergistically in reducing the viability of AML cells. The implication of tumor reversion in reprogramming cancer cells and in disclosing new therapeutic targets as well as its potential role in tumor heterogeneity will be discussed.
Citation Format: Robert Amson, Salvatore Pece, Pier Paolo Di Fiore, Judith Karp, Jean-Christophe Marine, Adam Telerman. Tumor reversion: From bench to potential clinical applications using sertraline and thioridazine. [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 4338. doi:10.1158/1538-7445.AM2013-4338
Abstract 4339: RGD-conjugated nanoparticles for targeted inhibition of adhesion and migration of integrin αvβ3-overexpressing breast cancer cells.
Authors: Shan Dan , Cai Ping , Prasad Preethy , Rauth Andrew Michael , Wu Xiao Yu 
Published: August 2014

Abstract
Background: Tumor cell adhesion and migration are critical in the establishment of metastasis. This study aims to develop a RGD-conjugated nanoparticle system that is able to target αvβ3 integrin receptor-overexpressing breast tumor cells while evading the liver uptake, thus enhancing treatment of cancer metastasis through inhibition of adhesion and migration of cancer cells.
Methods: The nanoparticle formulation was first optimized with a suitable concentration of RGD targeting moiety on the nanoparticle surface to maximize nanoparticle accumulation in tumor and minimize liver uptake. RGD-conjugated solid lipid nanoparticles (RGD-SLNs) were synthesized with a fatty acid lipid core and a poly(ethylene glycol) corona and decorated with varying concentrations of RGD peptides (0%, 0.5%, 1%, 5% and 10% mol/mol ratio). The quantity and kinetics of the nanoparticle binding to αvβ3 integrin receptor and in vitro cellular uptake on αvβ3 positive MDA-MB-231 cells were investigated by fluorescence microscopy and compared with the results with αvβ3 negative MCF-7 cells. The influence of RGD-SLNs on cell adhesion and migration via binding to αvβ3 integrin receptor was examined using standard adhesion and transwell migration assays. Whole animal biodistribution, tumor uptake and intratumoral distribution of quantum dot-loaded nanoparticles were investigated to identify optimized RGD-concentrations.
Results: RGD-SLNs showed specific binding for αvβ3 integrin receptors on MDA-MB-231 cells as compared to the negative control (MCF-7 cells). The RGD-SLN formed clusters at the cellular membrane and then entered the cells at a lower pace than SLN. The RGD-SLNs also exhibited higher cellular uptake compared to SLN in MDA-MB-231 cells while there was no detectable difference in uptake in αvβ3 negative MCF-7 cells. RGD concentration of 1% on the SLN surface was found to have most tumor retention and low liver uptake among all formulations. Receptor mediated uptake of RGD-SLNs reduced cell adhesion and migration towards fibronectin gradient, attributable to the occupation of the receptors by the RGD-SLN and slow recycling of the receptors to the cell surface.
Conclusions: We have optimized the RGD-SLN formulation to maximize tumor accumulation and minimize liver uptake. The RGD-SLN formulation has the potential to prevent metastasis through interference with cell adhesion and migration.
Citation Format: Dan Shan, Ping Cai, Preethy Prasad, Andrew Michael Rauth, Xiao Yu Wu. RGD-conjugated nanoparticles for targeted inhibition of adhesion and migration of integrin αvβ3-overexpressing breast cancer cells. [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 4339. doi:10.1158/1538-7445.AM2013-4339
Abstract 4347: Toxicology and drug delivery by novel Cucurbit[n]uril-type molecular containers.
Authors: Hettiarachchi Gaya , Ma Da , Nguyen Duc , Isaacs Lyle , Briken Volker 
Published: August 2014

Abstract
Background. Many drug delivery systems are based on the ability of certain macrocyclic compounds - such as cyclodextrins - to act as molecular containers for pharmaceutical agents in water. Cucurbit[n]urils (CB[n]) are a class of molecular containers that bind to a variety of cationic and neutral species with high affinity (Ka &gt; 10ˆ4 Mˆ-1) and therefore show great promise as a drug delivery system (Isaacs, 2009). Initial in vitro toxicity analysis demonstrated good biocompatibility of five different CB[n]-type compounds. We hypothesized that these nanocontainers can be used to increase solubility of hydrophobic small chemical compound drugs. Methodology. In this study we investigated the toxicology and bioactivity of one novel cucurbit[n]urils CB[n]-type container (named Motor1). The container induced no toxicity at concentrations of up to 10 mM in human cell lines originating from kidney, liver or blood tissue using assays for metabolic activity and cytotoxicity. Furthermore, the Motor1 container was tolerated in mice without any toxicity after intravenous dosing of up to 1.5g/kg bodyweight. Interestingly, Motor1 was able to bind the cancer drug paclitaxel and increase its solubility in water by a factor of 2000. Finally, bioactivity assays showed that the increase in solubility by paclitaxel via Motor1 led to a more efficient killing of the cervical cancer cell line HeLa. Conclusion. Our study reveals very low toxicity of a novel member of the cucurbit[n]uril family of nanocontainers. It demonstrates the increase in solubility of four commercially available drugs by the containers by factors ranging from 400-2700fold. Importantly, the increase in solubility of paclitaxel led to increased killing of cancer cells in vitro. These results provide initial proof-of-concept towards the use of CB[n] molecular containers as an advanced drug delivery system.
Citation Format: Gaya Hettiarachchi, Da Ma, Duc Nguyen, Lyle Isaacs, Volker Briken. Toxicology and drug delivery by novel Cucurbit[n]uril-type molecular containers. [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 4347. doi:10.1158/1538-7445.AM2013-4347
Abstract 4348: Antitumor activity of Tivantinib (ARQ 197) is due to inhibition of tubulin polymerization in addition to c-Met inhibition.
Authors: Katayama Ryohei , Aoyama Aki , Yamori Takao , Qi Jie , Ohara Tomoko , Song Youngchul , Engelman Jeffrey A. , Fujita Naoya 
Published: August 2014

Abstract
The receptor tyrosine kinase c-Met is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-Met axis is often dysregulated in tumors. Such c-Met activation is caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-Met inhibitors are under development as anti-cancer drugs. Tivantinib (ARQ 197) was reported as a small molecule Met inhibitor and early clinical studies suggest anti-tumor activity. To assess if the anti-tumor activity of tivantinib was due to inhibition of c-Met, we investigated the activity of tivantinib in both c-Met addicted and non-addicted cancer cells for cell viability. As expected, we observed that other Met inhibitors, crizotinib and PHA-665752, suppressed the growth of c-Met addicted cancers, but not the growth of c-Met non-addicted cells. In contrast, tivantinib inhibited cell viability similarly in both c-Met addicted and non-addicted cells. These results suggest that tivantinib exhibits its antitumor activity in a c-Met status independent manner. Tivantinib treatment increased the number of G2/M phase arrested EBC1 cells similarly as vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced cell cycle arrest at the G0/G1 phase. To identify the additional molecular target of tivantinib, we performed COMPARE analysis, in silico screening using extensive drug sensitivity database of 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib treated cells demonstrated typical microtubule disruption similar to vincristine. In vitro microtubule polymerization assay clearly demonstrated that tivantinib inhibited microtubule assembly. From these results, tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET.
Citation Format: Ryohei Katayama, Aki Aoyama, Takao Yamori, Jie Qi, Tomoko Ohara, Youngchul Song, Jeffrey A. Engelman, Naoya Fujita. Antitumor activity of Tivantinib (ARQ 197) is due to inhibition of tubulin polymerization in addition to c-Met 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 4348. doi:10.1158/1538-7445.AM2013-4348
Abstract 4352: Down regulation of retinoblastoma protein expressionimpedes the antileukemic activity of erufosine.
Authors: Zaharieva Maya M. , Kirilov Milen , Chai Minquang , Berger Stefan M. , Konstantinov Spiro M. , Berger Martin R. 
Published: August 2014

Abstract
Erufosine is a new antineoplastic agent from the class of alkylphosphocholines, which interferes with AKT phosphorylation, the related signal transduction and confers apoptosis. An improved understanding of its mode of action is important for its potential clinical application. The present study demonstrates that erufosine's antileukemic efficacy is related to the level of cellular retinoblastoma (Rb) protein expression.
Stable Rb-knockdown in SKW-3 leukemia T-cells was induced by lentiviral delivery of constructs expressing short-hairpin-RNA species with 21 or 27 bp lengths. The cytotoxicity of erufosine was tested via MTT proliferation test on thus engineered cell populations with reduced Rb expression levels. Likewise, the clonogenicity of these engineered cell populations was determined by CFU assay before and after treatment with erufosine. The effects on cell cycle were investigated by FACS analysis. The expression of signal transduction factors was examined by RT-PCR and immunoblot.
The Rb protein expression levels in the shRNA-transduced cells ranged from 1%- 36% of wild type or nonsense control. Low Rb expression correlated with significantly diminished antiproliferative and anticlonogenic activities of erufosine (p&lt;0.05) at concentrations near and above the IC50. Erufosine induced a G2 arrest, and complete Rb-deficiency aggravated this condition. With regard to proteins involved in cell cycle and apoptosis induction, Rb-deficiency reduced the expression of cyclin D3, that of the subsequently regulated kinase Cdk 4 and activated caspases 3 and 9, followed by PARP-cleavage. In partial variance, erufosine reduced cyclin D3 at RNA and protein levels, but affected not or only slightly the expression of its partner kinase Cdk 4.
Rb-knockdown impaired the cytotoxic effect of erufosine significantly and contributed to the formation of a resistant cell fraction. It is concluded that
Rb is a main mediator of erufosine's antileukemic activity and this suggests that the effect of the drug in patients might be predicted by determining the Rb expression status.
Citation Format: Maya M. Zaharieva, Milen Kirilov, Minquang Chai, Stefan M. Berger, Spiro M. Konstantinov, Martin R. Berger. Down regulation of retinoblastoma protein expressionimpedes the antileukemic activity of erufosine. [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 4352. doi:10.1158/1538-7445.AM2013-4352
Abstract 4369: Compound 1, a quinoxaline-based small molecule, regulates the cancer cell proliferantion by the down-regulation of maternal embryonic leucine zipper kinase gene expression in brain tumor cells.
Authors: Choi Sang-Un , Park Chi Hoon , Ahmed Mansoor M. , Yoo Stephen , Park Shin-Young , Kim Kwangrok 
Published: August 2014

Abstract
Maternal embryonic leucine zipper kinase (MELK), a member of the snf1/AMPK family of serine-threonine kinase, was indicated in stem cell renewal, cell cycle progression. Recently, several groups reported that MELK expression level is highly correlated with malignancy of a variety of tumors and its expression in the cancer cells is a negative factor of radiotherapy in cancer patients. Therefore, MELK can be a good target for cancer drug development. Previously, we tested the neuronal cell differentiation by the compound-1, a quinoxaline-based small molecule, with rat mesenchymal stem cells, and we found that the gene expression level of MELK is dramatically decreased in the differentiated cells in comparison with the parental stem cells. Based on this phenomenon, we checked the MELK gene expression in the several central nerve system cancer cell lines such as U87MG, XL498 and SNB19, and examined the change of the gene expression level by treatment of compound 1. All the cancer cells tested in this study expressed the MELK gene and its expression level is significantly decreased by the treatment of 20 uM compound 1. To confirm the relationship between the MELK gene expression and cell proliferation in brain tumor cells, we transfected the MELK gene to the U87MG cells and tested the cell growth rate in the presence or absence of compound 1 in comparison with parental cells. The cell growth rate of MELK gene-transfected cancer cells increased in comparison with the non-transfected control cells, and its overexpression can recover the down-regulation of the cell proliferation by treatment of compound 1. Meanwhile, the treatment of MELK gene siRNA decreased the cell proliferation rate of the U87MG cells in time dependent manner. In the cell cycle analysis, compound 1 induced both the increase of apoptotic cell rate from less than 5% to 22% and the decrease of G0/G1 phase U87MG cells in comparison with control. Meanwhile, the S and G2/M phase is not changed by the treatment of compound 1 in the U87MG cells. These results support MELK has an effect on regulation of cancer cell proliferation, and it may be a good target for cancer drug development.
Citation Format: Sang-Un Choi, Chi Hoon Park, Mansoor M. Ahmed, Stephen Yoo, Shin-Young Park, Kwangrok Kim. Compound 1, a quinoxaline-based small molecule, regulates the cancer cell proliferantion by the down-regulation of maternal embryonic leucine zipper kinase gene expression in brain tumor cells. [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 4369. doi:10.1158/1538-7445.AM2013-4369
Abstract 4378: Poly(ADP-ribose)glycohydrolase (PARG) is a novel therapeutic target in breast cancer.
Authors: Lovato Amanda , Zhao Tiejun , Sun Qiang , Witcher Michael 
Published: August 2014

Abstract
Poly(ADP-ribose)polymerase (PARP) is an enzyme responsible for catalyzing the addition of poly(ADP-ribose) chains onto target proteins in a process known as PARylation. This post-translational modification has been implicated in numerous cellular processes including gene expression, chromatin remodeling, apoptosis and DNA damage repair. In particular, the role of PARP activation in response to DNA damage has been intensely studied. BRCA mutated tumors are highly sensitive to DNA breaks and are therefore critically dependent on alternative repair mechanisms involving PARP. This forms the basis for a synthetic lethal therapeutic approach that has been met with much success in the clinic. BRCA mutated breast and ovarian tumors, in particular, are acutely sensitive to PARP inhibitors. Currently, it is unclear from in vitro and clinical studies to what extent PARP inhibitors can be used as chemotherapeutics to treat tumors beyond those harboring BRCA mutations. Due to the insensitivity of most solid tumors to PARP inhibitors, we have begun to study the role of the dePARylating enzyme poly(ADP-ribose)glycohydrolase (PARG), as a possible target in cancer therapy. PARG, like PARP, maintains a critical role in DNA repair and can therefore be a target in cells with defective repair mechanisms (e.g. BRCA mutant cells). We further hypothesize that targeting this factor may activate the expression of tumor suppressor genes, thus limiting cell proliferation. Thus far, we have novel data indicating that targeting PARG may indeed have therapeutic benefit. We show that PARG knockdowns of the T47D and MDA-MB-468 breast cancer cell lines have dramatically reduced rates of cellular proliferation. Gene expression analyses of the knockdown cells indicated that cell cycle related pathways may be affected. As such, we examined cell cycle profiles by BrdU and PI staining and found that PARG knockdown cells were arrested in S phase. These results are particularly striking given that these cells show resistance to PARP inhibition. Subsequent studies using the PARG inhibitor gallotannin successfully reconstituted the results obtained with the PARG knockdowns. Overall, our data illustrates that PARG has great potential as a new anti-cancer target.
Citation Format: Amanda Lovato, Tiejun Zhao, Qiang Sun, Michael Witcher. Poly(ADP-ribose)glycohydrolase (PARG) is a novel therapeutic target 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 4378. doi:10.1158/1538-7445.AM2013-4378
Abstract 4395: Targeting ribosomal proteins for therapeutic inhibition of melanoma growth.
Authors: Kardos Gregory R. , Robertson Gavin P. 
Published: August 2014

Abstract
Disruption of ribosome biogenesis leads to the activation of the RP-MDM2-p53 pathway along with other yet to be identified pathways. Ribosome biogenesis is inherently tied to protein synthesis, a process relied upon in cancer to sustain its increased proliferative properties. The ability to activate a tumor suppressor and simultaneously target a process heavily dependent upon for cancer growth is a promising therapeutic angle that deserves exploration. In the present study, we knocked down expression of all large subunit ribosomal proteins to examine their effect on melanoma growth. We found that targeting many ribosomal proteins lead to decreased cancer cell viability. siRNA mediated knocking down of RPL13, a representative ribosomal protein of this group, resulted in increased p53 expression and cell cycle arrest dependent on the RP-MDM2-p53 pathway. Furthermore, inhibition of protein synthesis in culture and decreased tumor growth by 50-90% in animals was observed upon knockdown of RPL13. We conclude that the cell cycle arrest is due in large part to the increased p53 expression caused by the binding of RPL5 and RPL11 to MDM2, however the inhibition of melanoma growth cannot be explained solely by an increase in the tumor suppressor. The accompaniment of decreased protein synthesis provides an additional mechanism contributing to decreased growth. Thus, targeting ribosomal proteins in cancer may serve as an underappreciated therapeutic treatment.
Citation Format: Gregory R. Kardos, Gavin P. Robertson. Targeting ribosomal proteins for therapeutic inhibition of melanoma growth. [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 4395. doi:10.1158/1538-7445.AM2013-4395