bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C24: Phase I trial of dasatinib and ixabepilone in patients with solid tumors.
Authors: Herbolsheimer Pia M. , Kapoor Rita , Smith Karen L. , Perry David , Verma Nitin , Veytsman Irina , Jelinek James , Swain Sandra M. 
Published: June 2012

Abstract
Background: Ixabepilone is an epothilone B analog that stabilizes tubulin, disrupts homeostasis and induces apoptosis. Dasatinib is a potent oral tyrosine kinase inhibitor (TKI), which inhibits multiple targets including SRC. Synergistic activity has been reported when combining dasatinib with chemotherapy agents. This phase I study was conducted to determine the dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), pharmacokinetics (PK) and preliminary antitumor activity for ixabepilone and dasatinib when used in combination.
Methods: Patients with metastatic or unresectable solid tumors who progressed on standard therapy received ixabepilone and dasatinib at escalating doses. An expansion cohort was formed after the MTD was reached. PK studies were performed.
Results: Nineteen patients were enrolled. No DLTs were seen at dose level (DL) 1 (ixabepilone 30 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD). At DL 2 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 100 mg PO QD), the second patient had 3 DLTs (grade 3 diarrhea, grade 4 neutropenia and grade 3 febrile neutropenia), thus DL 2 was expanded to include 6 patients. No additional DLTs were seen at DL 2. At DL 3 (ixabepilone 40 mg/m2 IV Q 3 weeks, dasatinib 150 mg PO QD), the first patient developed grade 3 diarrhea during cycle 2 and the second patient had a DLT (grade 3 diarrhea) and grade 3 mucositis during cycle 2. Accrual to DL 3 was halted due to these toxicities and MTDs were designated to be ixabepilone 40 mg/m2 IV every 3 weeks and dasatinib 100 mg PO daily (DL 2). Additional 8 patients were then enrolled to DL 2. Three of these patients experienced DLTs (grade 4 neutropenia, grade 3 hyperkalemia and grade 3 fatigue). The best responses included one (5%) partial response (PR) in a lung cancer patient. Twelve (63%) patients had stable disease (SD) for at least 2 cycles. Altogether 13 (68%) patients came off study due to toxicities.
Conclusion: The combination of ixabepilone and dasatinib showed modest clinical activity with doses 40 mg/m2 IV every 3 weeks and100 mg PO QD, respectively. Treatment related toxicities were seen frequently.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C24.
Abstract C4: Specific targeting of spontaneous medulloblastoma tumors in mice by IRDye 800CW chlorotoxin.
Authors: Kovar Joy L. , Curtis Evan , Othman Shadi F. , Simpson Melanie A. , Olive D. Michael 
Published: June 2012

Abstract
Studies of primary brain tumors such as medulloblastoma are hampered by the nature of the cancer and the location of these tumors. Improving our ability to detect and assess intracranial tumor growth would significantly advance diagnosis and inform recommendations by clinicians for subsequent therapy and treatment. Use of molecular imaging with targeted near infrared optical imaging agents has been successfully implemented in the visualization, characterization and measurement of biological processes including cancer. Our studies seek to define the use of IRDye 800CW chlorotoxin (CLTX) as a targeted imaging agent for brain tumors in a spontaneous mouse model of medulloblastoma, ND2:SmoA1. Early detection of tumors was accomplished by MRI followed by IRDye 800CW CLTX administration. Blood-brain-barrier integrity was examined by Evan's Blue testing prior to sacrifice. Additional information was obtained with brain imaging and tissue section analysis of H&E staining to confirm colocalization of tumor and fluorescent probe signal. Results show IRDye 800CW CLTX successfully targeted tumor tissue with minimal Evan's Blue staining, indicating retention of blood-brain-barrier integrity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C4.
Abstract C40: Understanding the mechanism of action of novel iron chelators on drug-resistant neoplastic cells.
Authors: Yamagishi Tetsuo , Jansson Patric J. , Sharp Danae , Richardson Des R. 
Published: June 2012

Abstract
Introduction: Deprivation of cellular iron (Fe) may represent a novel and effective anti-cancer strategy1. Our laboratory has developed iron chelators with marked and selective anti-tumor activity against a variety of tumor types in vitro and in vivo. One of our leading compounds, Dp44mT, demonstrated potent anti-tumor activity against drug-resistant cell lines1,2 over-expressing P-gp and MRP1. Moreover, these compounds possess high activity at releasing cellular 59Fe3.
Aims: To further understand the mechanism of chelator-mediated cellular 59Fe release we investigated:The difference in iron efflux between drug-resistant MCF7-VP (MRP1 hyper-expressing) cells and their wild-type counterparts (MCF7);Whether chelator-mediated Fe release was MRP1 and/or GSH-dependent and;If chelator-mediated cellular Fe release was temperature-dependent.
Results: These studies demonstrated that MRP1 over-expressing MCF7-VP cells showed reduced chelator-mediated59Fe release compared to MCF-7 cells (P&lt;0.001). However, this was not due to functional MRP1 and was not GSH-dependent, as neither MRP1 inhibition (using MK571) nor GSH-depletion (using BSO) had any effect on chelator-mediated 59Fe efflux. We found 59Fe efflux was shown to be temperature-dependent, as chelator-mediated 59Fe efflux was reduced at 4°C compared to 37°C. This suggested chelator-mediated Fe release by chelators was an energy dependent process.
Interestingly, MCF7-VP cells showed higher 59Fe uptake from 59Fe-transferrin than wild-type cells. This was due to marked transferrin receptor-1 expression in MCF7-VP compared to MCF7 cells. Additionally, the only known Fe efflux pump, ferroportin1, was down-regulated in MCF7-VP cells. This latter observation was intriguing as chelator-mediated Fe efflux was depressed in this cell type. These studies indicate that chelator-mediated 59Fe release is temperature-dependent and MRP-independent. Further studies will examine the role of MRP1 in Fe uptake and metabolism.
References:
1. Whitnall, M., Howard, J., Ponka, P., and Richardson, D. R., Proc Natl Acad Sci U S A 103 (40), 14901 (2006).
2. Richardson, D. R. and Milnes, K., Blood 89 (8), 3025 (1997).
3. Richardson, D. R., Biochim Biophys Acta 1320 (1), 45 (1997).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C40.
Abstract C46: Design, synthesis, and functional evaluation of leukocyte-function associated antigen-1 (LFA-1) antagonists in early and late stages of cancer development.
Authors: Sebastin Eider San , Zimmerman Tahl , Zubia Aizpea , Vara Yosu , Martin Elyette , Dejaegere Annick , Stote Roland H. , Lopez Xabier , Pantoja-Uceda David , Valcarcel Maria , Mendoza Lorea , Vidal-Vanaclocha Fernando , Cossio Fernando P. , Blanco Francisco J. 
Published: June 2012

Abstract
The integrin Leukocyte Function-associated Antigen-1 (LFA-1) recognizes and binds the Intercellular Adhesion Molecule-1 (ICAM-1) by its L chain Inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report here the rational in silico design, small scale synthesis and biological activity evaluation of a novel family of potent LFA-1 antagonists. The structure-based design led to the synthesis of a family of highly substituted homoquiral pyrrolidines that mimic key residues of the ICAM-1 moiety. Some of these compounds showed both antiproliferative and anti-metastatic activity in a murine model of melanoma, as well as potent anti-adhesive properties in several cancer cell lines in the low micromolar range. The molecular mechanism of action of selected antagonists have been investigated by NMR analysis of their binding to the isolated I-domain of LFA-1. We show that the compounds bind to the I-domain Allosteric Site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C46.
Abstract C48: Detection of GNAQ/GNA11 mutations in circulating cell-free DNA as a biomarker of uveal melanoma.
Authors: Madic Jordan , Trouillet Benedicte , Gentien David , Milder Maud , Saada Stephanie , Assayag Franck , Nemati Fariba , Decaudin Didier , Desjardins Laurence , Piperno-Neumann Sophie , Lantz Olivier , Stern Marc-Henri 
Published: June 2012

Abstract
Background: Circulating tumor-derived DNA (ctDNA) can be detected in the plasma of cancer patients. Recently, ctDNA was proposed as a biomarker to follow tumor burden and monitor treatment efficacy (1). However, ctDNA represents a tiny fraction of the normal cell-free circulating DNA, and its assessment is challenging due to specificity, sensitivity and quantitative issues.
Patients and methods: We developed a real-time PCR based on the pyrophosphorolysis-activated polymerization (bi-PAP) for the quantification of ctDNA in plasma of patients with uveal melanoma (UM). Bi-PAP can detect known point mutations independently of large excess of normal DNA (2). Our assay targets the activating mutation of codon 626 of GNAQ or GNA11 which are present in most UM (3, 4).
Results: Bi-PAP primer pairs specific for GNAQ 626A&gt;T, GNAQ 626A&gt;C and GNA11 626A&gt;T have been chosen. Their sensitivity and specificity were assessed on serial dilutions of tumor DNA in normal DNA. Each assay could detect a single mutated molecule per reaction, while 104 copies of normal DNA were not detected. In plasma of mice bearing UM xenografts, ctDNA were proportional to the amount of circulating human DNA and to the size of the xenograft. Furthermore, in a retrospective analysis of 19 UM patient sera, 8 were found positive.
Conclusion: Bi-PAP represents a promising tool for the quantification of ctDNA in the blood of UM patients. A prospective study is on going to confirm the clinical value of ctDNA level in metastatic UM patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C48.
Abstract C68: Suppression of AKT/mTOR antiapoptotic signaling by a novel drug candidate results in growth arrest and apoptosis of hepatocellular carcinoma-derived cell lines.
Authors: Cuconati Andrea , Mills Courtney , Zhang Xianchao , Yu Wenquan , Goddard Cally , Guo Haitao , Xu Xiadong , Block Timothy M. 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer fatalities worldwide, with chronic hepatitis B infection accounting for 60% of cases. In the majority of new diagnoses, primary tumor size contraindicates surgical resection, limiting available treatment options to rarely-curative interventions that generally have severe side effects. Overall, advanced HCC is largely incurable, with a five year survival rate of &lt;5%. To expand the treatment pipeline, we conducted a high-throughput screening campaign of our 85,000-compound small molecule library to identify agents that would exhibit selective cytotoxicity for HCC-derived cell lines, as compared to immortalized non-transformed human hepatocytes. A disubstituted aminothiazole, termed HBF-0079, emerged as a potent and selective inhibitor of cell growth and viability in the HCC lines Huh7, Hep3b, HepaRG, MHCC97H and MHCC97L, and the hepatoblastoma line HepG2, with EC50 values from 0.7 to 33 μM. Conversely, growth and viability in the non-tumorigenic hepatocyte lines THLE2 and PH5CH, and several other non-HCC cancer lines, showed only moderate to no sensitivity. Subsequent structure-activity relationship studies have identified relevant features of the molecule, and resulted in two compounds that retain selectivity and improve EC50 to &lt; 0.1 μM in Huh7. In a murine xenograft model, growth of Hep3B-derived tumors was significantly delayed by either systemic or intratumoral administration of HBF-0079. As determined in cell culture withdrawal experiments, incubation of Huh7 cells with HBF-0079 resulted in irreversible onset of growth arrest and apoptosis. Cell cycle analysis indicated arrest in G1/G0, with subsequent entry of cells into a sub-G0 population consistent with apoptotic cell death. While a putative molecular target is currently being confirmed, we have determined that treated Huh7 cells undergo loss of AKT phosphorylation at the mTORC2-targeted residue S473, with subsequent loss of phosphorylation of the mTORC1 targets SK6 and 4EBP1; these observations are consistent with cell cycle arrest and onset of apoptosis, ostensibly through loss of AKT survival signaling and global translational shutoff. Conversely, phosphorylation of Akt or mTORC1 targets is not affected in the non-sensitive PH5CH line. Thus, we have identified a cytotoxic molecule with in vitro selectivity for liver-derived cancer cells. In vivo efficacy studies and chemical hit-to-lead optimization are currently ongoing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C68.
Abstract C96: A novel polyclonal antibody library for expression profiling of poorly characterized membrane and secreted human proteins.
Authors: Grifantini Renata Maria , Pagani Massimiliano , Pierleoni Andrea , Grandi Alberto , Parri Matteo , Campagnoli Susanna , Pileri Piero , Cattaneo Davide , Pontillo Angela , Canidio Elena , Nogarotto Renzo , De Camilli Elisa , Abrignani Sergio , Viale Giuseppe , Sarmientos Paolo , Grandi Guido 
Published: June 2012

Abstract
The YOMICS™ antibody library (http://www.yomics.com/) presented in this article is a new collection of 1559 murine polyclonal antibodies specific for 1287 distinct human proteins. This antibody library is designed to target marginally characterized membrane-associated and secreted proteins. It was generated against human proteins annotated as transmembrane or secreted in GenBank, EnsEMBL, Vega and Uniprot genome databases, described in no or very few dedicated PubMed-linked publications. The selected proteins/protein regions were expressed in E. coli, purified and used to raise antibodies in the mouse. The capability of YOMICS™ antibodies to specifically recognize their target proteins either as recombinant form or as expressed in cells and tissues was confirmed through several experimental approaches, including Western blot, confocal microscopy and immunohistochemistry (IHC). Moreover, to show the applicability of the library for biomarker investigation by IHC, five antibodies against proteins either known to be expressed in some cancers or homologous to tumor-associated proteins were tested on tissue microarrays carrying tumor and normal tissues from breast, colon, lung, ovary and prostate. A consistent differential expression in cancer was observed. Our results indicate that the YOMICS™ antibody library is a tool for systematic protein expression profile analysis that nicely complements the already available commercial antibody collections.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C96.
Abstract CN01-02: canSAR: An integrated cancer drug discovery informatics platform allowing systematic target evaluation.
Authors: Al-Lazikani Bissan , Patel Mishal , Bulusu Krishna , Halling-Brown Mark 
Published: June 2012

Abstract
Large-scale systematic analyses of the underlying genetics and proteomics of cancer, as well as the systematic mapping of effects of RNAi and chemical screens on different cancer cells are empowering cancer drug discovery and paving the way to wider stratified medicine approaches to the treatment of cancer. However, this deluge of data poses an equally large challenge of effectively integrating such massive and heterogeneous datasets in a manner that allows researchers to benefit from a multidisciplinary view across different. To address this need, we have developed a multidisciplinary cancer platform, canSAR (http://cansar.icr.ac.uk). It integrates millions of experimental datapoints ranging from chemical and RNAi screening, to expression, drug ADMET studies and 3D structural complexes. In this presentation we describe canSAR and show examples of how it has been utilized in the knowledge-driven prioritization of targets for drug discovery.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN01-02.
Abstract CN02-01: Functional genomics to identify targets and resistance.
Authors: Hahn William C. 
Published: June 2012

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. While these approaches will yield critical information regarding the identify, number, and types of alterations found in human tumors, a complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. In pilot studies, we have identified several genes that act as synthetic lethal partners to known oncogenes or mediate resistance to targeted therapies. In recent work, we have expanded the scale of these experiments to genome scale in more than 100 cell lines, which has permitted greatly expanded and deeper investigation into genes that program the malignant state. Taken together, these studies suggest that combining forward and reverse genetic approaches with information derived from the cancer genome characterization projects will yield a comprehensive list of cancer vulnerabilities and establish a general approach for the rational identification of oncogenic and co-dependent pathways in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN02-01.
Abstract CN05-01: Targeting Mdm2 in DNA repair and chromosome instability.
Authors: Eischen Christine M. 
Published: June 2012

Abstract
Mdm2, a direct inhibitor of the p53 tumor suppressor, is frequently overexpressed in many human malignancies. Increased levels of Mdm2 negatively impact genome stability, a common property of cancer cells. Recently, it has been appreciated that both p53-dependent and p53-independent functions of Mdm2 contribute to genome instability and tumorigenesis. Specifically, Mdm2 induces chromosome instability not only by inhibiting p53 activity, but also through inhibition of the Mre11/Rad50/Nbs1 DNA repair complex. We have shown that Mdm2 binds Nbs1 and inhibits early DNA damage signaling, resulting in a delay in DNA break repair. This delay in DNA repair leads to increased chromosome breaks, altered ploidy, and enhanced cellular transformation potential. Elevated Mdm2 levels also increase the severity and frequency of chromosome abnormalities that arise during aging and that have been linked to cancer development. Therefore, Mdm2 negatively influences genome stability, which contributes to tumorigenesis. However, this effect of Mdm2 on the genome may be therapeutically exploitable for the treatment of malignancies. In pursuit of this goal, we have begun testing small molecule inhibitors of Mdm2:p53 interaction, such as Nutlin, for consequences on DNA break repair.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN05-01.
Abstract CN06-02: TGF-beta and cancer stem cells.
Authors: Seoane Joan 
Published: June 2012

Abstract
Cancer stem cells also known as cancer-initiating cells (CICs) are cells with stem cell-like characteristics that are present within the tumor mass. CICs are considered to be responsible for tumor initiation, maintenance and recurrence, and hence are optimal therapeutic targets against cancer. Moreover, CICs are resistant to conventional therapy and, when inoculated in immunocompromised mice, generate tumors with the same characteristics as the original tumor from the patient. We have focused our studies in CICs obtained from human glioblastoma (GICs). Analyzing human glioma biopsies, primary cultured patient-derived tumor cells, patient-derived GICs and mice reproducing the human tumor, we have discerned the mechanisms and molecular determinants of GICs. The talk will be focused on the effect of TGF-beta on GICs. TGF-beta is a cytokine with an important role in cancer and several inhibitors of the TGF-beta signaling pathway are being developed to be used as anti-cancer therapies. However, it is crucial to understand the molecular pathways implicated in the malignant role of TGF-beta in oncogenesis in order to select the patient population that may benefit from an anti-TGF-beta therapy. We have observed that TGF-beta induces the self-renewal capacity of GICs and inhibition of TGF-beta decreases the amount of GICs present in the tumor. Our results have important implications on anti-TGF-beta therapeutic approaches that are being tested in clinical trials in our Hospital.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN06-02.