bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A125: Silencing Stat3 signaling in human cancers: Identifying potent small molecule inhibitors of Stat3 function.
Authors: Page Brent D. G. , Zhang Xialoei , Atkinson Jennifer , Li Zhi Hua , Schimmer Aaron D. , Trudel Suzanne , Turkson James , Gunning Patrick T. 
Published: June 2012

Abstract
Stat3 is essential for transducing signals from extracellular stimuli, but also functions as a nuclear transcription factor required for regulating genes involved in proliferation, apoptosis, angiogenesis and invasion, in addition to genes encoding cytokines, chemokines and growth factors. In contrast to the transient nature of Stat3 activation in normal cells, many human cancers, including breast, prostate, ovarian, brain and multiple myeloma (MM) harbor constitutive Stat3 activity. Stat3 downstream target genes are critical to the dysregulated biological processes that promote tumor cell growth, survival and induce chemoresistance, thus targeting Stat3 signaling represents an important therapeutic target in cancer therapy.
We have rationally designed and developed Stat3 inhibitors that disrupt transcriptionaly active Stat3-Stat3 homo-dimers, suppress Stat3 activation (phosphorylation), inhibit Stat3-target gene expression (c-Myc, Bcl-xL, survivin) and potently induce apoptosis in tumor cells harboring aberrant Stat3 activity. Moreover, lead compound BP-1–102, a salicylic acid containing small molecule, induced strong antitumor effects on human breast cancer (MDA-MB-231) xenografts and in MM preclinical tumor models. Most notably, given via oral gavage, BP-1–102 strongly inhibited the growth of human breast tumor xenografts, identifying it as a most potent orally bioavailable Stat3-targeting inhibitor.
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 A125.
Abstract A130: Fragment-based discovery and optimization of Rho kinase inhibitors.
Authors: Liu Yan , Wang Binglin , Patel Ronil A. , Sun Nan , Sung Shen-Shu , Pireddu Roberta , Lawrence Nicholas J. , Sebti Said M. , Li Rongshi 
Published: June 2012

Abstract
Using high concentration biochemical assays and fragment-based screening, we designed and optimized a novel class of Rho-kinase inhibitors. Ligand Efficiency (LE) was employed to assess the binding potential of the fragments and to guide the optimization process. In addition, molecular modeling was used to aide the design of potent inhibitors. A series of fragments as hinge binders were designed and synthesized, and screened using high concentration biochemical assays. Both the spacer length and isomeric tail molecules played key roles in both activity and selectivity. Structure activity relationship studies led to optimization of fragments that yielded potent and selective ROCK 1 and ROCK 2 inhibitors. For instance, compound 24 was highly potent and selective for ROCK 2 (IC50 = 100 nM) over ROCK 1 (IC50 = 1690 nM) whereas compound 18 was potent and selective for ROCK 1 (IC50 = 460 nM) over ROCK 2 (IC50 = 700nM). Compound 24 but not its inactive stereoisomer 23, and compound 18 but not its inactive analog 11 inhibited the phosphorylation of Rho Kinase substrates in intact human cancer cells.
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 A130.
Abstract A131: Drugging the telomere: A rational approach for the selection quadruplex DNA targeting agents for the treatment of cancer.
Authors: Hummersone Marc G. 
Published: June 2012

Abstract
The pentacyclic acridinium class of small molecule telomere targeting agents have been shown to stabilise the 3'single-stranded guanine-rich telomeric overhang to fold into a G-quadruplex structure. Stabilisation of the latter is incompatible with an attachment of telomerase and a collection of protective proteins referred to as the shelterin complex to the telomere. G-quadruplex ligands can effectively inhibit the telomere maintenance functions of telomerase while revealing the chromosomal termini to the unwanted attention of DNA repair proteins resulting in telomere specific damage. Potent antitumor properties of the G-quadruplex ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) have been reported and shown to be driven by telomere uncapping events. However, in preliminary toxological studies the original lead compound (RHPS4) revealed cardiovascular liabilities related to interactions with hERG receptor (IC50 0.2 uM) as well as additional receptor interactions including muscarinic M1, M2 and M3 and Beta2 adrenergic receptors.
Pharminox have designed and synthesised second generation agents with significantly improved on and off target profiles. Here we describe the modification and optimisation of new telomere targeting agents with an emphasis on their specific effect on telomeres.
Specific bio-molecular assays have been performed on the best compounds of the series, as defined by telomeric DNA binding characteristics and cancer cell activities, “normal” cell selectivities and off target affinities. It was found that all new compounds examined were more potent than RHPS4 as telomere damage inducers. Specifically, at the dose of 0,1 uM, the compounds PMX-000177-761-785 trigger a percentage of TIF-positive cells comparable to that induced by RHPS4 at a 5 fold higher drug concentration. Activation of damage response mainly occurred in replicating cells for the compounds PMX-000177 and -785, suggesting that they can work with a RHPS4-like mechanism of action. As part of a defined screening cascade and candidate target profile, these studies are being used to differentiate between compounds as they progress towards pre-clinical candidate selection status.
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 A131.
Abstract A132: S1PR5 structural model and its application in drug discovery.
Authors: Sung Shen-Shu 
Published: June 2012

Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of these activities are mediated through five closely related G-protein-coupled receptors (GPCR) of the S1P receptor (S1PR) family. Because of the technical challenges in crystallization of membrane-bound proteins, S1PR structures have not become publicly available. Instead, homology models were built based on a theoretical model of the retina pigment rhodopsin, which is a GPCR with a covalently bound ligand (Parrill, A. L. et al. J. Biol. Chem. 2000, 275, 39379). Recently, new techniques in crystallization have made more GPCR structures available, including those in complex with their agonist, antagonist, or inverse agonist. These structures provide more realistic basis for building S1PR structural models, and at the same time raise a new question about which structure to use in drug design and virtual screening. In this presentation, two structural models of S1PR subtype 5 (S1PR5, Kothapalli, R, Kusmartseva I, and Loughran Jr T. P. et al. Biochim. Biophys. Acta 2002, 1579, 117) are constructed based on crystal structures of β2-adrenergic receptor (β2AR), one of the most extensively studied GPCR. A nanobody-stabilized active state of β2AR (Soren, G. F. et al. Nature 2011, 469, 175) and an inactive state of β2AR in complex with its partial inverse agonist (Cherezov, V. et al. Science 2007, 318, 1258; Hanson, M. A. et al. Structure 2008, 16, 897) are used in building the two models, which are subsequently tested by in silico docking of their known ligands. The models based on active and inactive β2AR are used in virtual screening to find potential activators and inhibitors, respectively. Results from the two models are compared and their different applications are discussed.
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 A132.
Abstract A139: Development of EML4-ALK addicted cell models for evaluating sensitivity to ALK inhibitors.
Authors: Ise Nobuyuki , Nambara Daisuke , Omi Kazuya , Goishi Katsutoshi 
Published: June 2012

Abstract
Background: EML4-ALK fusion tyrosine kinase has been implicated in the pathogenesis of a subset of non-small-cell lung cancers (NSCLCs). The fusion kinase is a rational therapeutic target for addicted cancer cells whose sustained proliferation and survival depend on it. Cancer cell lines harboring the fusion kinase gene are useful for screening effective therapeutic agents. However, few cell lines have been identified so far, and these cell lines do not represent all the variants discovered in clinical specimens. Moreover, drug-resistant mutations in the fusion gene have recently been identified in patients treated with ALK inhibitors. Techniques to establish cell models addicted to certain genes will be invaluable for developing effective drugs for molecular targeted therapy. We have developed a new method to easily and efficiently establish cell models exhibiting addiction to introduced oncogenes. We evaluated the method for variants of EML4-ALK fusion oncogene including drug-resistant mutants.
Material and methods: EGFR-addicted NSCLC cell lines were transfected with each variant of EML4-ALK fusion gene, and the cells addicted to the introduced fusion gene for their growth and survival were selected. Expression of EML4-ALKs in the obtained cells was confirmed by immunoblotting. Their dependence on the introduced fusion gene was assessed by MTS assay following ALK inhibitors treatment. Direct inhibitory effect of the drugs was analyzed by monitoring the autophosphorylation levels of EML4-ALKs.
Results: EML4-ALK addicted cells were efficiently established from all the transfectants. They expressed the introduced variant of EML4-ALK. Each of the ALK inhibitors tested in this study exerted distinct anti-growth activities toward the established cell models. PF-2341066 had the strongest, dose-dependent inhibitory effect on the growth of the addicted cells. This agent also inhibited autophosphorylation of EML4-ALKs in parallel with the growth inhibition activity, but failed to inhibit cells expressing drug-resistant EML-4-ALK.
Conclusions: We demonstrated that cancer cell models addicted to EML4-ALK can be easily established from EGFR-addicted cell lines. Since the established cells depended on the introduced EML4-ALK genes for their growth and survival, the introduced genes likely preserved their oncogenic functions in these cells. Our method will provide useful cell models to evaluate the efficacy of various inhibitors in vitro and elucidate functions and signaling pathway of EML4-ALKs.
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 A139.
Abstract A140: Development of high-throughput assay for new agents that inhibit the transcription of the HIF-1alpha gene.
Authors: Sun Daekyu , Shin Yoon-Joo , Uribe Diana 
Published: June 2012

Abstract
The hypoxic (low-oxygen) region is developed in most solid tumors as they grow and outstrip their blood supply. A critical mediator of this series of hypoxic responses is known as the transcription factor hypoxia-inducible factor 1 (HIF-1), which mediates increased expression of proteins that promote angiogenesis, anaerobic metabolism, and many other survival pathways. Therefore, HIF-1 alpha has been proposed as a particular target for therapeutic intervention of human cancer. Thus, there is need for extensive discovery of new types of more specific HIF-1 inhibitors, including small molecules that directly inhibit the transcription of the HIF-1 alpha gene. In our preliminary studies, we have demonstrated that the transcription of HIF-1 alpha gene is greatly dependent upon the presence of the pPu/pPy tract within its proximal promoter region. We further explored if it is feasible to identify small molecules that inhibit the transcription of the HIF-1 alpha gene by interfering with the assembly of the transcription machinery to the proximal promoter region of this gene. As a means of measuring promoter response to small molecules in cells, the luciferase reporter-based cell assays would be simple, straightforward, and very effective. Thus, this assay could also be used to identify transcriptional inhibitors of the HIF-1 alpha gene. To determine if luciferase reporter assay is amenable for high-throughput screening for novel inhibitors of the transcription of the HIF-1 alpha gene, we used the Flp-In system to generate genetically engineered Flp-In 293 cell lines stably expressing the firefly luciferase gene under the control of the HIF-1 alpha promoter as described in our preliminary studies. In our preliminary studies, we have also demonstrated that the transcription of HIF-1 alpha gene is greatly dependent upon the presence of the pPu/pPy tract within its proximal promoter region.
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 A140.
Abstract A141: Analysis of cellular kinase activity of resistance-related MET mutants using transmembrane-domain (TMD) activated kinase variants.
Authors: Weber Holger , Mueller Daniel , Totzke Frank , Feger Daniel , Mueller Melanie , Birkle Marianne , Kubbutat Michael HG , Schaechtele Christoph , Ballmer-Hofer Kurt , Ehlert Jan E. , Graeser Ralph 
Published: June 2012

Abstract
Kinases are important targets in oncology. However, the frequent emergence of resistance (gatekeeper) mutants in target kinases seriously limits the patient's response time to a given drug. Secondary drugs need to be developed that specifically target mutant enzymes. The discovery of such kinase inhibitors requires relevant assay systems. In order to efficiently analyze whether novel inhibitors target gatekeeper mutants of a given kinase in a cellular context we set out to establish a suitable cellular test system for the receptor tyrosine kinase MET. Our aim was to minimize variations such as cellular background and ligand dependent activation while putting the focus on the mutation of interest. In an approach to uncouple kinase activity from ligand activation, we screened a set of artificial transmembrane domains (TMD) to identify a TMD that induces constitutive MET autophosphorylation in transient transfections. Subsequently, Rat1 cells were transduced to express the tag-labelled intracellular wild-type (wt) MET domain harbouring the activating TMD while lacking the extracellular domain. Characterization of TMD-MET-wt in Rat1 cells showed constitutive MET expression and phosphorylation. ELISA studies to analyze the inhibition of MET phosphorylation by cognate MET inhibitors revealed comparable IC50 values to those obtained with wild-type MET naturally over expressed in MKN45 gastric carcinoma cells. Moreover, expression of TMD-MET-wt in Rat1 cells led to cell transformation as assessed by growth in soft agar as well as in vivo as a subcutaneous xenograft. Interestingly, the same artificial TMD induced constitutive activity of various gatekeeper mutants of MET when transduced into Rat1 cells. This observation allowed for the comparative analysis of various small molecule MET inhibitors on multiple MET mutants in an identical cellular background and without the need of ligand-induced kinase activation. Using a straight forward ELISA-based approach, we generated profiles of various MET inhibitors on cellular MET mutant phosphorylation and compared these with inhibition profiles obtained in biochemical MET activity assays.
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 A141.
Abstract A145: EGFR-targeting of carbon nanovectors loaded with paclitaxel improves their antitumor efficacy and radiosensitization of head and neck squamous cell carcinoma in vivo.
Authors: Sano Daisuke , Berlin Jacob M. , Marcano Daniela C. , Valdecanas David R. , Zhou Ge , Milas Luka , Tour James M. , Myers Jeffrey N. 
Published: June 2012

Abstract
Nanoparticels have been researched broadly as new generation of diagnostics, imaging agents, and drugs for detecting and treating cancer. We previously developed PEGylated small hydrophilic carbon clusters (PEG-HCCs) and reported that PEG-HCCs conjugated with paclitaxel (PTX/PEG-HCCs) is a stable effective drug delivery system with minimal toxicity. Here, we describe the establishment of targeted nanovectors by simply mixing PTX/PEG-HCCs with cetuximab (ImClone Systems), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. The specificity of this EGFR targeted method of delivery of PTX/PEG-HCCs was demonstrated in mice implanted subcutaneously on opposing flanks with EGFR expressing, OSC-19 (head and neck squamous cell carcinoma: HNSCC) cells and non-EGFR-expressing MCF-7 cells in a nude mouse. The targeted nanovector system, Cet/PTX/PEG-HCCs, showed greater efficacy superior than PTX/PEG-HCCs on OSC-19 tumor growth, but not on MCF-7 tumors. Cet/PTX/PEG-HCCs also showed greater growth inhibition prolonged survival compared to PTX or PTX/PEG-HCCs in an orthotopic nude mouse model of human HNSCC. These results suggested that Cet/PTX/PEG-HCCs can targeted to HNSCC overexpressing EGFR cells. In addition, Cet/PTX/PEG-HCCs were found to radiosensitize HNSCC cells both in vitro and in vivo. Cet/PTX/PEG-HCCs plus radiation inhibited tumor growth and prolonged survival in vivo. This work is highly significant as success would allow for targeted chemotherapy for HNSCC by simply mixing commercially available drugs and antibodies with a nanovector solution.
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 A145.
Abstract A16: Defining the essential in vivo oncogenic function of p63 in squamous cell carcinoma.
Authors: Ramsey Matthew R. , Wilson Catherine , Ory Benjamin , Faquin William C. , Milla Alea A. , Ellisen Leif W. 
Published: June 2012

Abstract
The p63 transcription factor controls diverse functional programs within the epithelium. Despite its essential developmental role, however, the precise contribution of p63 in cancer remains controversial, and the relevant p63-dependent pathways remain poorly understood. Squamous Cell Carcinoma (SCC) is a common and treatment-refractory form of human cancer that can arise in various epithelial tissues including the lungs, skin, and head and neck region. In SCC, the p63 locus is frequently targeted for genomic amplification and/or overexpression, leading to tumor-specific up-regulation of ΔNp63α. In vitro studies point to a role for ΔNp63α in survival of SCC cells, yet such models are unlikely to fully reflect the contribution of p63 in squamous cancers. We therefore developed an in vivo model in order to address in a definitive manner the role of p63 in progression and maintenance of this disease. We generated a murine model of SCC that faithfully recapitulates the molecular and pathological features of human SCC, including high-level expression of p63, invasion and metastasis. We crossed this model to a conditional p63-null allele (p63flox) and a tamoxifen-inducible Cre transgene, K14-CreER. Remarkably, we find that genetic excision of endogenous p63 in SCC-bearing mice results in rapid, dramatic, and sustained regression of tumors. This effect is due in large part to increased tumor-specific apoptosis, and is associated with no appreciable effects on normal p63-expressing tissues. We then performed global gene expression profiling and extensive validation in order to uncover the key transcriptional programs mediating this survival effect. Unlike previous in vitro work which defined a predominant role for pro-apoptotic Bcl-2 family members in p63-dependent tumor cell survival, our in vivo studies have uncovered a key role for growth factor receptor tyrosine kinases (RTKs) downstream of p63. We find that p63 is a direct transcriptional regulator of these RTK genes, and we support the relevance of these findings to human disease by showing a strong correlation between p63 and these essential p63-regulated genes in human head and neck SCC tumors. Collectively, these studies have established the oncogenic function of p63 in SCC, and they have uncovered a novel and essential pathway mediating p63-dependent tumor maintenance. Ongoing work to be presented seeks to validate this RTK pathway as a potentially important therapeutic target in SCCs which overexpress p63.
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 A16.