bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4629: Tumor penetration and retention of different sized FGFR4 targeting scaffolds
Authors: Muchekehu Ruth , Pirie-Shepherd Steven , Coronella Julia 
Published: August 2012

Abstract
Poor drug concentration, distribution and retention pose significant obstacles to effective therapy of solid tumors. Antibody based immunotherapies must balance pharmacokinetics (PK), molecular weight and potency in order to maximize tumor penetration and retention. Low molecular weight constructs may have superior tumor diffusion properties, but short in vivo half life, whereas whole IgG molecules have improved PK properties and slow heterogeneous penetration. We hypothesise a molecule with a mass of 100-150 kDa and a KD of 1- 10 nM will have the ideal characteristics for maximum tumor penetration. A CovX-Body is the fusion of two targeting moieties (typically a peptide; in this study an FGFR4 targeting peptide is used) with an IgG scaffold. Constructs with variable molecular weights and affinities for FGFR4 have been generated by enzymatic digestion of the CovX body. As measured by ELISA, surface plasmon resonance (SPR), and flow cytometry (FACS), the bivalent CovX-Body and F(ab)2 constructs had similar FGFR4 binding properties (KD = 0.7 nM and 0.8 nM respectively), while the monovalent Fab construct showed ∼10-fold decreased binding (KD =11 nM). Initial in vivo studies measured total tumor levels of the full length CovX-Body in Colo205 Xenografts 72 hours post-injection with various doses. CovX-body levels were measured using an anti-idiotype CovX-body ELISA. The FGFR4-targeting CovX-Body reaches 8-fold higher total tumor levels compared to non-targeting CovX-bodies following a 10 mg/kg dose. Tumor penetration into the centre of the tumor was also measured, and showed 16-fold higher levels of the targeted CovX-body in the centre of the tumor compared to the non-targeting. Future work will involve measuring the biodistribution and tumor penetration properties of the different constructs. Lower molecular weight constructs should rapidly achieve high but transient levels of drug within the tumor, while IgG should achieve longer term, but lower intratumoral concentrations.
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 4629. doi:1538-7445.AM2012-4629
Abstract 464: CXCR7 protein is strongly expressed in B-acute lymphoblastic leukemia (ALL) but not in T-ALL or acute myelogenous leukemia
Authors: Sridharan Santhi , Mirza Imran , Marquez-Curtis Leah A. , Turner A. Robert , Larratt Lorree , Shirvaikar Neeta , Surmawala Amir , Janowska-Wieczorek Anna 
Published: August 2012

Abstract
The identification of CXCR7 in addition to CXCR4 as a receptor for the chemokine CXCL12/SDF-1 and recent reports that CXCR7 is expressed in many cancers including breast, lung and prostate prompted us to evaluate the role of CXCR7 in hematological malignancies. While CXCR4 is known to be involved in the progression of acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML), the role of CXCR7 in leukemic dissemination remains unknown. Using immunohistochemistry, we evaluated the expression patterns of CXCR7 and CXCR4 in tissue microarrays (TMAs) constructed from bone marrow biopsies obtained from patients diagnosed with pre B- and B-ALL (n=75; median age 5 yrs, range 6 mo-72 yrs), T-ALL (n=11; median age 12 yrs, range 4-29 yrs) and AML (n=140; median age 62 yrs, range 1-83 yrs). CXCR7 expression was also evaluated at the gene and protein levels in peripheral blood mononuclear cells from ALL and AML patients and in B-cell lines (Raji, NC-37, Ramos, Nalm-6, Reh), T-cell lines (Jurkat, Hut-102B, Sez-4, CEM), and myeloid cell lines (KG-1, HL-60, THP-1, U-937, K562, HEL) using RT-PCR and flow cytometry. We found that in B-and preB-ALL TMAs, CXCR7 was immunopositive in 79% of the patients, in contrast to negative immunostaining in 100% of T-ALL and AML samples. Consistently, flow cytometry showed that CXCR7 protein is expressed on the surface of preB-ALL cells, but not on T-ALL, AML or normal controls. CXCR7 surface expression in the cell lines studied showed that three (NC-37, Raji, Reh) out of five B-cell lines expressed CXCR7, but not in any of the T-cell lines, and only weakly in one (KG-1) of six myeloid cell lines studied. Analysis of the functional role of CXCR7 in leukemia revealed that CXCR7 did not mediate chemotaxis of CXCR7-positive NC-37 B-cell line and CXCR7-negative HL-60 myeloid cell line towards an SDF-1 gradient. However, CXCR7 was found to mediate the trans-endothelial migration, adhesion to HUVEC and survival of NC-37 cells, but not the adhesion to HUVEC or survival of HL-60 cells. In conclusion, the selective strong expression of CXCR7 in B-ALL but not in T-ALL or AML suggests a differential role this protein may play in various types of leukemia. As CXCR7 mediates trans-endothelial migration, adhesion and survival of B-cell line, further investigations into the functional role of CXCR7 in primary B-ALL are warranted with the aim of identifying new therapeutic targets.
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 464. doi:1538-7445.AM2012-464
Abstract 4640: Development of antibody-drug conjugate technology based on novel DNA-interacting agents and unique linker technology
Authors: De Groot Vincent F.M.H. , Beusker Patrick , Joosten John , Spijker Henri , Coumans Ruud , Menge Wiro , Elgersma Ronald 
Published: August 2012

Abstract
Antibody-Drug Conjugation (ADC) is gaining momentum as a next generation antibody therapeutics approach in oncology. Tumor specific delivery of the cell-killing agent maximizes the agent's potency while avoiding damage to healthy tissue resulting in a high therapeutic window. Synthon's Potent Payload Technology comprises the combination of highly potent DNA-alkylating duocarmycin derivatives and unique releasable linker technology. Duocarmycin analogs and the CC-1065 derivatives represent a class of highly potent, cell-killing, DNA-alkylating, minor groove binding agents. This class is suitable to target solid tumors and has shown activity in a variety of Multi-Drug Resistant (MDR) models.Synthon SpaceLink technology is the only releasable linker technology for ADC that can couple the toxin via its hydroxyl group to the antibody, validated in vivo. Synthon has combined its linkers with duocarmycin derivatives that have a hydroxyl group crucial for biological activity. The data package to be presented supports that SpaceLink and duocarmycins form an excellent chemical match for ADC therapy, possessing an intrinsic complementarity. Strong in vivo Proof of Concept with Potent Payload ADCs has been obtained against multiple targets. In human tumor xenograft models, substantial efficacies have been obtained based on low, single dose treatments, with minimal or absent side effects. We discuss applicability and several other aspects of multiple, validated Potent Payload-based Antibody-Drug Conjugates (ADCs). Latest results of preclinical development progress (in vivo efficacy, safety, etc.) will be presented, including in vitro drug and ADC potencies, plasma stabilities, cathepsin cleavage kinetics, linker cyclization kinetics and in vivo therapeutic window aspects for ADCs directed against HER2 and potentially other (collaborator) targets.
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 4640. doi:1538-7445.AM2012-4640
Abstract 4647: Caspase-dependent post-translational modulation of Mcl-1 by ABT-737 in acute lymphoblastic cell lines
Authors: Ryu Yong-Ku , Kang Min H. 
Published: August 2012

Abstract
Background: ABT-737 is a BH3-mimetic that has a wide spectrum of single-agent activity against acute lymphoblastic leukemia (ALL) cell lines and xenografts. Previously (J Nat Cancer Inst 100:580-595, 2008), we reported that Mcl-1, an anti-apoptotic Bcl-2 family protein that is not inhibited by ABT-737, decreased in response to ABT-737 in ABT-737-sensitive ALL cell lines while a reactionary Mcl-1 increase is observed in ABT-737-resistant cell lines. In the current study, we investigated the pathways of Mc-1 down-regulation in response to ABT-737 in ALL cell lines. Methods: To identify caspase cleavage sites and to determine whether the cleavage products are pro-apoptotic or anti-apoptotic, we transduced into the NALM-6 ALL cell line lentiviral vectors with several Mcl-1 variants tagged with V5 epitope, including wild type: Mcl-1 1-350 full length tagged with V5, point mutations at aspartate 127 and aspartate 157 to alanine: Mcl-1 D127A and Mcl-1 D157A, and C-terminus fragments of caspase cleavage, deleted: Mcl-1 β127 and Mcl-1 α157. Localization of Mcl-1 1-350 and Mcl-1 β157 in ALL cells, cytosol and mitochondria were fractionated from the cells expressing the proteins, and Mcl-1 and V5 were assayed in the fractions. Results: The decrease in Mcl-1 by ABT-737 in ABT-737-sensitive cell lines was via formation of an Mcl-1 fragment which is prevented by a caspase inhibitor (Boc-d-fmk), but not a proteosome inhibitor (MG-132), indicating that Mcl-1 cleavage is caspase-dependent. Of the two caspase-dependent Mcl-1 cleavage sites (D127 and D157), D157 is the major site of cleavage in response to ABT-737 treatment in ALL cells. Localization experiments revealed that full length Mcl-1 resides in both the cytosol and mitochondrial fractions, while the Mcl-1_158-350 fragment localizes mostly to mitochondria. Caspase 3- and caspase 9-activation in response to ABT-737 was higher in transduced cells expressing the Mcl-1 β157 fragment, suggesting that the fragment increases sensitivity to apoptotic stimuli. Pretreating cells with okadaic acid, a protein phosphatase inhibitor, resulted in greater fragmentation of Mcl-1 in resistant cell lines while the effect of okadaric acid was minimal in a ABT-737-sensitive cell line, suggesting that dephosphorylation makes Mcl-1 more susceptible to Mcl-1 cleavage in response to ABT-737. Conclusion: Mcl-1 is cleaved to Mcl-1 β157 by caspases in ALL cells that are treated with ABT-737, and the pro-apopoptotic activity of Mcl-1 β157 contributes to a vicious cycle promoting cell death.
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 4647. doi:1538-7445.AM2012-4647
Abstract 4665: Sensitization of head and neck cancer cells toward cisplatin by inhibition of autophagy
Authors: Guo Changxiong , Rao Krishna , Robbins Thomas , Nie Daotai 
Published: August 2012

Abstract
Cisplatin is a commonly used chemotherapeutics but its efficacy is limited by the resistance presented by some tumor cells. Autophagy is a form of cell death by self-digesting organelles. The present study was undertaken to examine whether cisplatin can induce autophagy and whether autophagy modulates the efficacy of cisplatin against head and neck squamous cancer cells (HNSCC). In responses to increasing doses of cisplatin, there was a steady increase in autophagy, as indicated by LC3 punctate staining, in a cisplatin resistant UMSCC-15S cell line, whereas induction of autophagy was rapidly peaked at low doses of cisplatin in the UMSCC-10B cell line which was more sensitive toward cisplatin. Further studies found that there were increased autophagic fluxes at basal level in the cisplatin sensitive UMSCC-10B cells when compared to cisplatin resistant UMSCC-15S cells. Inhibition of autophagy by chloroquine significantly reduced colony formation of both cell lines, and sensitized UMSCC-15S cells toward cisplatin treatment. Our studies suggest that autophagy responses can be modulated to augment the efficacy of cisplatin against HNSCCs.
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 4665. doi:1538-7445.AM2012-4665
Abstract 4669: A combination of raloxifene and gefitinib potentiates the cytotoxicity and induces apoptosis in estrogen receptor negative breast cancer cell lines
Authors: Taurin Sebastien , Yadav Babasaheb D. , Nimick Mhairi , Rosengren Rhonda J. 
Published: August 2012

Abstract
In recent years, numerous studies have shown that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of invasive breast carcinoma. However, while SERMs do prevent the development of many estrogen-receptor (ER)-positive breast cancers, few studies suggest a potential effect of these drugs in the prevention of the development of ER-negative breast cancers. Although, the therapeutic efficacy of raloxifene in cancer therapy is thought to arise primarily from its ability to compete with estrogens; raloxifene has been shown to have effects through estrogen receptor (ER)-independent mechanisms. Recently, a study perform in our laboratory demonstrated that raloxifene decreased the level of EGFR expression in xenograft tumors. Based on these results, we hypothesized that a combination of raloxifene and a tyrosine kinase inhibitor, gefitinib may improve cytotoxicity towards ER-negative breast cancers. In the present study, we show that raloxifene (5µM) in combination with gefitinib (10µM) further decrease cell viability of two human ER-negative breast cancer cell lines, MDA-MB-468 and MDA-MB-231, compare to a single treatment from either of these two drugs. The combination potentiates apoptosis in MDA-MB-231 by 6 fold and in MDA-MB-468 by 3 fold after 36 h. Expression and phosphorylation pattern of proteins involved in cell proliferation such as NFκB, β-catenin, epidermal growth factor (EGFR) were also markedly affected by the combination treatment. Furthermore, evidence of apoptosis activation was also observed by an increase of the cleaved form of caspase-3. Additional studies demonstrated that the combination decreased cell migration and tumorigenicity of breast cancer cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. All together, these results suggested the potential of the combination of gefitinib and raloxifene for the prevention of tumor growth and appearance of metastatic events. In conclusion, these results provide us with the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.
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 4669. doi:1538-7445.AM2012-4669
Abstract 4672: Anti-angiogenic effects of zoledronic acid on osteotropic breast cancer cells
Authors: Contreras Cynthia , Morshedian Shaghayegh , Hamud Walid , Dhakal Bishal , Khanal Bijay , Bush Jason A. 
Published: August 2012

Abstract
Emerging data suggest the bisphosphonate, zoledronic acid (ZOL), exerts both indirect and direct anti-tumor effects by decreasing tumor cell proliferation, increasing apoptosis, and inhibiting angiogenesis. Recent data indicate that anti-angiogenic factors exert cellular effects via suppression of mitochondrial oxidative phosphorylation/respiration and elevation of intracellular ROS levels. This project intended to define proteins involved in response to ZOL-treatment of an osteotropic breast cancer cell line, MDA-231BO. Results demonstrate that MDA-231BO cells are more sensitive to ZOL cytotoxicity and salutary effects are both media- and calcium-dependent. To investigate pro-apoptotic mechanisms of ZOL, total RNA, whole cell protein lysates, or mitochondrial-enriched fractions were isolated from MDA-231BO cells and using a combination of RT-PCR, 1D/2D-PAGE separation and MALDI-MS/MS, we identified several angiogenesis inhibitors that were upregulated and pro-angiogenic factors that were downregulated after ZOL treatment. Functional studies demonstrate the improved efficacy of ZOL on MDA-231BO compared to MDA-MB-231 controls. Taken together, these results further support a model that ZOL tips the ‘angiogenic switch’ in favor of anti-angiogenic factors in cancer cells with a propensity for bone metastases.
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 4672. doi:1538-7445.AM2012-4672
Abstract 4813: EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors
Authors: Morel Anne-Pierre , Thomas Clémence , Hinkal George , Fauvet Frederique , Courtois-Cox Stephanie , Wierinckx Anne , Devouassoux-Shisheboran Mojgan , Tissier Agnes , GRAS Baptiste , Pourchet Julie , Puisieux Isabelle , Browne Gareth , Spicer Douglas B. , Lachuer Joel , Ansieau Stephane , Puisieux Alain 
Published: August 2012

Abstract
The malignant transformation of human epithelial cells is generally described as a multistep process resulting from the accumulation of five to seven rate-limiting changes. Here, we challenge this dogma and demonstrate that this number is radically reduced when cells undergo an epithelial-mesenchymal transition (EMT). EMT is an embryonic transdifferentiation process that consists of the conversion of polarized epithelial cells into motile mesenchymal ones. EMT-inducing transcription factors, including Twist and Zeb proteins, are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. We demonstrate that, beyond their prometastatic potential, EMT inducers also act as potent drivers of tumorigenesis. We indeed show that the Twist1 EMT-inducing transcription factor promotes breast and skin cancer development in vivo in cooperation with the K-RasG12D oncoprotein. Importantly, in the model of breast tumorigenesis, transgene expression in differentiated mammary epithelial cells leads to the development of undifferentiated tumors exhibiting all the characteristic features of the claudin-low subtype. These observations challenge the concept that this tumor subtype specifically arises from transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Consistently, oncogenic cooperation assays performed in human mammary epithelial cells with Twist or Zeb EMT-inducers in combination with H-RasG12V generate transformed cell lines displaying all characteristics of claudin-low tumors including mesenchymal features, undifferentiated traits, and stem-cell-like properties. EMT might thus drive the development of claudin-low tumors by exhibiting a dual role in cell transformation and dedifferentiation. In other terms, the claudin-low tumor subtype of breast cancers might thus constitute a first example of human adult malignancies driven by aberrant reactivation of an embryonic transdifferentiation program.
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 4813. doi:1538-7445.AM2012-4813
Abstract 4835: Genetic determinants of mTOR inhibitor response in breast and endometrial cancer
Authors: Weigelt Britta , Warne Patricia H. , Lambros Maryou , Reis-Filho Jorge S. , Downward Julian 
Published: August 2012

Abstract
Background: Breast and endometrial cancers frequently harbour genetic aberrations that result in increased activation of the PI3K-AKT-mTOR signalling pathway including amplification and overexpression of receptor tyrosine kinases, activating PIK3CA mutations, and inactivating PTEN mutations or loss of PTEN function. Given the pivotal role of the PI3K-AKT-mTOR pathway in cancer cell growth and survival, inhibitors of several of its components are currently being tested in clinical trials. The aim of this study was to define the genetic determinants of mTOR inhibitor response in breast and endometrial cancer cells. Methods: A panel of 31 breast and 26 endometrial cancer cell lines was treated with serial dilutions of ‘rapalogs’ (i.e. allosteric inhibitors of mTOR complex 1 (mTORC1)) and mTOR kinase inhibitors targeting mTORC1 and mTORC2. Cell viability was determined using CellTiter Blue. PTEN protein levels and mutations in PTEN transcripts were assessed in all cell lines using western blotting and Sanger sequencing, respectively. PIK3CA mutations were assessed using Sanger sequencing in the breast cancer cells, and hot-spot mutations in PIK3CA and 18 additional oncogenes using the Sequenom OncoCarta Panel v1.0 in the endometrial cancer cells. Results: Response of breast cancer cells to both the rapalog everolimus and the mTOR kinase inhibitor PP242 was determined by the presence of activating PIK3CA mutations but not PTEN loss of function. In addition, PP242 treatment induced a more efficient response in HER2-amplified breast cancer cell lines, irrespective of the PIK3CA mutation status. By contrast, endometrial cancer cell lines not only harbouring mutations in PIK3CA but also in PTEN were sensitive to treatment with the rapalog temsirolimus. The mTOR kinase inhibitor AZD8055 induced a strong reduction in cell viability in all endometrial cancer cell lines tested. Conclusions: Our results suggest that response to mTOR inhibitors in breast and endometrial cancer cells may be determined by the presence of alterations affecting PIK3CA and PTEN. Our data further indicate, however, that the epistatic interactions between different components of the PI3K-AKT-mTOR pathway are distinct in cancers of the breast and endometrium.
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 4835. doi:1538-7445.AM2012-4835