bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B7: The bone metastasis secretome: Identification of potential therapeutic targets via high-throughput proteomics
Authors: Blanco Mario Andres , LeRoy Gary , Zee Barry , Aleckovic Maša , Garcia Benjamin , Kang Yibin 
Published: January 2011

Abstract
Secreted tumor proteins are critical for establishing the requisite tumor-stromal interactions in the process of metastasis and are superior therapeutic targets. Here we present a proteome-scale analysis to identify novel secreted proteins associated with bone metastasis. To characterize the complete set of secreted proteins involved in tissue-specific metastasis, we analyzed the secreted protein fractions from four sublines of the MDA-MB-231 breast cancer cell line which differ in bone metastasis ability. Using LC-MS/MS mass spectrometry technology, we identified 1153 total unique proteins from these fractions and filtered out those proteins predicted to be non-secreted using SignalP 3.0. This analysis yielded 206 unique secretory-predicted proteins, thus providing the first view of the MDA-MB-231 secretome. To determine potential therapeutic targets, we looked at which secreted proteins were found only in the highly bone metastatic cell lines. This 32-protein bone metastasis “secretome signature” contained several proteins already known to play a role in promoting bone metastasis (eg. MMP1, CTGF, and TGF-) as well as many novel proteins with no prior link to metastasis or cancer. GO categories significantly enriched in this signature included “extracellular region,” “calcium ion binding,” and “ IGF-binding,” further confirming its biological relevance. Oncomine database analysis indicated that 6 of 32 secretome signature proteins are strongly upregulated in multiple human cancers as compared to matched normal tissue. To narrow the secretome signature biologically, we repeated the LC-MS/MS analysis on two additional sets of matched parental vs. highly bone metastatic derivative cell lines. From the three total secretome analyses, 5 secreted proteins were found to be unique to bone metastatic derivatives in two of three cell types, and one protein was found in every bone metastatic derivative (and in none of the weakly bone metastatic lines). Oncomine analysis indicated that three of these five proteins were also strongly upregulated in multiple human cancers as compared to normal tissue. This analysis of the metastasis secretome and its associated bone metastasis-specific changes has identified multiple novel secreted proteins strongly implicated in clinical malignant progression. Following experimental and clinical validation, any could be considered for therapeutic targeting via monoclonal antibody.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B7
Abstract B9: Germline conservation of hypermutable codons in gatekeeper tumor suppressor genes implicates pro-carcinogenic CpG sites in vivo as anti-teratogenic ‘shock absorbers’ in utero
Authors: Zhao Yongzhong , Epstein Richard J. 
Published: January 2011

Abstract
Purpose: Methylated CpG sites are readily mutated, yet are strongly conserved in tumor suppressor genes. Uniquely, the arginine-encoding CGA codon may undergo methylation-dependent point mutation to a stop codon (TGA), whereas the arginine-encoding AGA codon is stable. To clarify the relationship between germline codon mutability and somatic carcinogenesis, we compared patterns of codon usage in tumor suppressor gene subsets known to differ in function and evolutionary stability.
Procedures: Human tumor suppressor genes were classified as either pro-apoptotic (gatekeepers; high-essentiality, low Ka/Ks) or repair-type (caretakers; low-essentiality, high Ka/Ks). Reference normal and tumor gene sequence databases were analysed in terms of nucleotide composition (GC%), intragenic CpG sites, and CGA/AGA codon patterns. Phylogenetic analyses of relevant codon frequencies across 24 species from the UCSC database were performed as a control.
Results: Species-specific stop codon frequency varies with genomic GC content in a methylation-regulated manner, whereas CGA frequency is GC-independent. Whole-genome frequencies of CGA and TGA codons are positively correlated (p = 0.013). CGA mutation in tumors is asymmetric (TGA &gt;&gt; CAA; p &lt; 0.001), with such mutations 3-fold more likely to be nonsense-type in gatekeepers than in caretakers. Non-random CGA clustering is demonstrable in canonical gatekeepers such as NF1, Rb and TP53 (p &lt; 0.02).
Conclusion: Human pro-apoptotic suppressor genes are selectively enriched for the presence of nonsense-prone CpG-containing codons involved in somatic adult-onset tumor progression. We propose that this germline vulnerability is conserved as part of a methylation-dependent embryonic response to environmental teratogens which otherwise cause excessive apoptosis, somatic malformations, and reduced fitness.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B9
Abstract CN2-2: Development of therapeutic cancer vaccine and construction of clinical research network in Japan
Authors: Nakamura Yusuke 
Published: January 2011

Abstract
cDNA microarray technologies have enabled us to obtain comprehensive data for gene expression profiles of human cancers. To isolate novel molecular targets for diagnosis and treatment of cancer, we constructed expression profile database of cancer cells originated from various organs with their corresponding non-cancerous tissues using a cDNA microarray that consists of more than 30,000 genes or ESTs. These experiments disclosed a number of genes that appeared to be involved in development and/or progression of cancers in those tissues. We also constructed expression profile database for 30 normal human tissues/organs. So far, we have analyzed approximately 1,400 clinical cancer samples of the liver, pancreas, stomach, colon, esophagus, bile duct, uterus, lung, ovary, kidney, urinary bladder, testis, prostate, breast, and soft tissues as well as acute and chronic myeloid leukemias. We have selected hundreds of candidate genes by the following criteria; (1) gene expressions were transactivated in a large proportion of cancer tissues in comparison with their corresponding normal tissues and (2) expression was not observed or hardly detectable in any of important vital organs. The further functional analysis of these molecules identified dozens of genes that are likely to function as oncogenes in various cancers. The suppression of expression of such genes with siRNA induced cell cycle arrest, apoptosis, or suppression of anchoring-dependent cell growth. We screened 9- or 10-amino-acid peptides corresponding to a part of such oncoantigens that induce cytotoxic T lymphocytes that would specifically kill cancer cells in an HLA-A restricted and antigen-dependent manner. We have already isolated nearly 60 peptides (HLA-A02 or HLA-A24 restricted) derived from about 50 oncoantigens and started translational research using some of them in August 2006. We have organized a group that performs translational research and now consists of ∼60 hospitals (Cancer Peptide Vaccine Translational Research Network = Captivation Network). We are now running more than 30 different protocols and more than 900 cancer patients have been enrolled by the end of 2009. The promising clinical data and immunological analysis of our translational research will be introduced in the meeting. These results indicated that systematic expression analysis should be a very effective approach for identification of molecules that are potential targets for development of novel therapeutic drugs.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN2-2
Abstract ED1-1: The role of informatics in translational research: The interplay of epidemiology, clinical studies, and discovery research
Authors: Koehler Jacob 
Published: January 2011

Abstract
Whilst drug discovery costs are increasing, the number of successful new drugs is decreasing. Lack of efficacy, toxicology and commercial reasons are the main reasons why drugs are discontinued. Further, there is an ever growing demand to demonstrate safety and comparative effectiveness to payers, regulatory agencies and patients. A range of computational, data driven translational approaches provide new opportunities for improving drug discovery, development and utilization.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED1-1
Abstract ED4-1: Functional imaging: Beyond FDG
Authors: Price Patricia M. 
Published: January 2011

Abstract
Whole body FDG has become an important part of the diagnosis and staging of cancer. Worldwide, over 90% of PET imaging is now clinical whole body FDG imaging. However, in vivo molecular imaging with PET is an emerging discipline that is of importance to the development of anti-cancer therapies. As anti-cancer strategies become more directed towards a defined molecular target, we need information that is relevant to humans about whether the molecular target is expressed, the selectivity and binding of the compound for that target, and the effects of such an interaction.
PET is the most sensitive and specific technique for imaging molecular pathways in vivo in humans. PET uses positron emitting radionuclides to label molecules which can then be imaged in vivo. The inherent sensitivity and specificity of PET is the major strength of this technique, able to provide quantitative kinetic information down to sub-picomolar levels.
Molecular imaging with PET can provide pharmacokinetic, pharmacodynamic and mechanistic information. Use of the technique in early clinical trials can (1) provide information on optimum biological dose and PK/PD relationships; (2) identify tumours containing specific molecular targets; and (3) provide in vivo pharmacodynamic evaluation of compounds.
Molecular imaging with PET has the potential to ensure a paradigm shift in drug development, to revolutionise, streamline and accelerate drug development in oncology. Examples will presented where in vivo clinical tumour and normal tissue pharmacokinetics measured by PET have helped drug development, from use with small molecules to antisense therapy.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED4-1
Abstract KN1: Finding mechanisms and biomarkers of drug resistance in cancer
Authors: Bernards René 
Published: January 2011

Abstract
Unresponsiveness to therapy remains a significant problem in the treatment of cancer, also with the new classes of targeted therapeutics. In my laboratory, we use functional genetic approaches to identify biomarkers that can predict responsiveness to clinically relevant cancer therapeutics. We focus on targeted cancer drugs such as trastuzumab (Herceptin), PI3K inhibitors, MEK inhibitors, ALK inhibitors, mTOR inhibitors, Histone Deacetylase inhibitors and retinoic acid. These drug target specific molecules or pathways that are often activated in cancer. Nevertheless, it remains poorly explained why a significant number of tumors do not respond to the therapy. We aim to elucidate the molecular pathways that contribute to unresponsiveness to targeted cancer therapeutics using a functional genetic approach. This will yield biomarkers that may be useful to predict how individual patients will respond to these drugs. Furthermore, this work may allow the development of drugs that act in synergy with the established drug in the treatment of cancer. To identify biomarkers that control tumor cell responsiveness to cancer therapeutics, we use two complementary approaches. First, we use genome wide loss-of-function genetic screens (with shRNA interference libraries) in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest (resistance screens). In addition, we use single well siRNA screens with a low dose of the drug to screen for genes whose inhibition enhances the toxicity of the cancer drug (sensitizer screens). Once we have identified resistance and/or sensitizer genes, we ask if their expression is correlated with clinical response to the drug-of-interest using tumor samples of cancer patients treated with the drug in question, whose response to therapy is documented. Examples of genetic screens to identify mechanisms of resistance to different cancer drugs will be presented.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):KN1
Abstract PL3-2: Translating multiple myeloma stem cells
Authors: Matsui William 
Published: January 2011

Abstract
Emerging evidence suggest that many human cancers consist of phenotypically and functionally heterogeneous cell types. Moreover, the capacity for clonogenic growth and self-renewal may be restricted to specific cell populations. In multiple myeloma, malignant plasma cells make up the vast majority of tumor cells and are responsible for symptoms arising within the disease. However, myeloma plasma cells also appear to be terminally differentiated like their normal counterparts and incapable of long-term proliferation. Similar to other laboratories, we have identified minor populations of B cells that share the identical immunoglobulin gene rearrangements as the malignant plasma cells in most myeloma patients. We have further studied the functional capacity of these clonotypic B cells and found that they have ability to produce ectopic tumor growth both in vitro and in immunodeficient mice in which they recapitulate human disease. Moreover, these cells are relatively resistant to several agents currently used to treat multiple myeloma suggesting that they persist following treatment and are responsible for tumor regrowth and disease relapse. In order to inhibit these drug resistant cancer stem cells, we have studied cellular pathways that regulate the self-renewal of normal adult stem cells and found that several, including the developmental pathway Hedgehog, are potential therapeutic targets. Lastly, we have begun to develop biomarker strategies to serially quantify myeloma stem cells in patients undergoing treatment. We hope that these will serve as useful endpoints as myeloma stem cell directed therapies enter the clinic.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL3-2
Abstract PL4-1: Immunotherapy of established lesions caused by high-risk HPV
Authors: Melief C.J.M. , Welters M.J.P. , Valentijn A.R.P.M. , Berends-van der Meer T.M.A. , Löwik M.J.G. , Vloon A.P.G. , Essahsah F. , Fathers L.M. , Offringa R. , Drijfhout J.W. , Oostendorp J. , Fleuren G.J. , van der Burg S.H. , Kenter G.G. 
Published: January 2011

Abstract
Therapeutic vaccination with a synthetic long peptide (SLP®) vaccine mediated the eradication of established human papilloma virus type 16 (HPV16)-positive tumors in mice and controlled wart growth and latent virus infection in rabbits persistently infected with cottontail rabbit papilloma virus. Subsequent phase I/II studies with an HPV16 SLP® vaccine, consisting of 13 long peptides covering the HPV16 E6 and E7 antigens, in patients with advanced HPV16-positive cervical cancer, revealed that this vaccine was safe and highly immunogenic. The purpose of the current study was to test the clinical efficacy of this HPV16 SLP® vaccine in HPV16-induced high grade vulvar intraepithelial neoplasia (VIN3), a premalignant epithelial disorder, spontaneous regression of which occurs in less than 2% of patients and in which recurrence after standard treatment is high.
In a phase 2 trial, 20 women with VIN3 were vaccinated three times sc in the limbs with a mix of the HPV16 E6 and E7 synthetic long peptides formulated in Montanide ISA-51. The endpoints were objective clinical responses, defined as reduction of at least 50% in lesion size (partial response) or complete regressions, and HPV16-specific T-cell responses, determined before and after vaccination.
The vaccine was safe, as no side effects exceeding CTC grade 2 were observed. At 3 and 12 months after the last vaccination an objective response was observed in 12/20 (60%) and 15/19 (79%) patients respectively. Nine of them showed a complete and durable regression of the lesions at 12 months and at 24 months. The strength of the vaccine-induced HPV16-specific T-cell response was significantly higher in the group of patients with a complete regression of their lesions as compared to non-responders.
This study shows that in women with VIN3 objective clinical responses can be achieved by therapeutic vaccination with synthetic long peptides that is able to induce effective HVP16-specific T-cell responses.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL4-1
Abstract PL6-1: Resistance to targeted therapies in a realistic mouse breast cancer model
Authors: Borst Piet , Rottenberg Sven , Jonkers Jos , Zander Serge , Pajic Marina , Jaspers Janneke 
Published: January 2011

Abstract
The contribution of ABC-transporters to resistance in patients has remained controversial. We have tackled this problem in a mammary mouse tumor model. These Brca1−/−, p53−/− tumors arise “spontaneously” and closely resemble human breast cancer in BRCA1+/− carriers (Rottenberg, PNAS 2007;104:12117–22; 2008;105:17079–84). The tumors respond to chemotherapeutic agents used in human breast cancer, but eventually end up being resistant to most drugs.
Resistance to doxorubicin in this tumor model is nearly always due to P-glycoprotein upregulation at the transcriptional level. A 5-fold increase in the low basal level of P-glycoprotein RNA in these tumors is sufficient for complete resistance. These levels of P-glycoprotein are not detectable with standard immunocytochemistry using the C219 Mab (Pajic, Cancer Res 2009;69:6396–404). Crossing in null alleles for Mdr1a/b made the tumors hypersensitive to doxorubicin, docetaxel, and to the PARP inhibitor olaparib. In about half of the mice treated with topotecan, resistance is associated with upregulation of Abcg2 (Bcrp). Tumors in Abcg2−/− mice take longer to become resistant (Zander, Cancer Res 2009 in press). Notwithstanding the complete remissions often obtained with some drugs, we are rarely able to eradicate the tumor. This is not due to the hypothetical unique properties of tumor stem cells. Supported by Dutch Cancer Foundation and EU Framework Program.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL6-1
Abstract PL6-2: Antibody-initiated cancer immunotherapy
Authors: Weiner Louis M. , Tang Yong , Wang Shangzi , Surana Rishi , Xu Wei , Zhou Yu , Marks James D. , Golemis Erica 
Published: January 2011

Abstract
We have previously described the critical structural determinants of anti-tumor antibodies that promote in vivo tumor targeting and antibody-dependent cellular cytotoxicity (ADCC). We now describe treatment strategies in murine models that 1) improve in vitro and in vivo ADCC, 2) dissect the relative contributions of tumor signaling perturbation and ADCC for in vivo therapeutic efficacy, and 3) identify therapy conditions that promote the induction of host-protective adaptive immunity. We also have identified tumor-intrinsic factors that sensitize tumor cells to EGFR-directed antibody therapy, using a siRNA library focused on genes functionally linked to the EGFR signaling pathway. We predict that these findings will be important for the improved efficacy of EGFR family-directed antibody therapies. Supported by CA50633, CA121033.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL6-2
Preclinical Studies on the Mechanism of Action and the Anti-Lymphoma Activity of the Novel Anti-CD20 Antibody GA101
Authors: Dalle Stephane , Reslan Lina , Besseyre de Horts Timothee , Herveau Stephanie , Herting Frank , Plesa Adriana , Friess Thomas , Umana Pablo , Klein Christian , Dumontet Charles 
Published: January 2011

Abstract
GA101 is a novel glycoengineered Type II CD20 monoclonal antibody. When compared with rituximab, it mediates less complement-dependent cytotoxicity (CDC). As expected for a Type II antibody, GA101 appears not to act through CDC and is more potent than the Type I antibody rituximab in inducing cell death via nonclassical induction of apoptosis cytotoxicity, with more direct cytotoxicity and more antibody-dependent cell-mediated cytotoxicity. We evaluated the antitumor activity of GA101 against the human-transformed follicular lymphoma RL model in vivo in severe combined immunodeficient mice (SCID) mice. GA101 induced stronger inhibition of tumor growth than rituximab. Combination of GA101 with cyclophosphamide in vivo confirmed the superiority of GA101 over rituximab. Neutralizing the complement system with cobra venom factor partially impaired the antitumor activity of rituximab, but had no impact on the efficacy of GA101. In vitro GA101 more potently induced cell death of RL cells than rituximab. The expression of a limited number of genes was found to be induced by both antibodies after exposure in vitro. Among these, early growth response 1 and activation transcription factor 3 were confirmed to be increased at the protein level, suggesting a possible role of these proteins in the apoptotic signalling of anti-CD20 antibodies. These data imply that GA101 is superior to rituximab not only as a single agent, but also in combination with chemotherapy. These data suggest the presence of novel signalization pathways activated after exposure to anti-CD20 antibodies. Mol Cancer Ther; 10(1); 178–85. ©2011 AACR.
Celecoxib Can Induce Vascular Endothelial Growth Factor Expression and Tumor Angiogenesis
Authors: Xu Kaiming , Gao Huiying , Shu Hui-Kuo G. 
Published: January 2011

AbstractIncreased COX-2 expression has been linked to increased angiogenesis and a worse prognosis in patients with malignant gliomas and other tumor types. This led to our interest in assessing the response of glioma cell lines to treatment with celecoxib, a selective COX-2 inhibitor. However, contrary to its reported antiangiogenic effects, treatment with celecoxib actually induced the expression of VEGF in multiple glioma as well as other cancer cell lines. This induction of VEGF was comparable to, if not greater than, that found after exposure of cells to hypoxia. Pharmacologic inhibition and siRNA silencing of p38-mitogen-activated protein kinase and the Sp1 transcription factor revealed their involvement in this celecoxib-induced VEGF expression. Consistent with the documented role of Sp1 in this effect, VEGF induction was found to involve transcriptional activation and not to change the stability of VEGF mRNA. The biological significance of this effect was confirmed in vivo by showing both induction of VEGF expression and microvessel density in tumor xenografts and increased angiogenesis in a matrigel plug assay in nude mice that were administered celecoxib. We speculate that treatment with celecoxib may, in some instances, enhance tumor cell expression of VEGF as well as angiogenesis and, consequently, may have detrimental effects on the response of tumors to this drug. Mol Cancer Ther; 10(1); 138–47. ©2011 AACR.