bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3610: Potent preclinical anti-tumor activity of MGCD265, an oral Met/VEGFR multitargeted kinase inhibitor in clinical development, in combination with taxanes
Authors: Maroun Christiane R. , Ste-Croix Helene , Beaulieu Normand , Bonfils Claire , Fournel Marielle , Dupont Isabelle , Lemoyne Christian , Wand James , Besterman Jeffrey M. 
Published: June 2012

Abstract
MGCD265, a multitargeted receptor tyrosine kinase inhibitor in clinical development, inhibits the activation of Met, VEGFR1, 2, 3, Tie-2 and Ron. Met is a promising molecular target for the development of cancer therapeutics and is found overexpressed and phosphorylated in a large proportion of NSCLC patients. Several agents targeting Met are currently under clinical investigation in NSCLC including MGCD265, and early clinical results are encouraging. Interestingly, to our knowledge, no Met inhibitor has been explored in NSCLC in combination with a taxane. In support of the clinical development of MGCD265, we have investigated preclinically the anti-tumor activity of MGCD265 in combination with taxanes.
The combination of MGCD265 with docetaxel or paclitaxel resulted in enhanced anti-tumor activities compared to treatment with either agent alone in multiple xenograft models, including human NSCLC, glioblastoma, breast, prostate and gastric carcinomas. Enhanced efficacy occurred in the absence of overt toxicity. Moreover, PK analyses demonstrated lack of drug-drug interactions. Interestingly, in a gastric Met-driven carcinoma model in which MET is amplified (MKN45), treatment with MGCD265 in combination with docetaxel resulted in tumor regression at suboptimal doses of the taxane. Immunohistochemistry analyses in this model showed that this combination altered tumor vascularization as detected by endothelial cells labeling (CD31). While it has been suggested that changes in tumor vascularization may increase tumor exposure to docetaxel, the exposure of either MGCD265 or docetaxel was not altered in tumors treated with the combination. To gain insights into the molecular mechanism through which improved anti-tumor activities were achieved by the combination, we performed gene expression analyses on xenograft tumors. Genes differentially regulated by either agent alone were simultaneously regulated and sometimes enhanced, when the two agents were combined. Confirmations are currently ongoing. Together, these studies provide support for the development of MGCD265 in combination with taxanes for the treatment of cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3610. doi:10.1158/1538-7445.AM2011-3610
Abstract 3622: An antibody-based multifaceted approach targeting the human transferrin receptor for the treatment of multiple myeloma
Authors: Daniels Tracy R. , Ortiz-Sanchez Elizabeth , Luria-Perez Rosendo , Quintero Rafaela , Helguera Gustavo , Bonavida Benjamin , Martinez-Maza Otoniel , Penichet Manuel L. 
Published: June 2012

Abstract
We previously developed an antibody-avidin fusion protein (ch128.1Av) targeting the human transferrin receptor 1 (TfR1, CD71) that demonstrates direct in vitro cytotoxicity against malignant hematopoietic cells. This cytotoxicity is due to its ability to decrease TfR1 levels leading to lethal iron deprivation. We now report that ch128.1Av shows the ability to bind the Fc gamma receptors and the complement component C1q, suggesting that is capable of eliciting Fc-mediated effector functions such as antibody-dependent cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). Additionally, in two disseminated multiple myeloma xenograft mouse models, we show that a single dose of ch128.1Av results in significant anti-tumor activity including long-term survival. Interestingly, the parental antibody without avidin (ch128.1) also shows remarkable in vivo anti-cancer activity despite its lack of in vitro cytotoxicity. Finally, we demonstrate that ch128.1Av is not toxic to pluripotent hematopoietic progenitor cells using the Long-Term Cell-Initiating Culture (LTC-IC) assay suggesting that these important progenitors would be preserved in different therapeutic approaches, including the in vitro purging of cancer cells for autologous transplantation and in vivo passive immunotherapy. Our results suggest that ch128.1Av and ch128.1 may be effective in the therapy of human multiple myeloma and potentially other hematopoietic malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3622. doi:10.1158/1538-7445.AM2011-3622
Abstract 3627: Targeted delivery of gelonin to claudin-expressing cancer cells and use of activatable cell penetrating peptides to enhance potency
Authors: Lin Xinjian , Yuan Xiaoqin , Manorek Gerald , Howell Stephen B. 
Published: June 2012

Abstract
Treatment of tumors with macromolecular toxins directed to cytoplasmic targets requires selective endocytosis followed by release of intact toxin from the endosome/lysosome compartment. The latter step remains a particular challenge. Claudins 3 and 4 are tight junction proteins that are over-expressed in many types of tumors. Although their functional role in cancer progression remains unclear, the differential expression of these proteins between tumor and normal cells, in addition to their membrane localization, makes them prime candidates for targeted cancer therapy. This study utilized the C-terminal 30 amino acid fragment of C. perfringens enterotoxin (CPE), that binds to claudins 3 and 4, to deliver the toxin gelonin (rGel) and examined a new strategy for enhancing delivery to the cytoplasm. CPE was fused to rGel at its N-terminal end via a flexible G4S linker. This molecule was internalized into vesicles from which location it produced little cytotoxicity. Arginine-rich peptides have been extensively used to enhance cellular uptake of various types of cargo, and there is a reasonable presumption that they can deliver cargo out of subcellular compartments as well. To enhance release from the endosomal/lysosomal compartment a poly-arginine sequence (R9) was introduced between the CPE and the rGel. CPE-R9-rGel was 10-fold more cytotoxic but selectivity for claudin-expressing cells was lost. Given that the R9 moiety was so effective at enhancing uptake, we reasoned that it would likely also be good at releasing rGel from the compartment into which CPE delivered it. However, to make use of the R9 sequence in this manner it is necessary to mask the R9 until after CPE-mediated and claudin-dependent endocytotic uptake. To this end an E9-G4S-R9-rGel fusion protein was produced and tested for cytotoxicity. The addition of the E9 through a G4S linker to R9-rGel increased the IC50 by 5.3-fold from 38 to 202 nM indicating that the inhibitory E9 domain can largely neutralize the R9. Addition of CPE to the E9-G4S-R9-rGel fusion protein further reduced the IC50 to 482 nM consistent with the concept that the CPE directs the CPE-E9-G4S-R9-rGel to intracellular vesicles from which it has difficulty in fully escaping. However, addition of endosomolytic reagent chloroquine at a non-toxic concentration increased the inhibition of growth produced by 31.25 nM CPE-E9-G4S-R9-rGel from 10% to 76%. Thus, while CPE provides targeting to claudin-expressing tumor cells, R9 plus chloroquine provide a mechanism for getting out of intracellular compartment, and E9 offers an approach to masking the non-specific toxicity of R9-rGel.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3627. doi:10.1158/1538-7445.AM2011-3627
Abstract 3649: Contribution of fatty acid accumulation to myeloid-derived suppressor cell function in cancer
Authors: Cao Wei , Gabrilovich Dmitry 
Published: June 2012

Abstract
MDSCs are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells (IMCs). In healthy individuals, IMCs that are generated in the bone marrow quickly differentiate into mature granulocytes, macrophages or dendritic cells (DCs). By contrast, under pathological conditions, such as cancer, a partial block in the differentiation of IMCs and activation of these cells results in the expansion of the population with potent immune suppressive activity – myeloid-derived suppressor cells. We investigated the mechanism of MDSC effect on immune system and focused our attention on possible role of fatty acids (FA) in this process. Recently, we found FA accumulation in dendritic cells (DCs) from tumor bearing mice or cancer patients. It was caused by increased uptake of extracellular lipids due to up-regulation of scavenger receptor A. FA accumulation in DCs resulted in the dysfunction of DCs. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. In parallel, we also observed dramatic lipid accumulation in MDSC from tumor bearing mice. Interestingly, MDSCs don't have up-regulation of scavenger receptor A, but instead have increased expression of fatty acid transporter FATP4. Over-expression of FATP4 in MDSCs induced lipid accumulation. This suggested that FATP4 may be involved in the accumulation of lipid in these cells. MDSCs with lipid overload exerted stronger inhibitory effect on immune cells than MDSC with normal lipid level. MDSCs treated with unsaturated FA linoleic acid displayed stronger inhibitory effect than MDSCs treated with saturated FA palmitic acid. Since MDSCs has strong oxidizing environment, the data suggested that oxidized FA may be involved in the inhibitory effect of MDSCs. Elucidation of this mechanism in detail will be helpful for the development of potential therapeutic targets regulating immune function in tumor-bearing hosts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3649. doi:10.1158/1538-7445.AM2011-3649
Abstract 3665: Enzymatic depletion of pericellular HA from tumor cell surface sensitizes Erbitux dependent immune cell-mediated cytotoxicity
Authors: Singha Netai C. , Jiang Ping , Frost Gregory I. , Shepard H Michael 
Published: June 2012

Abstract
Hyaluronan (HA), a ubiquitous high-molar-mass linear glycosaminoglycan (GAG) plays a critical role in cell adhesion, motility, growth and differentiation. HA accumulation is associated with many human cancers. Human tumor cells can form HA rich pericellular matrix which might favor tumor growth by preventing the access of host immune cells to malignant cells. Monoclonal antibody (MAb) based therapeutics are emerging as an important component of therapy for human malignancies. Despite the very high specificity of monoclonal antibodies, resistance to MAb therapy is common. Antibody Dependent Cell-mediated Cytotoxicity (ADCC) is an important effector for the clinical efficacy of MAbs and relies on effective interaction between the Fc domain of antigen bound antibody and FcγRIII positive immune cells. We hypothesize that pericellular HA coating may contribute to resistance of HA-rich malignant cells to MAb mediated therapy by preventing efficient access of effector cells to their tumor targets. Enzymatic depletion of HA with PEGPH20 hyaluronidase could potentially sensitize such tumors to MAb mediated therapy. remove ell surface and ated therapy by preventing tumor cells contact
EGFR positive breast carcinoma cell line MDA-MB-231luc and genetically engineered HAS2 over expressing MDA-MB-231HAS2 were used to investigate the role of HA-rich pericellular matrix in inhibition of ADCC. ADCC assay was performed by incubating Calcein AM labeled monolayer cells with monoclonal antibody (1h at 37°C) followed by co-incubation of recombinant human IL-2 (rhIL-2) activated human peripheral blood mononuclear cells (PBMC, 5h at 37°C, 5% CO2) with or without PEGPH20. Live cells from each treatment were assessed by fluorescence readings at Ex/Em 488nm/537nm (SpectraMax M2e plate reader) at the end of the assay. Percentages of cell killing were calculated against control. The student's t test was used to compare the difference between treatments.
Particle exclusion assay demonstrated that HAS2 over expressing MDA-MB-231HAS2 cells formed a pericellular coat that inhibited access of the rhIL-2 activated PBMC to tumor cells. Incubation with PEGPH20 removed the HA-rich pericellular matrix and promoted contact of PBMC to tumor cells. Incubation of Erbitux with rhIL-2 activated PBMC induced a dose dependent killing of both MDA-MB-231luc and MDA-MB-231HAS2 cells. PEGPH20 increased ADCC by 10% on MDA-MB-231luc (HAlow) and 25% on MDA-MB-231HAS2 (HAhigh) tumor cells. Our results show that the HA-rich pericellular matrix on adherent tumor cells inhibits ADCC and PEGPH20 depletion of this coat sensitizes the tumor cells to ADCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2011-3665
Abstract 3669: Bisphosphonate use following first primary ER+ breast cancer and risk of second primary breast cancer
Authors: Monsees Genevieve M. , Newcomb Polly , Malone Kathi , Li Christopher 
Published: June 2012

Abstract
Background: Recent studies suggest that bisphosphonates, drugs commonly prescribed for the prevention and treatment of osteoporosis, may reduce risk of developing a first breast cancer. This is the first population-based assessment of the effect of bisphosphonate use on risk of developing a second breast cancer among breast cancer survivors.
Methods: Within a population-based nested case-control study of women diagnosed with a first primary ER+ invasive breast cancer (BC) at ages 40-79, we assessed the association between bisphosphonate use after first breast cancer diagnosis and risk of asynchronous primary in the contralateral breast (CBC). Conditional logistic regression was used to compare 359 CBC cases to 649 incidence density matched controls (women not diagnosed with CBC). Analyses of duration were restricted to women followed for similar time periods.
Results: Use of nitrogenous bisphosphonates for ≥12 months following first primary ER+ BC diagnosis was associated with a 56% decrease in CBC risk relative to no bisphosphonate use in this period (95% CI: 0.24-0.80, p-value: 0.008). Increasing duration of bisphosphonate use was associated with greater reductions in CBC risk (OR≥6months: 0.52, 95% CI: 0.31-0.89, p-value: 0.02; OR≥16months: 0.42, 95% CI: 0.21-0.83, p-value: 0.01; OR≥36months: 0.25, 95% CI: 0.07-0.84, p-value: 0.03). Use within 6 months also appeared protective (OR: 0.50, CI: 0.29-0.88, p-value: 0.02).
Conclusions: This study suggests that use of nitrogenous bisphosphonates, following diagnosis with ER+ BC, may reduce second primary CBC. Given bisphosphonate tolerability and other potential benefits in this high-risk population, bisphosphonate therapy may be a feasible approach for CBC risk reduction, and merits further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3669. doi:10.1158/1538-7445.AM2011-3669
Abstract 3684: Saffron protects against liver cancer in animal model: Molecular and imaging insights
Authors: Amin Amr , Mahmoud-Ghoneim Doaa , Corr Peter , Hamza Alaaeldin , Daoud Sayel 
Published: June 2012

Abstract
Saffron is a natural product that is a promising chemo-preventive agent against different cancer. The aim of the present work was to investigate the chemo-protective effect of saffron ethanol extract on chemically-induced liver cancer in rats. Hepatocarcinogenesis was induced by a single intraperitoneal injection of diethyl nitrosamine (DEN) (200 mg/kg body weight) and 2 weeks later, the carcinogenic effect was promoted by 2-acetylaminofluorene (2-AAF) (0.05%). 42 Wister rats were divided into seven groups: negative control, positive control (DEN+2-AAF), saffron-alone group (saffron for 22 weeks, no DEN or 2-AAF) and 3 preventive groups (where saffron was administered at 300, 150 and 75 mg/kg for 2 weeks before and 20 weeks after inducing cancer). The incidence and multiplicity of liver tumors as well as the expression of cancer marker, glutathione S-transferase placental form, were significantly reduced in preventive groups. This hepatopreventive effect was confirmed by the decreasing in cancer marker, α feto protein in plasma. Immunohistochemical analyses showed a decrease in cell proliferation marker (Ki67) and an increase of TUNEL-and caspase 3-positive apoptotic cells along with strong expressions of p53 in liver of preventive groups. These protective effect found to be mediated by anti-inflammatory and antioxidant effects. The anti-inflammatory activity was confirmed by saffron-based inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. The effect of saffron on the expression of nuclear factor nuclear factor-Kappa B (NF-kappa B) was also assessed. The expression of NF-kappa B in the preventive groups was significantly low compared to positive control. The in vitro antioxidant capacity of saffron (FRAP Assay, DPPH Scavenging activity and ABST+ Assay) was significantly high in ethanol-based extract. In addition, NF-kappa B transcription factor seems to regulate the saffron chemo-protective effects. Finally, texture analysis was applied to analyze in vivo MRI images and results were consistent with that of histopathology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3684. doi:10.1158/1538-7445.AM2011-3684
Abstract 3703: Chemopreventive efficacy of vandetanib, a multikinase inhibitor, in a primary respiratory tract epithelial cell transformation assay
Authors: Sharma Sheela , Zou Minxu , Lee Jin , Steele Vernon E. 
Published: June 2012

Abstract
Targeted therapies by means of compounds that inhibit multiple target molecules represent a new perspective in the treatment and prevention of cancer. Vandetanib (Zactima™) is an orally active, selective inhibitor of VEGFR-2 (vascular endothelial growth factor receptor-2) receptor tyrosine kinase that also demonstrates activity against EGFR (epidermal growth factor receptor) and RET (rearranged during transfection) tyrosine kinases. As there are indications of Vandetanib being effective in advanced NSLC patients for disease free survival, we have tested Vandetanib for efficacy in a primary rat tracheal epithelial (RTE) cell transformation model, which was originally developed for identifying potential chemopreventive agents belonging to different chemical classes/biological activity. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of Vandetanib and the resulting foci at the end of 30 days were scored for inhibition of transformation. In addition, the effect on mechanistic biomarkers at different stages of RTE cell transformation was tested. The results indicated that Vandetanib at half-log concentrations ranging from 0.003 – 0.3 μM, elicited an excellent dose-related inhibition of transformation (75-93%) compared to B[a]P group. There was also a 2-fold induction of apoptosis at 0.3 μM, and it inhibited survivin, a late stage biomarker, at all concentrations by 18-28%. Remarkably, a significant dose-dependent inhibition (39- 93%) of phosphorylated tyrosine kinase activity was also observed in Vandetanib-treated groups compared to B[a]P group. In conclusion, the data shows that there is a very good correlation between the inhibition of B[a]P-induced transformation and corresponding inhibition of activated tyrosine kinase and other biomarkers. Based on this data, animal studies are planned to develop this drug for lung cancer prevention by administering it directly to the lungs (Supported by NCI #N01-CN-43301).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2011-3703
Abstract 3747: Leukocyte LINE1 and Alu DNA methylation and gastric cancer risk in the Shanghai Women's Health Study cohort
Authors: Gao Ying , Chow Wong-Ho 
Published: June 2012

Abstract
Aberrant DNA methylation is a well-recognized feature of malignant epithelial component in human carcinomas. Recent data also suggested a link between blood leukocyte DNA methylation and cancer risk. However, data on DNA methylation from a prospective study, which may provide evidence for causality, are unavailable. We explored the association between methylation levels in two repetitive elements, i.e. Alu and LINE-1, in blood leukocyte DNA and gastric cancer risk in a case-control study nested in the Shanghai Women's Health Study cohort. A total of 213 incident gastric cancer cases and 426 age- and menopause status- matched controls were included in the study. Using prediagnostic DNA extracted from blood leukocytes, methylation of LINE1 and Alu were evaluated using bisulfate-pyrosequencing. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders. Decreased Alu methylation was associated with increased gastric cancer risk at the lowest quartile (OR=1.85, 95%CI=1.10-3.11) compared to the highest quartile. We did not observe appreciable changes in the association with increasing interval between blood draw and cancer diagnosis or reference date for controls. Excluding the cases diagnosed within 1 year after study enrollment and their matched controls did not alter the results substantially. When stratified by potential effect modifiers, a significant interaction was observed with isoflavone intake (p=0.04), with a positive association between Alu methylation and gastric cancer risk restricted to individuals with high isoflavone intake. Associations with Alu were also strengthened among subjects with tea use and high intake of folate and fruit. Conversely, lower methylaiton levels of LINE1 were associated with slightly decreased, but not statistically significant, risk of gastric cancer. This prospective study suggests that DNA methylation of Alu in blood leukocytes may be inversely associated with risk of gastric cancer. The divergent associations with Alu and LINE1 raise the possibility that the role of DNA methylation in these two regions is different in gastric cancer etiology, and warrant further research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3747. doi:10.1158/1538-7445.AM2011-3747