bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2849: Optimization and pharmacokinetic characterization of potent CXCR4 antagonist CovX-Bodies
Authors: Coronella Julia A. , Fu Yanwen , Johnson Kim , Sakamuri Sukumar , Rizzo John , Willhite Dorian , Rosario Joselyn Del , Doppalapudi Venkata , Bhat Abhijit , Levin Nancy 
Published: August 2012

Abstract
Here we describe a series of CXCR4 antagonist CovX-Bodies, produced by covalently attaching CXCR4 antagonist peptides to a humanized IgG1 molecule with the goal of producing molecules with the potency and specificity of peptides and the pharmacokinetic parameters of an antibody. Extensive SAR was performed on peptides derived from T140, a highly charged 14 amino acid cyclic peptide containing 4 Arginine residues. Both the free peptides and the associated CovX-bodies were potent antagonists of CXCR4 in vitro, and SAR studies were consistent with a model of both allosteric and orthosteric inhibition. However, in vivo pharmacokinetic (PK) studies revealed an unexpected and CXCR4-independent disappearance of the CovX-Bodies from circulation, such that approximately 10% of the injected CovX-Body remained in circulation 1 hour after i.v. injection into mice. Based on the known nonspecific cell-penetrating properties of Arginine-rich peptides, we hypothesized that Arginine replacement and charge neutralization would improve the pharmacokinetics of the CovX-Bodies. We identified substitutions that could replace up to 3 of the 4 Arg residues while retaining potent CXCR4 binding and antagonism, but Arg2 was obligate. However, these CovX-Bodies were only modestly improved in PK, indicating that that the anomalous in vivo behavior was not solely a function of charge or the net number of Arg residues. Only the replacement of Arg2 significantly improved the pharmacokinetics of the CovX-Bodies, but also resulted in a loss of CXCR4 antagonism. Extensive SAR failed to identify a suitable replacement residue for Arg2, nor did alternative structural forms such as 5 member, bicyclic, or reversed ring molecules have significantly improved pharmacokinetics. Based on these data, we conclude that the specific property of the peptide that allows potent inhibition of CXCR4, of which Arg2 is an integral component, also mediates binding to moieties other than CXCR4, leading to the depletion of these molecules from circulation.
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 2849. doi:1538-7445.AM2012-2849
Abstract 2850: Demonstration of anti-tumor efficacy in multiple preclinical cancer models using a novel peptide inhibitor (Aurigene-012) of the PD1 signaling pathway
Authors: Sasikumar Pottayil G. , Satyam Leena K. , Shrimali Rajeev K. , Subbarao Krishnaprasad , Ramachandra Raghuveer , Vadlamani Sureshkumar , Reddy Amarnadh , Kumar Aswani , Srinivas Adurthi , Reddy Subba , Gopinath Sreevalsam , Samiulla Dodderi S. , Ramachandra Murali 
Published: August 2012

Abstract
Programmed cell death-1 (PD-1), an immunoreceptor belonging to the CD28 family, plays an important role in negatively regulating immune responses. Blocking of PD-1 signalling pathway has been shown to result in restoration of defective immune cell functions in cancer and chronic infections. PD-1 targeted therapies in the ongoing clinical trials are based on either antibodies or fusion proteins. To exploit unique advantages of peptides over antibodies or fusion proteins towards addressing the limitations of the current clinical candidates, herein we report a peptide based strategy to block the PD-1 signaling pathway. Sequences critical for ligand-receptor interaction were identified and combined in a non-linear fashion. The strategy resulted in a novel peptide, AUR-012 (29-mer), which displayed sub-nanomolar potency in disruption of PD1-PDL1/2 interaction, and highly effective restoration of proliferation and effector functions of splenocytes and PBMCs. In vivo studies demonstrated an excellent PK-PD correlation with sustained PD for &gt;24 h. In preclinical models of melanoma, breast and kidney cancers, AUR-012 showed superior efficacy compared to therapeutic agents currently used in the clinic in inhibition of both primary tumor growth and metastasis. Interestingly, dosing once in three days was equally efficacious as once a day dosing with no signs of overt toxicity and generation of neutralizing activity. These findings support further development of AUR-012 for potential clinical use.
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 2850. doi:1538-7445.AM2012-2850
Abstract 2852: Combination therapy: Galectin-3C and bortezomib potent anticancer activity and inhibition of angiogenesis, chemotaxis, and NF-kB activation in human multiple myeloma
Authors: Yu Yuefei , Mirandola Leonardo , Jenkins Marjorie R. , Cobos Everardo , Chiriva-Internati Maurizio , Chui Kitty , John Constance M. 
Published: August 2012

Abstract
Introduction Galectin-3 is a human lectin involved in cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Methods We analyzed 9 human MM cell lines tested in vitro for cell proliferation/viability; chemotaxis. The human MM cell lines used in this study were RPMI-8226, U266 (American Type Culture Collection, VA, USA), ARP-1, ARK-B, (gifts from J. Epstein, University of Arkansas for Medical Sciences, Little Rock, AR, USA). The 8226/Dox and 8226/LR-5 cell lines were kindly provided by Dr. William S. Dalton of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. All MM cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) in 5% CO2 at 37 °C. The 8226/Dox cells were cultured with 40 nM doxorubicin (Sigma-Aldrich, St. Louis, MO, USA). The 8226/LR-5 cells were cultured in media containing 5 µM mephalan (Sigma-Aldrich). 8226/Dox and 8226/LR-5 cells were maintained in drug-free medium for 1 week prior to drug sensitivity assays. Human umbilical cord vascular endothelial cells (HUVEC, American Type Culture Collection, VA, USA) were maintained in EGM-2 medium (Lonza, Houston, TX, USA) and were used within 10 passages. Furthermore we used U266 MM model in the NOD/SCID mice to evaluate the efficacy of galectin-3C in single or in combination with BOR. Results Galectin-3C exhibited modest anti-proliferative effects on MM cells in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. Bortezomib, a proteasome inhibitor approved by the F.D.A. for MM treatment, also inhibited the growth of the U266 tumors. Treatment with both agents was more effective than either alone, such that the average tumor volume of the combination group was just 14.0% of controls at day 35. We show that mechanisms by which galectin-3C facilitates the anticancer activity of BOR include inhibition of angiogenesis, chemotaxis, and NF-kB activation. Conclusion In conclusion, our study shows that in a mouse model of human MM, treatment with galectin-3C alone is efficacious, and that it enhances the anti-tumor activity of bortezomib. These findings provide the proof-of-principle to test galectin-3C clinically for human MM.
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 2852. doi:1538-7445.AM2012-2852
Abstract 2853: Discovery of phosphatases that regulate growth and tumorigenicity of ER-negative breast cancers
Authors: den Hollander Petra , Mazumdar Abhijit , Tsimelzon Anna , Hilsenbeck Susan , Chang Jenny , Mills Gordon , Brown Powel 
Published: August 2012

Abstract
Background: As the leading cause of cancer-related death in women, there is an urgent need to identify therapeutic means for breast cancer in women. 60-70% of breast cancers express the estrogen receptor (ER) and respond to therapies targeting this receptor. The remaining 30-40% of breast cancers that do not express this receptor are cannot be treated with these therapies. To identify novel targets for treatment, we are investigating growth-regulatory pathways in ER-negative breast cancers. The goal is to identify phosphatases that are critical for the growth and tumorigenicity of ER-negative breast cancer. Methods: To identify signaling pathways important in ER-negative breast cancer, we used Affymetrix microarray data obtained from profiling 221 ER-negative and 56 ER-positive breast cancers from the Baylor College of Medicine Tumor Bank. We then performed supervised cluster analysis to identify phosphatases that were differentially expressed in ER-negative and ER-positive breast cancers. This analysis identified 20 phosphatases upregulated (&gt;1.5-fold; FDR=0.05), and 29 phosphatases down-regulated (&lt; 0.66-fold, FDR=0.05) in ER-negative breast cancers as compared to ER-positive breast cancers. Specific siRNA were used to knock-down each of the 20 highly expressed phosphatases in 4 ER-negative, 4 ER-positive breast cancer cell lines, HMECs immortalized with TERT, and HMECs. Cell growth was measured by cell count, and anchorage-independent growth was tested with the soft agar assay. Colonies were counted after 14 days with the Gelcount software. Results: Of the 20 overexpressed phosphatases, 9 showed significant growth reduction after treatment with siRNA in at least 2 of the 4 ER-negative breast cancer cell lines. These 9 phosphatases are now being tested in anchorage-independent growth assays. Based on our results, 3 phosphatases (ACP1, PTP4A3, and CDC25B) have been selected for further study. These are now being tested for their transforming capability in in vitro and in vivo transformation and tumorigenicity assays. Conclusion: We identified a set of phosphatases highly over-expressed in ER-negative breast cancer, and showed that a sub-set of these phosphatases are critical for anchorage-dependent and -independent breast cancer cell growth. These studies have identified critical growth-regulatory phosphatases in ER-negative breast tumors that may be novel targets for the treatment of ER-negative breast cancer. Supported by Komen Promise grant KG081694 (PHB) & Komen SAB grant SAB08-00006 (PHB).
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 2853. doi:1538-7445.AM2012-2853
Abstract 286: Development and evaluation of a molecular decoy against SLUG function in the breast cancer cells
Authors: Mittal Mukul K. , Chaudhuri Gautam 
Published: August 2012

Abstract
SLUG, also known as SNAI2, is a member of the SNAI superfamily of zinc-finger transcriptional repressors. It is a C2H2-type zinc finger transcription factor that binds to E2-box motif (5′-CAGGTG-3′/5′-CACCTG-3′), and silences gene expression by chromatin remodeling. More than ninety genes are shown to bind tightly to SLUG as was revealed by ChIP-on-chip analysis, showing the large regulatory network involving SLUG. It is recently implicated as the major mediator of the master transcriptional regulator protein TWIST. SLUG represses several genes to directly contribute towards the metastatic transformation of several epithelial cancer cells. Specific inhibitor against SLUG is not known. We describe here the development and evaluation of a nuclease resistant double-stranded DNA decoy that specifically inhibit the repressor activity of SLUG in the human breast cancer cells. The decoy is designed from the VDR gene promoter which is repressed by SLUG. This decoy has two SLUG-binding E2-box sequences. EMSA analysis showed in vitro binding of SLUG to the wild-type decoy but not to the E2-box mutated decoy. In vitro pull down analysis also showed high affinity binding of SLUG to the decoy. Biotin-tagged wild-type decoy DNA could immunopull down SLUG but little SNAIL from the extracts from decoy-transfected cells. The decoy increased the mRNA and protein levels of several SLUG target genes in MDA-MB-231 cells. The decoy also alleviated the repressive activity of SLUG on the SLUG target gene promoters in MDA-MB-231 cells. Since SLUG overexpression is implicated in the drug-resistance and antiapoptosis development in breast cancer cells, the SLUG decoy we developed should be useful to combat breast cancer progression when used with classical anticancer drugs. Supported in parts by the DOD-CDMRP grants BC050641, BC086542 and BC103645 to GC.
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 286. doi:1538-7445.AM2012-286
Abstract 2865: Gemcitabine causes telomere shortening by stabilizing TRF2
Authors: Chih-Hao Su , Ying-Chieh Tsai , Wei-Ping Lee 
Published: August 2012

Abstract
Gemcitabine is an effective anti-cancer agent against sold tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. Here, we report that gemcitabine treatment not only induced growth arrest and apoptosis in HeLa cells, but also caused telomere shortening without affecting telomerase activity. We performed cycloheximide chase assay to confirm that the half-life of TRF2, a telomere regulator, was prolonged in a dose-pendent manner under the treatment of gemcitabine. In addition, we did in vivo ubiquitination assay and found gemcitabine treatment increased TRF2 protein level by reducing the amount of ubiquitinated TRF2. And, the results of subcellular fractionation and immunostaining showed that the accumulated TRF2 indeed translocates into nucleus. Since TRF2 is a telomeric DNA binding protein, we then made an attempt to determine whether the accumulated TRF2 binds on telomeric DNA. We did chromatin immunoprecipitation and the result revealed that the accumulated TRF2 not only translocates into nucleus but also binds to telomeric DNA. Previous study has shown that XPF-ERCC1, a structure-specific endonuclease and negative mediator of telomere length, interacts with TRF2, also required for TRF2-promoting telomere shortening. To confirm this interaction also exists in HeLa cells under the treatment of gemcitabine, we carried out immunoprecipitation with anti-TRF2 and anti-XPF antibodies and a de-telomeric DNA pull-down assay. Consistently, the results of both assay indicated that increased nuclear TRF2 which was induced by gemcitabine treatment is capable of recruiting more XPF/ERCC1 complex onto telomeric DNA. Besides, the binding studies by experimental manipulation of TRF2 confirmed that the binding ability of XPF-ERCC1 to telomere closely relates to TRF2 and resulted in telomere shortening. Together, these results show that gemcitabine enhances the nuclear accumulation of TRF2 and increased the amount of DNA-bound TRF2, therefore recruiting more XPF/ERCC1 to telomeric DNA and strengthening the nuclease activity of XPF, and resulting in telomere shortening. Since telomere loss is closely related to occurrence of apoptosis, gemcitabine may exert its anti-cancer effect by inducing TRF2 and telomere shortening.
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 2865. doi:1538-7445.AM2012-2865
Abstract 2872: Functional inhibition of HSP90 potentiates the effects of ionizing radiation in colorectal cancer
Authors: Nagaraju Ganji Purnachandra , Wen Jing , El-Rayes Bassel F. , Landry Jerome C. , Park Wungki , Diaz Roberto 
Published: August 2012

Abstract
Purpose/Objectives: Attempts at improving the outcome of colorectal cancer patients by incorporating novel agents have been disappointing indicating that in the majority of patients the therapeutic challenge remains primary resistance to chemoradiotherapy. Major cellular signaling pathways contributing to growth and resistance to chemoradiotherapy in rectal cancer includes the PI3K/AKT/NF-κB pathway. The heat shock protein 90 (HSP90) regulates the activity, turnover, and trafficking of several proteins involved in these pathways of resistance. Inhibition of HSP90 provides a novel mechanism to target these pathways simultaneously. Ganetespib (STA-9090) is a small molecule functional inhibitor of HSP90. We tested the hypothesis that HSP90 inhibition can sensitize colorectal cell lines to the effects of ionizing radiation (XRT). Methods: Immunohistochemical (IHC) analyses of 10 colorectal paired normal and tumor tissue samples from the same 10 patients were stained with antibodies against HSP90, HSP70, and p-AKT. Cell proliferation (XTT), colony formation (clonogenic assay), migration (spheroid), apoptosis (Apoptosis/Necrosis Detection Kit), and Western blot analyses were carried out in HCT-116 and HT-29 colorectal cell lines to determine the effect of ganetespib alone or in combination with XRT. Results: IHC analyses of paired human colorectal normal and tumor samples revealed significant overexpression of HSP90, HSP70, and p-AKT in the tumors when compared to the normal tissues. In both colorectal cell lines, treatment with ganetespib significantly inhibits proliferation in the XTT assay (p&lt;0.001); significantly decreased expression of PI3K and p-AKT, as well as significantly increased levels of HSP70 in Western blot analyses (p&lt;0.05); and inhibited the nuclear translocation (immunocyto studies) and the DNA binding activity (EMSA) of the NF-κB p65 molecules. We found that ganetespib indeed potentiates the effects of XRT in both cell lines: significant decrease in colony formation as determined by the clonogenic assay (p&lt;0.001); increase in the induction of necrosis; and decreased migration. Conclusions: The HSP90 pathway is selectively activated in patient's rectal tumors and is a rational target for drug development. HSP90 inhibition potentiates the effects of ionizing radiation in preclinical models. Evaluating HSP90 inhibitors in rectal cancer is a rational approach that could have a significant impact on the outcome of this common and deadly 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 2872. doi:1538-7445.AM2012-2872
Abstract 2880: Dasatinib induces apoptosis in head and neck squamous cell carcinoma cells through down-regulation of epidermal growth factor receptor (EGFR) in vitro and in vivo
Authors: Lin Yu-Chin , Wu Meng-Hsuan , Wei Tzu-Tang , Chung Shu-Hui , Chen Kuen-Feng , Cheng Ann-Lii , Chen Ching-Chow 
Published: August 2012

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Dasatinib, a bcr-abl inhibitor, has been approved clinically for the treatment of chronic myeloid leukemia and demonstrated to be effective against solid tumors in vitro through Src inhibition. Here, we disclose that dasatinib induced apoptosis of HNSCC cells in vitro and in vivo through down-regulation of EGFR. Methods: HNSCC cells, including Ca9-22, FaDu, HSC3, SAS, SCC-25, and UMSCC1 were treated with dasatinib. Cell viability, apoptosis, and underlying signal transduction were evaluated. Results: Dasatinib exhibited differential sensitivities against HNSCC cells. The growth inhibition and apoptosis were correlated with its inhibition on Akt, Erk, and bcl-2, but irrespective of Src inhibition. Accordingly, we found that down-regulation of epidermal growth factor receptor (EGFR) was a determinant of dasatinib sensitivity. Dasatinib inhibited EGFR through lysosome degradation. Increased EGFR activation by ligand administration rescued cells from dasatinib-induced apoptosis, whereas inhibition of EGFR enhanced its apoptotic effect. Estrogen receptor (ER) was demonstrated to play a role in bcl-2 expression, and dasatinib inhibited ER at pre-translational level. ER worked in concert with EGFR to regulate dasatinib-induced apoptosis. Furthermore, xenograft model showed that dasatinib inhibited HSC3 tumor growth through in vivo down-regulation of EGFR and ER. Conclusion: Down-regulation of EGFR is a novel mechanism responsible for dasatinib-induced apoptosis in HNSCC.
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 2880. doi:1538-7445.AM2012-2880
Abstract 2888: Lipid nanoparticle-mediated delivery of siRNA to extrahepatic tumors
Authors: Davide Joseph P. , Ng Bruce , Mao Xianzhi , Patel Manishkumar , Shi Bin , Hochman Jerome , Cunningham James J. , Sepp-Lorenzino Laura , Tao Weikang 
Published: August 2012

Abstract
While lipid nanoparticles (LNPs) proved to be effective in delivering siRNA to the liver and hepatocellular carcinoma (HCC) via systemic administration, they showed inferior or no efficacy in the extrahepatic tumor models. To understand the underlying mechanism for LNP activity in delivering siRNA to extrahepatic tumors, we determined siRNA biodistribution and gene-silencing activity of the LNP-siRNA nanoparticles containing different percentages of a polyethylene glycol (PEG) lipid, distinct PEG lipids with a short (C-14) or long (C-18) alkyl chain, or an identical composition with different particle sizes in mouse subcutaneous tumor xenograft models derived from either human HCC (Hep3B) or colon cancer (HT29 or HCT116) cells. We show that the LNPs containing C-18 DSA PEG exhibited a higher retention of siRNA in both Hep3B and HT29 tumors than those with C-14 DMA PEG following an intravenous administration. Intriguingly, LNPs containing 2% of DSA or DMA PEG resulted in similar levels (∼50%) of target knockdown in Hep3B tumors while those containing 6% of DSA or DMA PEG caused no target silencing. Also, none of these LNPs reduced target expression in HT29 tumors despite the retention of siRNA in tumor tissues. When LNPs with an identical composition (2% DMG PEG) but different particle sizes (80 nm vs. 120 nm) were tested, we observed a comparable and moderate suppression of target expression in Hep3B tumors, but no target knockdown in HCT116 tumors. This is despite the fact that the expression of low density lipid receptor, which is shown to be involved in mediating LNP efficacy, is detected in HT29 and HCT116 tumors. Finally, intratumor injection of LNPs only induced minimal target silencing in subcutaneous tumors while provoking significant target knockdown in the liver. Together, enhanced tumor retention of siRNA might not be readily translated to target silencing activity in tumors. Other factors such as the efficiency of transfecting tumor cells and the passive targeting effect through opsonization could impact on LNP efficacy in extrahepatic 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 2888. doi:1538-7445.AM2012-2888