bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3183: The role of G-protein coupled receptor-associated sorting protein 1 (GASP-1) in breast cancer progression
Authors: Tuszynski George , Rothman Vicki L. , Gutu Mohammed , Chang Frank 
Published: June 2012

Abstract
An innovative “2-D High Performance Liquid Electrophoresis” (2-D HPLE) technology was used to identify serum biomarkers associated with the earliest stage of breast cancer in addition to other more advanced stages. 2-D HPLE is a newly developed electrophoretic technology that separates 100's of serum albumin complexes on a polyvinyl membrane based on their surface charges. Association of cancer proteins (biomarkers) with pre-existing albumin complexes in the blood of cancer patients results in altered mobility on the membrane. Using 2-D HPLE we identified that G-protein coupled receptor-associated sorting protein 1(GASP-1) was present in the sera of patients with early stage disease but absent in sera of normal patients. GASP-1 has been shown to modulate lysosomal sorting and functional down-regulation of a variety of G-protein coupled receptors in neuronal cells. However, no reports have linked GASP-1 to breast cancer pathogenesis. GASP-1 was detected in tumor extracts of 7 cases of stage 2 and stage 3 breast cancer but not in adjacent normal tissue as revealed by Western Blot analysis using an antibody developed against a GASP-1 peptide identified by our 2-D HPLE technology. Using this antibody, we immunohistochemically detected over-expression of GASP-1 in all 59 cases of archived ductal breast carcinoma tumor samples. When GASP-1 was silenced in MB-231 breast carcinoma, the cells grew more than 5 fold slower than corresponding vector controls. These studies identify GASP-1 as a potential new serum and tumor biomarker for breast cancer and suggest that GASP-1 may be a novel target for development of breast cancer therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3183. doi:10.1158/1538-7445.AM2011-3183
Abstract 3213: Induction chemotherapy for stage 4 gastric cancer and prognostic molecular markers
Authors: Ueda Shugo , Hattori Kengo , Inoue Yoshikage , Kadono Kentaro , Yoshimura Mio , Yoshida Masahiro , Yoshitomi Mami , Nomura Akinari , Hashida Hiroki , Terajima Hiroaki , Ozaki Nobuhiro , Fukushima Masakazu 
Published: June 2012

Abstract
The prognosis of gastric cancer with distant metastasis is very poor. Improvement of chemotherapy and investigation of molecular markers are required. We investigated the characteristics and the prognosis of patients with stage 4 gastric cancer with peritoneal or other distant metastases. 132 patients with stage 4 gastric carcinoma in Kitano hospital in between 2002 and 2009 were evaluated. The prognosis of the patients treated without chemotherapy was very poor. The prognosis of the patients with one factor of stage 4 was better than those with multiple factors. We tried induction chemotherapy with S-1 plus cisplatin for the patients without gastric bleeding or malignant gastric outlet obstruction. Our retrospective analysis demonstrated that induction chemotherapy improved the prognosis compared with adjuvant chemotheray after gastrectomy.
In order to develop molecular markers for chemotherapeutic efficacy for advanced gastric cancer, we investigated the gene expression in the gastric carcinoma before treatment. We identified novel markers of gastric cancer using focused microarray analysis, hypoxanthine phosphoribosyltransferase 1 (HPRT1) and transforming growth factor-alpha (TGF-α), low gene expression of which was associated with less malignant potential.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3213. doi:10.1158/1538-7445.AM2011-3213
Abstract 3224: Targeted non-invasive therapy of prostate cancer using fusogenic liposomes
Authors: Nesbitt Rae , Pink Desmond , Duncan Roy , Lewis John 
Published: June 2012

Abstract
Prostate cancer is the most common cancer in Canadian men. Most chemotherapeutic drugs do not preferentially target the tumour and therefore subject the patient's healthy cells to significant toxicity. There is therefore an urgent need for a novel strategy to deliver chemotherapeutic drugs specifically to the tumour. P14 is a fusion associated small transmembrane (FAST) protein which mediates efficient cell-cell interaction. When we incorporate this p14 FAST protein into liposomes we increase the fusion of the liposome to cell membranes. I hypothesize that targeted ablation of prostate cancer may be achieved by delivering chemotherapeutics encapsulated inside fusogenic liposomes targeted to the gastrin releasing peptide receptors. The objectives of the study are to i) validate the fusogenic properties of p14-containg liposomes ii) express and purify p14-bomesin fusion protein, iii) assemble targeted fusogenic lipsoomes iv) and assess the targeted ablation of human prostate cancer in a xenograft model. To validate the fusogenic properties of p14-containing liposomes in our cell lines, we encapsulated fluorescent dextran inside liposomes containing either no p14, mutant p14 (fusogenic incompetent) or an active p14. We incubated the liposomes on human fibrosarcoma cells (HT1080) and measured the uptake of fluorescent dextran using fluorescent microscopy. To construct a fusion protein, we used PCR amplification to fuse bombesin to the C-terminus of the p14 protein. Our analysis demonstrates that the incorporation of the p14 protein significantly increased the fluorescent dextran uptake in the cytoplasm of the HT1080 cells compared to the liposomes that contained no p14 and the mutant p14. Protein purification of the p14-bombesin fusion protein is still in progress. I propose to use these targeted fusogenic liposomes for future studies to evaluate the ability of bombesin-coated fusogenic liposomes to target prostate cells in vitro and deliver a toxic therapeutic payload to prostate tumours in vivo and assess tumour reduction.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3224. doi:10.1158/1538-7445.AM2011-3224
Abstract 3226: In vitro evaluation of a thermally targeted conjugate of a highly potent doxorubicin derivative
Authors: Opacak-Bernardi Teuta , Robinson Leslie , Ajaj Khalid Abu , Kratz Felix , Raucher Drazen 
Published: June 2012

Abstract
Doxorubicin is an anthracycline used in the treatment of many types of cancer. It intercalates into the strands of DNA to inhibit the progression of topoisomerase II, stopping the cell from replicating. The side effects, however, are severe and include neutropenia, alopecia, nausea, myelosuppression, and cardiotoxicity. Due to its nonspecific effect, high doses are needed to treat cancer cells. These high doses are inadvertently harmful to normal cells. n-Butyldiacatodoxorubicin (NBD) is a doxorubicin derivative that is converted in vivo to 2-pyrrolinodoxorubicin that is ∼ 1000-fold more active than doxorubicin. Because of its high potency, an efficient drug delivery system is needed in order to deliver NBD to the tumor site. To retain potent antitumor activity while reducing systemic toxicity, NBD was coupled to a thermally responsive macromolecular carrier. The macromolecular carrier is based on elastin-like polypeptide (ELP) which remains in solution at physiological temperature and accumulates in the tumor site when external hyperthermia is applied. The N-terminus of ELP was modified with the cell penetrating peptide (CPP) SynB1. SynB1 is a 19 amino acid peptide derived from porcine leukocytes which facilitates cellular uptake of the ELP carrier. NBD was attached to a terminal cysteine residue of ELP by conjugation of a 6-maleimidocaproyl hydrazone derivative of NBD. This NBD drug bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered NBD inhibited MCF-7 cells growth in the nanomolar range. In addition, inhibition of cell proliferation was enhanced two-fold when hyperthermia was applied and cell proliferation was accompanied by apoptosis, which was enhanced 3-fold in MCF-7 cells when SynB1-ELP-NBD aggregation was induced with hyperthermia. These results suggest that the SynB1-ELP-NBD conjugate is a promising candidate for investigating its thermally targeting properties against solid tumors in animal models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3226. doi:10.1158/1538-7445.AM2011-3226
Abstract 3242: New chemical tools for disrupting the MDM2/p53 protein-protein interaction: Identification, synthesis and biological evaluation of a novel class of MDM2/p53 inhibitors
Authors: Pernazza Daniele , Li Xiaolong , Lawrence Harshani R. , Guida Wayne C. , DuBoulay Courtney J. , Watts Shawn , Sebti Saïd M. , Chen Jiandong , Lawrence Nicholas J. 
Published: June 2012

Abstract
MDM2 and MDMX function as key regulators of p53 by binding to its N terminus, inhibiting its transcriptional activity, and promoting its degradation. In particular, MDM2 is overexpressed in some of human tumors, and with MDMX contributes directly to loss of p53 function during the development of nearly 50% of human cancers. Due to p53 inactivation, MDM2 in many tumors confers tumor survival; therefore it is an important molecular target for anticancer therapy. Several studies showed that reactivation of wild type p53 in tumor cells can be obtained by disrupting the MDM2/p53 interaction with peptidic, peptidomimetic, and small molecule p53-mimetics. Specific successful examples include the Nutlins and spirooxindole analogs (MI-219 and MI-63). Amongst the peptidic and peptidomimetic inhibitors examined to date, none is nearly as effective as Nutlins and MI-219 in tumor killing in vitro. Hence, new inhibitors against MDM2 and/or MDMX are needed: as cell permeable chemical probes of the p53 pathway in cancer biology, and as templates for structure-based rational design of p53 activators for future therapeutic use. As part of our drug discovery program to identify antagonists of the p53/MDM2 and p53/MDMx protein-protein interactions, a high-throughput in-silico screen of a 3.2 millions virtual library of compounds (from Schrödinger, Inc.). A physical restraint was applied during the screen, in order to mimic binding to the hydrophobic cleft of MDM2 normally occupied by three p53 side chains (F19, W23, and L26) that are critical for MDM2/p53 binding. The top highest ranked 160 compounds were then assessed for their ability to block p53 interaction with MDM2 and MDMx in an ELISA assay. This resulted in the identification of E12/DP3-117, a small molecule disruptor of the p53/MDM2 protein-protein interaction with an IC50 value of 47 ± 14 μM. We will report the synthesis and biological evaluation of focused libraries based on the initial hit and on compounds showing improved activity. Structure activity relationship studies around the hits will be disclosed as well as the outcomes of further rounds of chemical design and biological assessment. Binding of E12/DP3-117 to MDM2 is currently being assessed via co-crystallization and other biophysical techniques. We will describe the use of the crystal structure of p53-like mutant peptides in complex with the N-terminal domains of Mdm2, as the basis for rational design of more potent MDM2 small-molecule/peptide hybrid inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2011-3242
Abstract 3248: New inhibitors of the Shp2 phosphatase
Authors: Gevariya Harsukh , Ortiz Emmanuel D. , Chen Liwei , Daniel Kenyon , Lawrence Harshani R. , Guida Wayne C. , Sebti Said M. , Wu Jie , Lawrence Nicholas J. 
Published: June 2012

Abstract
The Shp2 protein tyrosine phosphatase (PTP) mediates signal transduction of growth factor receptors and regulates cellular activities critical to tumor growth and metastasis. In the basal state, the interactions between the N-SH2 and PTP domains keep the phosphatase in an auto inhibited closed conformation. Upon growth factor or cytokine stimulation, the SH2 domains of Shp2 binds to tyrosine phosphorylated docking proteins such as Gab1 and Gab2, which activates Src, Ras, and the Erk1/2 (Erk) mitogen-activated protein (MAP) kinase pathway. Shp2 gain-of-function mutations are found in leukemias and solid tumors and are linked to Noonan syndrome. Although Shp2 is involved in pathogenesis of human cancers, it is not clear how Shp2 mediates tumorigenesis. Shp2 is therefore believed to be an important enzyme for targeted cancer therapy. Since no potent and selective Shp2 PTP inhibitor is currently available for chemical biology studies and experimental therapy, we and others have been actively engaged in the search for such agents. In our continuing efforts to develop potent and selective Shp2 inhibitors to serve as both chemical probes to further our understanding of the role and signaling mechanisms of Shp2 in human diseases and as potential drugs for cancer therapy.
We will report the screening of a focused library of a set of commercially available salicylic acid derivatives using the in vitro DIFMUP phosphatase assay for their ability to inhibit the Shp2 phosphatase domain. Activity of hits was confirmed using the Biomol Green assay to determine inhibition of dephosphorylation of a Shp2 peptide substrate derived from EphR. One such hit was a thiazole containing salicylic acid that inhibits Shp2 with an IC50 (DIFMUP) of 100 µM. We will report the design and synthesis of salicylic acid libraries along with their benzoic acid counterparts. The most potent compound to date is HM2-08-4 which has an IC50 (DIFMUP) 1.1 µM. Emerging structure-activity relationships as well as modeling and X-ray studies will be discussed. The preliminary use of selected compounds as tools to probe the pharmacological inhibition of Shp2 and elucidate its role in cancer will be described.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2011-3248
Abstract 3258: Development of novel ribonucleotide reductase inhibitors: A story from structural analysis to preclinical study
Authors: Zhou Bingsen , Su Leila , Yuan Yate-Ching , Hu Shuya , Yen Yun 
Published: June 2012

Abstract
The goal of this project is to develop new class inhibitors for Ribonucleotide Reductase (RR), a key enzyme for DNA synthesis. These inhibitors are more effective than existing small molecule therapies, and can overcome resistance from Hydroxyurea (HU), the only FDA approved drug for targeting RR-based cancers. In addition, this new class of inhibitors will ameliorate the severe iron chelating side effects associated with 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine®), a compound that is currently been testing in human phase II clinic trials.
A lead compound, COH29 (US Patent No. 54435.8056.US01) with sub-micro molar range inhibition was developed through modification of a hit identified from screening a diverse compound library from NCI Developmental Therapeutics Program (DTP). COH29 demonstrated 90.2% inhibitory activity of recombinant human RRM2/RRM1 enzyme complex at 9 µM in vitro. Moreover, examine the cytotoxicity of COH29 in a NCI broad panel of 60 human cancer cell lines in vitro by 5 doses MTT cytotoxicity assay indicated COH29 show a good inhibition against cancer cells special to leukemia and ovarian cancer cells. Importantly, COH29 shows less toxicity to human normal fibroblast cells as compared to 3-AP.
Results from computer modeling and biophysical measurements suggest that COH29 interferes with the radical transfer pathway at the interface between RRM1 and RRM2. This represents a unique binding mechanism that is completely different from existing known inhibitors. Biacore binding analysis, computer docking, as well as NMR Saturation Transfer Difference (STD) studies have been performed and identified COH29 binding is specific to RRM2. These studies further confirm a V-shaped binding pocket of RRM2 with COH29. Preliminary data suggest that COH29 represents a promising new class of RR inhibitors with the advantages of (a) a unique mechanism and target specificity that interferes with the radical transfer pathway at the RRM1-RRM2 interface, (b) greater potency than HU in the sub-µM range of IC50, and (c) avoiding iron chelating-related side effects compared to 3-AP. Therefore, our objectives are to optimize the properties of COH29 into a viable candidate as a future anticancer drug targeting over expressed RR based cancers. (This project was supported by NIH grant CA 127541)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3258. doi:10.1158/1538-7445.AM2011-3258
Abstract 3268: Targeting Semaphorin signaling to inhibit tumor growth and metastatic spreading
Authors: Casazza Andrea , Kigel Boaz , Rolny Charlotte , Neufeld Gera , Tamagnone Luca 
Published: June 2012

Abstract
The Semaphorins and their receptors, Neuropilins and Plexins, were originally implicated as guidance signals in the development of the central nervous system. However, a growing body of evidence indicates that semaphorins may regulate tumor progression, by promoting or inhibiting tumor angiogenesis, tumor cell survival and metastatic spreading, in fact mediating a crosstalk between tumor cells and multiple stromal cell types in the surrounding microenvironment.
Here, we provide two examples of the multifaceted activity of semaphorins during tumor progression. We found that Semaphorin 3A (SEMA3A) inhibits primary tumor growth and its metastatic dissemination by employing three different experimental approaches in mouse tumor models: (i) over-expression of SEMA3A in tumor cells; (ii) systemic expression of SEMA3A following gene transfer in mice; (iii) tumor-targeted release of SEMA3A using gene-modified Tie2-expressing monocytes (TEMs) as delivery vehicles. In each of these experimental settings, SEMA3A efficiently inhibited tumor growth by disrupting vessel function and inducing tumor hypoxia and necrosis, without promoting metastatic dissemination.
Moreover, we have recently shown that another secreted semaphorin known to regulate angiogenesis, Semaphorin 3E (SEMA3E), is abundantly expressed in metastatic human tumors, where it promotes cancer cell invasiveness and metastatic spreading. Notably, this biological activity of SEMA3E depends on a proteolytic conversion by furin-like convertases, generating the active fragment “p61”-SEMA3E. In cancer cells, p61-SEMA3E induces the association of the receptor PlexinD1 with the oncogenic tyrosine-kinase receptor ErbB2, leading to ErbB2 activation and enhanced tumor invasion and metastasis. Here we show that a mutated uncleavable variant of SEMA3E (Uncl-SEMA3E) binds the receptor PlexinD1 but it is unable to trigger ErbB2 signaling in cancer cells and lacks any pro-metastatic activity. On the other hand, Uncl-SEMA3E functions as a potent anti-angiogenic factor and displays striking tumor-suppressor properties in vivo. In summary, SEMA3A and Uncl-SEMA3E are potent inhibitors of tumor angiogenesis and tumor growth which concomitantly block the metastatic spreading of tumor cells.
These data provide evidence that support interfering with semaphorin-mediated signals as a promising anti-cancer strategy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3268. doi:10.1158/1538-7445.AM2011-3268
Abstract 327: Altered expression of insulin receptor isoforms in breast cancer
Authors: Jiaqi Huang , Morehouse Chris , Streicher Katie , Higgs Brandon W. , Gao Jin , Baffa Raffaele , Meggan Czapiga , Boutrin Anmarie , Brohawn Philip , Zhu Wei , LaVallee Theresa , Chang Yong , Richman Laura , Jallal Bahija , Yao Yihong 
Published: June 2012

Abstract
Human insulin receptor (INSR) isoform A (IR-A), one of the two primary isoforms of INSR, constitutes an important therapeutic target for the development of anticancer drugs. There is also crucial need to develop a quick and sensitive method to accurately measure each of the two isoforms in humans. A specific quantitative real-time PCR-based assay has been developed to distinguish IR-A from insulin receptor isoform B (IR-B). This assay provides greater sensitivity, reproducibility, and clinical applicability than previously established methodologies. We used this assay to evaluate the mRNA expression levels of the IR-A and IR-B as well as multiple tumor proliferation markers in breast tumor tissues. Results revealed a significant decrease in IR-B mRNA expression leading to a relative increase in IR-A mRNA proportion in tumor samples compared to normal breast tissue samples. We also identified a novel positive correlation between increased IR-A: IR-B mRNA ratio and cancer proliferation markers, including Ki67. Furthermore, we observed a statistically significant difference of IR-A: IR-B mRNA ratio between luminal-A and -B breast cancer subtypes. These results suggest that IR-A is the predominant isoform of insulin receptor in breast cancer and highlights the potential value of characterizing changes in the IR-A: IR-B mRNA ratio as a therapeutic indicator for drugs that target insulin growth factor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 327. doi:10.1158/1538-7445.AM2011-327