bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2566: Mesenchymal to epithelial transition associates with drug resistance in tongue squamous cell carcinoma cell line
Authors: Liu Xiqiang , Jiang Lu , Shi Fei , Zhou Xiaofeng 
Published: February 2011

Abstract
Epithelial to mesenchymal transition (EMT) has been implicated in altered drug sensitivity to various chemotherapeutic agents. Herein, we investigate whether this phenomenon would play a role in acquired resistance to cisplatin. We firstly established a cisplatin-resistant subline (UMcis, IC50 = 19.8 µM), which was derived from the cisplatin-sensitive tongue squamous cell carcinoma cell line, UM1 (IC50 = 3.6 µM). The UMcis cells showed cross-resistance against other chemotherapeutic drugs with divergent mechanisms of action [5-fluoro-uracil (5-FU), paclitaxel and epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib]. Genome-wide expressional profiling was performed on the paired cell lines. Interestingly, a large number of genes associated with EMT (or reversed EMT, MET) were differentially expressed between the two cell lines. We confirmed that increased expression of E-Cadherin combined with the loss of Vimentin, Slug, Twist1 and MMP2 by immunoblotting was associated with drug resistance. Importantly, downregulation of E-Cadherin in UMcis cells not only increased the expression of mesenchymal markers, such as Vimentin, Slug and Twist1, but also restored drug sensitivity. Moreover, concurrent treatment with transforming growth factor-beta 1 and epidermal growth factor induced EMT in the UMcis cells, which also led to altered chemo-responsiveness. Therefore, our results suggest that induction of MET may contribute to the decreased efficiency of cisplatin-based chemotherapy and acquired drug resistance in tongue cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2566.
Abstract 257: R4 knock-out mice showed lung hyperplasia and susceptible to urethane-induced lung carcinogenesis
Authors: Choi Ji Won , Kim Il Yong , Shin Jae Hoon , Lee Seo Hyun , Bae Yun Soo , Seong Je Kyung 
Published: February 2011

Abstract
Lung cancer is responsible for 1.3 million deaths worldwide annually. There have been several reports on candidate genes driving lung cancers including ras. However still it is needed to find new genes which can cause lung cancers.
Recently we developed R4 knock-out (KO) mice which showed larger relative lung weight and volume than age-matched wild-type (WT) mice. Lung hyperplasia was found with increased alveolar thickness in 6, 18 and 40 week-old R4 KO mice. Also, this finding was observed in E16.5 and 18.5 day KO mice. Cell cycle markers including PCNA and cyclinD1 were highly expressed in the lung of R4 KO mice than WT mice. PCNA positive cells were mostly type 2 pneumocytes.
To determine the susceptibility of lung cancer in R4 KO mice, we induced lung cancer by the injection of 1g/kg urethane weekly for a total of eight doses. Twenty weeks after the initial injection, mice were sacrificed, and the lungs were fixed, and the number of tumors on the lung surface was assessed. Also lung tumors were scanned by micro-CT at the end of the lung carcinogenesis protocol for measure the tumor diameter. Surface lung tumor number is significantly increased in KO mice. And tumor size is also significantly larger in KO mice than WT. Histological findings showed more severe well differentiated lung adenoma in urethane-injected R4 KO mice.
We conclude that R4 KO mice is susceptible to tumorigenesis in the urethane model and the functional loss of R4 gene may cause lung cancer. Therefore, R4 gene has a possibility as a potential target for chemoprevention of lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 257.
Abstract 2572: Quantitative proteomic and genomic analyses reveal that stress hormones induce a drug resistant phenotype of triple negative breast cancer cells treated with paclitaxel
Authors: Flint Melanie S. , Hood Brian L. , Bateman Nicholas W. , Conrads Thomas P. 
Published: February 2011

Abstract
Triple negative breast cancer (TNBC) is clinically characterized as an aggressive form of cancer which is unresponsive to hormone and trastuzumab based therapies and associated with poorer overall patient prognosis. TNBC can be treated with chemotherapeutic agents but unfortunately typically half of patients do not respond to treatment because their breast cancer cells become resistant. Recent evidence suggests that psychological distress in cancer patients equates to poor chemotherapeutic response, indeed the National Cancer Institute reports that 50% of cancer patients report anxiety due to the cancer diagnosis, the fear of dying and chemotherapy. Historically, single markers depicting breast cancer prognosis have failed to readily translate to the clinic therefore the expression pattern of multiple molecules may prove better predictors of drug resistance to chemotherapeutic agents. We hypothesize that drug resistance in breast cancer may arise in part due to stress hormone-induced alterations in intrinsic cellular proteins/genes in cancer cells. To examine the effects of stress, via stress hormones on drug resistance MDA-MB-231 breast cancer cells were incubated with paclitaxel in the presence of physiological concentrations of cortisol, norepinephrine and epinephrine for 48 h. We utilized a quantitative proteomic strategy, Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC), and LC-MS/MS to compare differences in protein abundance between paclitaxel-treated and stress hormone/paclitaxel-treated cells. For proteomic profiling, paclitaxel-treated cells cultured in unlabeled (no stress hormones) and labeled (stress hormones) SILAC media were mixed, lysed, and proteins were resolved by 1D-SDS PAGE, digested in-gel with trypsin and analyzed by LC-MS/MS. For genomic analyses, total RNA was isolated using TRIzol, cRNA was generated and hybridized to Affymetrix GeneChip HGU133 plus 2.0 arrays. We identified 220 proteins and 1201 genes whose expression levels were significantly altered by stress hormones. We further identified a unique molecular profile of predictive candidate biomarkers related to stress hormone- induced drug resistance including a significant decrease in the mitotic checkpoint serine/threonine-protein kinase BUB1 and the DNA damage response enzyme PARP-1, and increases in the immunophillin, FKBP-5 and the cell proliferation/apoptosis regulator C-MYC. In conclusion, our results demonstrate that stress hormones promote resistance to paclitaxel through modulation of several markers of drug resistance in TNBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2572.
Abstract 2575: Activation of antibody drug conjugate MDX-1203 by human carboxylesterase
Authors: Derwin Dan , Passmore David , Sung Janette , Tengco Daniel , Lee Brian , Aguilar Barbara , Chen Tim , Zhang Allen , Sufi Bilal , Cong Charlie , Salles Adam , Huber Mary , Stevens Alice , Rao Chetana , Gangwar Sanjeev , Deshpande Shrikant , Rangan Vangipuram S. 
Published: February 2011

Abstract
MDX-1203 is a human anti-CD70 antibody conjugated to a DNA alkylating cytotoxic Drug A. Drug A is an enzyme-activated prodrug that requires cleavage of its peptide linker and removal of an ester-linked protecting group for cytotoxic activity. Upon internalization of MDX-1203 in targeted cancer cells, peptide linker in drug A is cleaved by lysosomal enzymes to produce Drug B; which is further processed by intracellular enzymes to produce active drug. The purpose of this study was to determine if Drug B and n-acetyl-cysteine-conjugated Drug A (NAC-Drug A) are substrates of recombinant human carboxylesterase, and to determine kinetic parameters for the enzyme iso-forms rhCE1 and rhCE2. Furthermore, a comparison of rhCE1 and rhCE2 kinetics was made with CPT-11, a commercially available prodrug used to treat colon cancer that is preferentially activated by human CE2. Human carboxylesterase 1 and 2 with a C-terminal histidine tag were cloned and expressed in CHO cells. The enzymes were purified using immobilized metal ion affinity chromatography (IMAC), and their identities were confirmed by N-terminal protein sequencing and Western blot using an anti-his antibody. Enzyme reactions were carried out at 37°C by incubation with Drug A, NAC-Drug B, or CPT-11. The amount of enzymatically released drug product was determined by RP-HPLC. Drug B was determined to be a substrate for both rhCE1 and rhCE2; however, its Km was much lower with rhCE2 (1.5 uM) as compared to rhCE1 (53 uM), and the overall enzyme efficiency (Vmax/Km) was approximately 50 fold higher for rhCE2 as compared to rhCE1. Similarly, Drug B and NAC-Drug A were both found to be better substrates for rhCE2 as compared to rhCE1. Furthermore, recombinant human CE2 cleaves ester group in NAC-Drug A, 20 fold more efficiently as compared to CPT-11. These results indicate that expression of carboxylesterase 2 in targeted cancer cells is probably important for intracellular activation of MDX-1203.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2575.
Abstract 2579: Bax345/BLyS: A novel, completely human fusion construct targeting malignant B cells and delivering a unique mitochondrial toxin
Authors: Lyu Mi-Ae , Cheung Lawrence H. , Marks John W. , Rosenblum Michael G. 
Published: February 2011

Abstract
B lymphocyte stimulator (BLyS) is crucial for B-cell survival and the biological effects of BLyS are mediated by three cell surface receptors BAFF-R, TACI, and BCMA. Increased expression of BLyS and its receptors has been identified in diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). DLBCL and MCL are an aggressive sub-type of B-cell, non-Hodgkin's lymphoma (NHL). Despite recent advances in the understanding of the molecular and cellular basis for their pathogenesis, these tumors are still associated with poor response to treatment and a fatal outcome. Bcl-2 associated x protein (Bax) is a proapoptotic protein of the Bcl-2 family and is a gateway protein to mitochondria dependent apoptosis. We generated a highly cytotoxic fusion protein designated Bax345/BLyS for receptor-mediated delivery to malignant B cells. The Bax345/BLyS fusion protein has the BH3 and BH1 domains of Bax and contains full-length BLyS. This fusion protein was generated in bacteria and purified by IMAC. The final material was shown to be highly cytotoxic to activated B cell (ABC)-subtype DLBCL (IC50 ∼ 0.1 nM) and mantle cell lymphoma lines (IC50 ∼ 0.1-1 nM). The cytotoxic effects of Bax345/BLyS were inhibited by pretreatment with free BLyS demonstrating that the effects of the fusion construct are mediated through interaction with the BLyS receptors. Treatment of cells with Bax345/BLyS induced down-regulation of Akt, p-Akt, Mcl-1, and survivn and triggered accumulation of cells in the sub G1 phase of the cell cycle. In addition, treatment of cells with Bax345/BLyS induced up-regulation of Bax and apoptosis through caspase-3 activation, PARP cleavage, and DNA fragmentation. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of the pro-apoptotic molecule Bax345 to neoplastic B cells expressing the BLyS receptors, and Bax345/BLyS may be an excellent candidate for the treatment of the NHLs which are resistant to conventional chemotherapeutic regimens. This work was supported in part by the Clayton Foundation for Research and by LLS 6234-07 Translational Research Award from the Leukemia and Lymphoma Society.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2579.
Abstract 2584: The CEA/CD3-bispecific antibody MEDI-565 (MT111) binds a nonlinear epitope present in the full-length but not a short splice variant of CEA
Authors: Peng Li , Oberst Michael , Huang Jiaqi , Brohawn Philip , Lekstrom Kristen , Amann Maria , Baeuerle Patrick , Jallal Bahija , Trail Pamela , Wu Herren , Yao Yihong , Coats Steven , Dall”Acqua William , Damschroder Melissa , Hammond Scott A. 
Published: February 2011

Abstract
MEDI-565 (MT111) is a novel bispecific single-chain antibody of the BiTE (Bi-specific T-cell engager) class that transiently links carcinoembryonic antigen (CEA) on tumor cells with human CD3 on T cells. Engagement of CD3 and CEA by MEDI-565 induces T cells to kill CEA-positive cancer cells using similar elements and cellular machinery as required for T cells to kill through classic T cell receptor/major histocompatibility complex-peptide signaling. Examination of DNA sequence databases revealed a canonical CEA sequence (full length CEA; NCBI RefSeq NP_004354.2; 702 amino acids) and a previously uncharacterized shorter mRNA splice variant (short CEA; NCBI RefSeq CR749337420 amino acids) that lacks the second and third IgC-like domains and part of the N-terminal IgV-like domain. Expression of full-length CEA mRNA in colorectal, pancreatic, lung, and breast tumors was more widespread than that of short CEA; however, concordant expression of short CEA with the full length version was always observed. Mapping of the MEDI-565 binding region of CEA revealed a nonlinear, conformational epitope in the third immunoglobulin C-like domain. With a combination of deletion and swap variants, site directed mutagenesis, and computational homology modeling, we further identified the critical residues for MEDI-565 binding comprised of Phe292, Thr294, Asn299, Val354, Gly355, Pro356, Glu358, Ile374, and Asn376. CHO cells expressing only the short variant of CEA lacking this epitope failed to bind MEDI-565 and did not undergo T cell-directed lysis in the presence of MEDI-565. These studies suggest that MEDI-565 can discriminate between the full-length and short splice variant of CEA and may broadly target CEA-positive colorectal, pancreatic, lung, and breast tumors without regard for expression of the short splice variant of CEA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2584.
Abstract 2586: Adnectins as a platform for multi-specific targeted biologics: A novel bispecific inhibitor of EGFR and IGF-IR growth factor receptors
Authors: Emanuel Stuart L. , Engle Linda J. , Cao Carolyn , Chao Ginger , Lin Zheng , Zhu Rong-Rong , Yamniuk Aaron P. , Hosbach Jennifer , Brown Jennifer , Fitzpatrick Elizabeth , Gokemeijer Jochem , Morin Paul , Morse Brent , Carvajal Irvith , Fabrizio David , Wright Martin , DasGupta Ruchira , Gosselin Mike , Ryseck Rolf , Doyle Michael L. , Wong Tai W. , Camphausen Ray , Cload Sharon T. , Marsh Nick , Furfine Eric S. , Gottardis Marco M. 
Published: February 2011

Abstract
The epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGFR) are transmembrane receptor tyrosine kinases that mediate proliferative and invasive cell signaling in cancer. Inhibition of either receptor reduces tumor growth in both mouse models and in human clinical studies. Blocking the EGFR pathway can induce compensatory activation of the IGFR pathway to drive tumor growth and IGFR inhibition can result in activation of EGFR signaling in preclinical models. Therefore, blocking both receptors simultaneously may achieve superior efficacy to blocking either pathway alone. We developed individual optimized Adnectins™ specific for blocking either EGFR or IGFR signaling and engineered them into a single protein that linked both Adnectins together to construct a bi-specific Adnectin targeting the EGFR and IGFR (EI-tandem). The bifunctional molecule blocked activation of EGFR and IGFR, inhibited both EGF and IGF-induced down-stream cell signaling (MAPK and AKT pathways) and was antiproliferative in human cancer cell lines. Potency of the EI-tandem was comparable to anti-EGFR and anti-IGFR antibodies. The EI-tandem demonstrated a synergistic inhibition of IGFR phosphorylation and down-stream cell signaling compared to Adnectins specific for only EGFR or IGFR alone. Although Adnectins bound to the EGFR at a site distinct from the clinically approved anti-EGFR antibodies cetuximab, panitumumab and nimotuzumab, they still blocked binding of EGF to the EGFR. PEGylated EI-tandem inhibited the growth of human tumor xenografts driven by both EGFR and IGFR signaling, degraded EGFR and IGFR, and reduced phosphorylation of EGFR in tumors. Treatment of mice with EI-tandem caused increases in levels of the circulating ligands TGFα and IGF1 resulting from blockade of their respective receptors and provided convenient soluble biomarkers of target suppression. These results show that a bifunctional Adnectin can confer improved biological activity compared to monospecific biologics in tumors where growth is driven by multiple growth factors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2586.
Abstract 2588: Affitoxin - A novel approach to HER2-targeted therapy
Authors: Zielinski Rafal J. , Lyakhov Ilya , Kuban Monika , Capala Jacek 
Published: February 2011

Abstract
Expression of the human epidermal growth factor receptor 2 (HER2) is amplified in 25 −30% of breast cancers and has been associated with unfavorable prognosis. In spite of the development of new HER2-targeted therapies, such as trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA), which has revolutionized the treatment of HER2-overexpressing breast cancers, there is a significant number of patients with HER2-positive tumors who do not respond or acquire resistance to these therapies. An alternative treatment maybe constituted by immunotoxins. Immunotoxins are hybrid proteins composed of a targeting moiety such as an antibody, antibody fragment or ligand directed to an antigen or a receptor on the surface of tumor cells, and a toxic domain derived form plant (ricin) or bacteria (diphtheria toxin or Pseudomonas aeruginosa exotoxin A). The targeting moiety directs the toxin moiety to the tumor cell and, then, the active domain induces apoptosis by inhibition of protein synthesis. The PE38, which is a truncated version of Pseudomonas exotoxin A (PE), is preferred for construction of immunotoxin because its high toxic potential has been well documented and cytotoxic pathways described and understood.
Affitoxins are immunotoxin derivatives containing Affibody molecule as a targeting moiety instead of antibodies or antibodies fragments. Affibody molecules are a new class of relatively small (∼7-kDa) affinity proteins. Structurally, they are based on a 58-amino-acid scaffold, derived from the Z domain of the Staphylococcus aureus protein, and were obtained by combinatorial protein engineering.
Previously we reported construction, overxpression and characterization of Affitoxin targeting tumors with HER2 overexpression. Receptor-dependent binding and tumorocidal activity was confirmed on cell lines varying with receptor number. Both binding and toxicity was reverted when excess of Affibody molecules (acting as a competitor) was applied.
Here we report in vivo characterization of HER2 -Affitoxin. First we show that Affitoxin is well tolerated in athymic mice. Pharmacokinetic analysis indicates relatively short half-life of Affitoxin in the circulation most probably due to rapid renal clearance which seems to be compatible with fast binding of Affitoxin to HER2. Finally we show that HER2-Affitoxin is potent agent that leads to elimination of breast and ovarian xenografts (BT474 and SKOV3 s.c. tumors), while no such an effect was observed for off-target Affitoxin applied in the same concentration. Immunogenic potential of HER2 Affitoxin was also evaluated.
We conclude that our HER2-Affitoxin has potential to become an attractive alternative in treatment of tumors associated with expression of HER2 receptors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2588.
Abstract 2606: Absence of transcriptomic signature of response to chemotherapy in metastatic colorectal carcinoma patients
Authors: Laroche-Clary Audrey , Smith Denis , Laurand-Quancard Armelle , Evrard Serge , Robert Jacques , Morvan Valerie Le 
Published: February 2011

Abstract
Using whole genome tumour gene expression profiling in patients treated for metastatic colorectal cancer, we attempted to define a signature able to discriminate between responders and non-responders to first-line chemotherapy.
A total of 42 patients were prospectively included between 2003 and 2006. They all suffered from histologically proven colorectal adenocarcinoma and were metastatic at the time of diagnosis. All of them gave informed consent to the study. They were treated in first line with 5-fluorouracil (according to the de Gramont regimen in most cases) associated either with irinotecan (FolFiri regimen, 180 mg/m2 every two weeks, 22 pts) or with oxaliplatin (FolFox 4 regimen, 85 mg/m2, 20 pts) according to physician's decision. Response was evaluated using WHO criteria every 2 months after initiation of chemotherapy and patients were assigned to complete response (1 pt), partial response (24 pts), stable disease (13 pts) or progressive disease (4 pts).
From a tumour sample obtained at surgery (18 pts) or by biopsy (24 pts) and kept in RNA later, we extracted and purified total RNA. Gene expression profiling was performed by Cogenics using microarrays from Applied Biosystems (Human Genome Survey Microarray v2.0). We used three different methods for supervised data analysis: analysis of variance, SAM (statistical analysis of microarrays) and Limma (Bioconductor). We compared responders to non-responders in the whole set of patients and in the subsets of patients who received either irinotecan or oxaliplatin. With none of the three methods we were able to obtain a stable signature, i.e. a group of genes consistently associated with response to chemotherapy. On the contrary, we obtained very homogeneous gene expression profiles which were even difficult to clusterise using a non-supervised approach. These negative results show that the determinants of response to chemotherapy should be sought not only in the tumour molecular characteristics, but also among the processes leading to drug availability to the tumour (drug dose, drug disposition, etc.). Especially, the relatively low dose of irinotecan which is of standard use in Europe does not allow to recruit all the responders who could be identified at higher dosage, given the sharp dose-efficacy curve that has been identified long ago for this drug.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2606.