bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4764: Targeting formin autoinhibition to construct cell infrastructure
Authors: Lash-VanWhye Leanne , Kitchen-Goosen Susan , Alberts Arthur S. 
Published: August 2012

Abstract
Rho small GTP-binding proteins locally manage Diaphanous-related formins as they construct the cytoskeletal infrastructure that supports essential changes in cell morphology. Rho binding unlatches formin intramolecular autoinhibition. The autoinhibition is mediated by the Dia-inhibitory and -autoregulatory domains (DID & DAD) which flank the formin homology-2 (FH2) domain. The free FH2 domain guides the assembly of the linear actin and microtubule structures required for adhesion, migration, division, and polarity establishment. Microtubule stabilization is already known to be an effective anti-cancer strategy. Combined with the knowledge that formins can act as haploinsufficient tumor suppressor genes, a screen was conducted for agents that could impair autoinhibition in order to activate formins for therapeutic benefit. We have focused on two of the primary “hits” for development. VARI01 and VARI02 are nearly identical thioamide inhibitors of DID-DAD binding (IC50 values ≤ 140 nM). Exposure of cultured tumor cells to either compound triggered the expected changes in cell structure and signaling that were consistent with formin activation. These included microtubule stabilization, F-actin assembly, the activation of the transcription factor SRF, cell-cycle arrest, and eventual apoptosis. SRF senses changes in actin dynamics to activate the expression of genes that reinforce cell structure and monitor genome integrity. VARI01 and VARI02 both exhibit anti-tumor activity in xenograft studies. Ongoing studies are aimed at identifying VARI01/VARI02-sensitive tumor types and to define other potential therapeutic applications. Significance: Microtubule stabilization by taxol has proven to be an effective anti-cancer strategy, but it has significant deleterious side effects. Small-molecule formin activation serve as a novel class of anti-cancer agents that may provide tools for unlocking the biological roles of formins in signalling and disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4764. doi:1538-7445.AM2012-4764
Abstract 4770: Delivery of doxorubicin to multi-drug resistant murine xenografts via drug-loaded micelles formed from mixtures of amphiphilic triblock copolymers
Authors: Dulken Benjamin , Kim Tae Hee , Mount Christopher , Du Mengyuan , Gombotz Wayne , Pun Suzie 
Published: August 2012

Abstract
BACKGROUND: The toxicity of chemotherapeutic drugs is often the limiting factor in patient dosing and can be the source of severe discomfort and suffering for patients undergoing chemotherapy. For example, the anthracycline antibiotic doxorubicin (DOX) is a potent chemotherapeutic but prolonged use can also lead to permanent heart damage. Tumors can also develop resistance to DOX by increased expression of drug efflux pumps. Nanoparticle formulations of DOX have been reported to improve tumor-specific delivery via the enhanced permeability and retention (EPR) effect. METHODS: In this work, we have encapsulated DOX in polymeric micelles formed from mixtures of amphiphilic triblock copolymers. The copolymers are composed of a hydrophobic polymer segment flanked by two hydrophilic blocks. Two different copolymers were used to form the mixed micelles: a copolymer of poly(ethylene oxide) and poly(hydroxybutyrate) (PEO-PHB-PEO), and a copolymer of poly(ethylene oxide) and poly(propylene oxide) (Pluronic F127). We hypothesize that forming mixed micelles will improve drug loading and enable preparation at room temperature (where Pluronic F127 micelles are highly unstable), while facilitating drug delivery by utilizing the stability of Pluronic F127 micelles at physiological temperatures. RESULTS: We have demonstrated that the micelles formed from the mixtures of PEO-PHB-PEO and Pluronic F127 triblock copolymers provide a combination of high drug loading content and drug delivery capabilities. DOX loading for mixed micelles was greater than that for Pluronic F127-only micelles (p&lt;0.05 for all mixture ratios). DOX encapsulated in mixed micelles demonstrated increased uptake in a drug resistant MDA-435-MDR cell line over free doxorubicin (p&lt;.05 for all mixture ratios), while cytotoxicity of the micelle treatment was approximately equivalent to that of the free drug. Tumor treatment efficacy was assessed in mice with subcutaneous dual xenografts of MDA-435 and MDA-435-MDR (drug resistant) cell lines. Tumor suppression of drug resistant tumors was similar for encapsulated and free drug, but mice treated with micellar DOX showed no significant weight loss after treatment, while mice treated with unencapsulated DOX experienced severe weight loss after one week when compared to initial time point (18.2% +/− 2.1% weight loss, p = .0009). CONCLUSION: The cytotoxicity, drug uptake, and tumor suppression properties demonstrated by PEO-PHB-PEO/Pluronic F127 mixed micelles supports their viability as chemotherapeutic drug delivery systems for drug resistant tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4770. doi:1538-7445.AM2012-4770
Abstract 4779: K-983, an orally available small molecule inhibitor of FGFR, demonstrated prolonged survival in a mouse orthotopic gastric cancer model
Authors: Furuta Takayuki 
Published: August 2012

Abstract
The receptor tyrosine kinase FGFR and its ligand fibroblast growth factor (FGF) play important roles in cell growth, migration, and survival. Dysregulation of the FGFR/FGF signaling pathway has been found in many human malignancies. K-983 was identified as a novel, potent, and orally active small molecule inhibitor of FGFR. The anti-tumor activity of K-983 was evaluated in a rat xenograft models. K-983 displayed dose dependent anti-tumor efficacy. K-983 demonstrated dose dependent inhibition of FGFR phosphorylation and prolonged survival in a mouse peritoneal dissemination model of gastric cancer. Furthermore, K-983 was examined using an orthotopic model of human scirrhous gastric cancer in nude mouse. K-983 (80 mg/kg) was orally administered once daily to the mice for 28 days. Histopathological examination revealed that K-983 inhibited tumor growth at inoculated site, invasion in gastric wall and metastasis to other organs. K-983 also significantly prolonged the survival of mice in this orthotopic tumor model. In summary, these results demonstrated the promising therapeutic potential of K-983 in anticancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4779. doi:1538-7445.AM2012-4779
Abstract 4782: Two-dimensional gel analysis of protein expression profile in patients with invasive squamous cell carcinoma of the uterine cervix for identification of differentially expressed proteins in relation to response to radiation therapy
Authors: Srinivasan Radhika , Sood Swati , Ghosh Sujata , Patel Firuza 
Published: August 2012

Abstract
Background: Cancer of uterine cervix is the second most common cancer and an important cause of cancer related mortality among women worldwide. These patients are treated by chemoradiation, response to which is a major factor affecting their outcome. Objective: To identify differentially expressed proteins in the tissue biopsies of patients with invasive cervical cancer by two-dimensional gel electrophoresis [2-DE] and correlate it with their clinical outcome. Methods: After an informed consent, 10 patients of invasive squamous cervical cancer, stage IIB, between 40-50 years treated with chemoradiation as per standard protocol were recruited. Based on the 24 month-outcome, there were two groups (N=5): i) Evidence of disease (ED) and ii) No evidence of disease (NED). Pooled protein from the tissue biopsies were subjected to 2-DE using pH 3-10 IPG strips of 7cm length, silver stained and expression profile compared using Image Master 7.0 software (GE Healthsciences). The differentially expressed protein spots were identified and isoelectric point (pI) & Molecular Weight (MW) was determined from the plot of relative electrophoretic mobility (Rf) values of the marker against their respective molecular weight and the plot of pI marker against their respective distance from the anode respectively. The TagIdent software was used for their identification. Results: Out of a total of 327 spots identified, 89 spots showed differential expression, of which 40 were highly significant (ANOVA p &lt;0.03) between ED vs NED groups. Conclusion: 2-DE has provided preliminaryinformation regarding differentially expressed proteins which may help identify biomarkers for prediction of outcome in patients with invasive cervical cancer which needs further confirmation. Differentially expressed proteins in NED vs ED groups in invasive cervical cancer

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4782. doi:1538-7445.AM2012-4782
Abstract 4786: Biomarkers for lung adenocarcinoma in salivary proteome
Authors: Villagomez Jose Guillermo , Castellanos Lyssia , Ortega Alette , Zavala Diego , Ponciano Guadalupe , Arrieta Oscar G. , Reyes Juan Pablo , Mercado Gabriela E. 
Published: August 2012

Abstract
Lung cancer is the major cause of cancer-related deaths and has a poor prognosis with a 5-yr overall survival of &lt;10%, mostly due to lack of early stage diagnosis. Cigarette smoking is estimated to be responsible for &gt;80% of the cases. Previous studies have demonstrated that former smokers have a higher risk of lung cancer compared to nonsmokers. Early detection of lung cancer would improve the overall survival of this disease. However, there is no validated screening test for lung cancer. To develop an early detection test, we selected saliva as the biofluid of choice due to its accessibility, protein content that provides diagnostic information on a variety of diseases, including cancer. To identify differentially expressed proteins in saliva from individuals with lung adenocarcinoma, whole saliva samples were collected from 6 patients with lung adenocarcinoma and 6 matched healthy controls (male individuals, &gt;40 years, smokers &gt;10 pack year). Proteins and peptides from whole saliva samples were analyzed by two-dimensional gel electrophoresis identifying 20 differentially expressed protein spots. Mass spectrometry analysis identified 63 peptides and revealed fourteen non-redundant proteins in saliva obtained from lung adenocarcinoma patients. Four of these proteins have been previously reported as serum biomarkers of cancer, and two of them were associated with non-small cell lung cancer. These potential biomarkers are being tested in an independent and larger cohort for validation. Patient-based saliva proteomics is a promising approach to searching for cancer biomarkers. Further characterization of these markers may provide the basis for new, noninvasive tests for screening, detection, and monitoring of high-risk individuals.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4786. doi:1538-7445.AM2012-4786
Abstract 4863: Ubiquitination of the breast cancer oncogene IKKα is essential for transformation
Authors: Zhou Alicia Y. , Shen Rhine R. , Kim Eejung , Chen Zhijian , Hahn William C. 
Published: August 2012

Abstract
IKBKE (IKKα) is a breast cancer oncogene that promotes human mammary cell transformation through the activation of the NF-κB pathway. Here we show that IKKα is modified by ubiquitination in the context of cell transformation. By mass spectrometry, we identified three lysine residues of IKKα that are ubiquitinated - Lysine30, Lysine401, and Lysine416. Mutation of all three lysine residues together eliminates IKKα ubiquitination. Single mutations of the three lysines revealed that K30 and K401 are essential for IKKα-induced malignant transformation. Although wildtype IKKα drives transformation in immortalized human cells, the IKKα K30R and IKKα K401R mutants fail to transform immortalized human cells. In addition, the IKKα K30R and IKKα K401R mutants fail to activate the NF-κB pathway and are unable to phosphorylate CYLD, a downstream target of IKKα. The ubiquitination of IKKα does not affect the protein stability of IKKα protein. Using an inducible ubiquitin-knockdown U2OS cell system, we show that IKKα specifically undergoes K63-linked polyubiquitination, a proteasome- and degradation-independent form of ubiquitination. Taken together, these data provide evidence that IKKα is subject to direct regulation by K63-linked polyubiquitination and that this ubiquitination is essential for IKKα-mediated oncogenic transformation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4863. doi:1538-7445.AM2012-4863
Abstract 487: Invasion characteristics of tumor cells in a glioblastoma model of genetically modified neural stem cells
Authors: Sampetrean Oltea , Saga Isako , Osuka Satoru , Saya Hideyuki 
Published: August 2012

Abstract
Background: Although several types of cells in the brain are able to migrate during development or even in adulthood, only cells of high grade malignancies exhibit an invasive phenotype. The present study aims to characterize the differences between infiltrating tumor cells and their cells of origin using a model of genetically-induced glioblastoma-initiating cells (GICs) in the syngeneic mouse adult brain. Methods: Neural stem cells/ multipotent progenitor cells (NSCs/NPCs) were isolated from the subventricular zone of adult C57BL/6 mice with a homozygous deletion of the Ink4a/ARF locus and cultured as neurospheres. GICs were established by overexpression of H-RasV12 in the NSCs/NPCs. Tumor cells were isolated from the tumors formed by orthotopic implantation of the GICs into 6-week-old wild type mice and propagated as tumorspheres (TS). The motility of each type of cells and their response to various chemoattractants was assessed using in vitro migration assays. Their preference for anatomical structures and their ability to infiltrate the surrounding normal brain was analyzed by tracking the cells in cultured coronal brain slices established from stereotactically-implanted mice. Results: In vitro, both tumor cells and NSCs exhibited a similar degree of motility, but consistently varied in their response to a panel of chemoattractants. Compared to NSCs, GICs and TS responded only slightly to single growth factors or cytokines, but showed significant responses to combinations of chemoattractants. The most marked increase in migration was triggered by the supernatant of cultured tumor cells. Supernatants obtained from GICs, TS or human glioma cell lines induced migration to a similar degree. Timelapse microscopy confirmed motility of both normal and tumor cells, with all three groups being able to move both within the cortex and within the striatum, and both along blood vessels and fiber tracts. However, NSCs/NPCs did not leave the injection site as single cells, while GICs and TS entered and infiltrated the normal brain as solitary cells. This pattern of migration was greatly reduced by the administration of epithelial-to-mesenchymal transition (EMT) inhibitors, both in vitro and in vivo. Conclusion: Our results show that tumor invasion is multifactorial, with both autocrine secretion of several factors, as well as a mesenchymal phenotype being key regulators. Moreover, the mesenchymal phenotype in itself is a targetable attribute and should be assessed in patient samples in order to adjust anti-invasive therapy when warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 487. doi:1538-7445.AM2012-487
Abstract 4874: Small molecule inhibitor of ezrin inhibits metastasis in a transgenic mouse model of osteosarcoma
Authors: Murdoch Jared T. , Hong Sung-Hyeok , Bulut Gulay , Kosturko George W. , Drebing Lauren E. , Toretsky Jeffrey A. , Uren Aykut 
Published: August 2012

Abstract
Osteosarcoma is the predominant primary bone cancer in children with a low survival rate due to pulmonary metastasis. Research on the molecular mechanism driving pulmonary metastasis implicates the cytoskeletal protein ezrin as the critical component of the disease pathology. Ezrin links the actin cytoskeleton to the plasma membrane proteins, and its overexpression is associated with poor survival in patients and increased invasion in osteosarcoma cell lines. We used surface plasmon resonance technology to screen small molecule libraries for compounds directly binding to ezrin. Two molecules, NSC305787 and NSC668394, were chosen based on their ezrin binding affinities and ability to inhibit ezrin in multiple functional, biochemical, cellular, and in vivo assays. To test the anti-metastatic activity of these molecules in vivo, we utilized a tissue-specific transgenic mouse model expressing Cre recombinase to excise the Retinoblastoma (Rb) and p53 tumor suppressor genes in osteoblast progenitor cells. These animals develop spontaneous osteosarcoma with 100% penetrance and high frequency of liver and lung metastases, mimicking human disease. We tested the anti-metastatic potential of ezrin inhibitors that we discovered, NSC305787 and NSC668394, in this clinically relevant mouse model. We started the treatment on one group of animals at 2 months of age before any detectable tumor is present and on a second group of animals only after detection of smallest palpable tumor. Animals in each group were randomly assigned to one of three treatment options: DMSO (Control), NSC305787, or NSC668394. Animals were observed for primary tumor growth and metastasis formation. All animals were euthanized when primary tumor volume reached 2.0cm3, when animals had severe cachexia, or when animals showed signs of pulmonary insufficiency. Mice treated with NSC305787 and NSC668394 did not show any changes in the growth of their primary tumors and experienced similar survival times. However, our results suggest that NSC305787 inhibits osteosarcoma metastasis to lungs as confirmed by histopathological analysis. Therefore, when combined with adjuvant chemotherapy and surgical resection of the primary tumor, targeting ezrin with small molecules may yield a positive outcome and greater survival in a clinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4874. doi:1538-7445.AM2012-4874
Abstract 4881: Induction of Bim by the BRAF inhibitor PLX4720 sensitizes human melanoma cells to the BH3 mimetic ABT-737
Authors: Wroblewski David , Zhang Xu Dong , Hersey Peter 
Published: August 2012

Abstract
Once melanoma has metastasized to distant sites it has proved difficult to treat by a variety of chemotherapeutic and biological agents. Significant advances have been made in identifying subgroups of patients with activating mutations in signalling pathway proteins. In particular, the finding that approximately 50% of melanoma have V600E mutations in the BRAF serine/threonine kinase has resulted in the generation of a number of new drugs which target the mutated active form of BRAF. One of these drugs, Vemurafenib (PLX4032/RG704) has shown significant promise in prolonging survival compared to standard chemotherapy, however reports of patient relapse has prompted investigation into means of overcoming acquired resistance to the agent. We report here that efficacy of the PLX4032 analogue, PLX4720, is greatly enhanced by co-treatment with the BH3 mimetic, ABT-737. Treatment with either agent is able to induce apoptosis in melanoma cells, however the kinetics are typically slow, with cell death occurring 48 or 72 hours post treatment. In this study, while either agent was largely ineffective as a single treatment 24 hours following treatment, addition of the combination of drugs rapidly induced significant killing. We show that apoptosis was caspase-dependent, in that inhibition of caspase activation almost totally blocked induction of cell death by the combination of agents. Apoptosis was also associated with activation of the intrinsic apoptotic pathway, with reduction of mitochondrial membrane potential and activation of caspase-9. Exposure of melanoma cells to PLX4720 rapidly decreased phosphorylation of the pro-apoptotic BH3-only protein Bim, resulting in strong upregulation as early as 6 hours after addition of the compound. Strong upregulation of Bim was shown by RNAi knockdown to play an important role in sensitizing cells to co-treatment with ABT-737, by assisting in the inhibition of anti-apoptotic Bcl-2 family proteins. Further, the combination of agents induced significant levels of apoptosis in melanoma cells derived from patients harbouring the BRAFV600E mutation. Collectively, these results show that the BRAF inhibitor PLX4720 sensitizes melanoma cells to apoptosis by the BH3 mimetic ABT-737 in a Bim- and caspase-dependent manner. Additionally, these studies identify a potential clinical application for BH3 mimetics in overcoming resistance of melanoma to treatment with BRAF inhibitors, increasing efficacy of this class of agent and improving patient outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4881. doi:1538-7445.AM2012-4881