bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C132: Radiosensitization of solid tumors by an MDM2 inhibitor (HLI373989).
Authors: Cerna David , Carter Donna , Yoo Stephen S. 
Published: June 2012

Abstract
The tumor suppressor p53 is a key molecule in the prevention of cancer. More than half of all human cancers have mutation or loss of the p53 gene. A significant percentage of the other half contain overexpression of Hdm2 which serves as a ubiquitin ligase (E3) to target p53 for degradation. While it has been established that an inhibitor of Hdm2 ubiquitin E3 ligase activity HLI373 (5-(3-dimethylaminopropylamino)-3,10-dimethyl-10H-pyrimido(4,5-b)quinoline-2,4-dione, NSC373989), selectively kills tumor cells harboring wild-type p53, we investigated the effect of the Hdm2 inhibitor HLI373, in the response to ionizing radiation in solid tumor lines expressing wild-type, mutant or null p53 in vitro and in vivo. We now report HLI373 enhances radiosensitivity in a panel of human tumor cell lines in p53 deficient and competent cell lines using clonogenic assay. HCT116 cells exposed to HLI373 (5–7.5 uM) for 16 hours before and maintained in the medium after irradiation had an increase in radiosensitivity. Cell cycle distribution of treated cells after 16 hours was measured using flow cytometry. In a comparison of wildtype and null cell lines, cell cycle arrest in G1 was only detected in cells with active p53 at 5uM of HLI373. In contrast, cells with a null or mutated p53 progressed to and arrested in G2. In addition, wild type p53 cells pretreated with 5 uM HLI373 and irradiated continued to be arrested in G1 and did not progress to a G2. However, cells without p53 treated with HLI373 and radiation increased in accumulation in G2. Treatment with higher dosages of HLI373 (&gt;10uM) resulted in the accumulation of cells in G2 regardless of p53 status. These results indicate that HLI373 enhances tumor cell radiosensitivity in vitro and agents such as HLI373 may have potential for use in the clinics.
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 C132.
Abstract C141: Screening of novel RNA aptamer(s) that selectively bind(s) to prostatic acid phosphatase.
Authors: Kong Hoon Young , Byun Jonghoe 
Published: June 2012

Abstract
Prostate cancer is becoming one of the most popular non-skin cancers in Korea due to continued increase of western life styles. Since earlier detection of prostate cancer can lead to complete cure, a lot of studies have been done on prostate cancer markers such as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostate acid phosphatase (PAP) and prostate stem cell antigen (PSCA). Among these biomarkers, PAP is gaining renewed interest because of its potential merits in diagnosis and therapeutics. PAP, which was initially identified in 1935, is an abundant enzyme that is synthesized in prostate epithelial cells and has enzymatic activity in acidic conditions. PAP expression is androgen-independent and increases in proportion to prostate cancer progression. Indeed, PAP expression level has high correlation with cause-specific survival and its dephosphorylation activity is believed to play an important role in the incidence and development of prostate cancer. Here, we screened the in vitro transcribed RNA libraries to get aptamer(s) that can selectively bind to PAP. Aptamers are oligonucleic acid molecules that bind to a specific target through formation of tertiary structures. These chemical antibodies can bind their target molecules with a high affinity and specificity and have the advantage of being less immunogenic in vivo. For in vitro selection, the ectracellular domain of PAP were cloned from PC3 cells and subjected to 6 rounds of SELEX procedure. This resulted in enrichment of the RNA aptamers that bound to the PAP ectodomain with 3-fold higher affinity than the library control as evidenced by real-time RT-PCR and gel shift assay. Sequence analysis of the aptamers revealed three distinct groups (G1, G2, N) having variable sequences within the region comprising nucleotides 43 to 87. The Kd values of the best clones with the highest affinity were within 120nM. These clones could also bind to the PAP-positive cells such as PC3 and LNCaP cells. Interestingly, 2'-OH-modification of the aptamers led to loss of binding, implying that 2'-F modification may be essential in binding to PAP. Characterization of these aptamers is currently underway and initial minimization results suggest that the structure coming from the 50 nucleotides is essential for binding to PAP. With further optimization, these PAP RNA aptamers could find wide application in theragonosis of prostate 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 C141.
Abstract C145: Compounds that inhibit the activation of Grb2 by EGFR, HER2, and HER3 complexes.
Authors: Story Michael J. , Marshall Philip A. , Ayoub Mohammed A. , Pfleger Kevin DG 
Published: June 2012

Abstract
Purpose: To demonstrate that ORIL003 (Glc4-Rha2-Glc-diosgenin; full structure will be disclosed) inhibits the activation of Grb2 by EGFR, HER2 and HER3 complexes using the Receptor-Heteromer Investigation Technology (Receptor-HIT) on the bioluminescence resonance energy transfer (BRET) platform.
Introduction: The unique property of inhibiting a range of receptor tyrosine kinases (RTKs) in the cell plasma membrane has been demonstrated in a family of steroid saponins. As the compounds have a pan-inhibitory effect, they are effective in inhibiting a wide range of cancer cell types, including lung, breast, prostate, colorectal, melanoma, ovarian and leukemia.
Methods: Receptor-HIT, previously published in the form of G protein-coupled receptor heteromer identification technology (GPCR-HIT; See et al, 2011 Assay Drug Dev Technol 9:21–30), was used to determine close proximity and activation of ErbB growth factor receptors and Grb2. EGFR, HER2 and HER3 were tagged with Rluc8 (a variant of Renilla luciferase) as donor; Grb2 was tagged with GFP2 (a variant of green fluorescent protein) as acceptor. Human embryonic kidney 293 cells were stimulated with either epidermal growth factor (EGF) or heregulin (HRG) at a concentration of 20–50 nM. ORIL003 (as an example of the steroid saponin family) was applied to the cells at a concentration of 10 μM, which was known from in vitro studies to completely inhibit cancer cell growth.
Results: Stimulation by EGFR or HRG resulted in recruitment of Grb2. This recruitment was inhibited by the use of ORIL003 in a dose-dependent manner. Furthermore, constitutive interactions between the ErbB growth factor receptors and Grb2 also appear to be inhibited by ORIL003.
Conclusions: ORIL003 is effective in inhibiting the activation of Grb2 by EGFR, HER2 and HER3 complexes.
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 C145.
Abstract C150: CaMKKβ-mediated phosphorylation of Beclin 1 regulates autophagy and cell differentiation in neuroblastoma cells.
Authors: Wu Xiao-Qi , Li Dan-Dan , Deng Rong , Jiang Shan , Feng Gong-Kan , Zhu Xiao-Feng 
Published: June 2012

Abstract
Autophagy is an evolutionarily conserved degradative pathway by which components of the cells are degraded in the lysosome in response to stress. Beclin 1 plays a central role in autophagy. Pioneering work has indicated that the increase in cytosolic Ca(2+) can induce autophagy via the CaMKKβ-mediated activation of AMPK. Here, we demonstrate a novel signaling pathway in which CaMKKβ regulates autophagy and differentiation. We found that Ca(2+) mobilizing agents (ionomycin and EB1089) induced phosphorylation of Beclin 1 and autophagy through CaMKKβ-dependent pathway. Using In vitro kinase assay we demonstrated that CaMKKβ directly phosphorylated Beclin 1 Ser90. Moreover, autophagy induced by ionomycin or EB1089 contributed to degradation of Id1 (inhibitor of differentiation). The inhibitors of autophagy including Bafilomycin A1 and chloroquine and RNA interference of autophagy-associated gene atg 5 markedly increased the protein levels of Id1 and abrogated neuroblastoma cell differentiation. Taken together, CaMKKβ promoted autophagy by directly phosphorylating Beclin 1 at Ser90, and thus induced cell differentiation in neuroblastoma 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 C150.
Abstract C177: Chemical-driven biological probing: Discovery of a novel antimetastatic drug.
Authors: Xu Li , Farmer Rebecca , Huang Xiaoke , Valsecchi Matias , Pavese Janet , Voll Eric , Biddle Margaret , Nibbs Antoinette , Pruell Sean , Avram Michael , Scheidt Karl , Bergan Raymond C. 
Published: June 2012

Abstract
Chemicals constitute richly informative probes, have high resolving potential and are able to uncover complex biological processes. Harnessing this potential provides an avenue for the discovery of new therapeutics that act via novel mechanisms. We focused these principles upon an intractable problem: cancer metastasis. We started with a chemical scaffold with broad bioactivity, with desirable drug-like properties and that would support synthetic diversification. Initially focusing upon human prostate cancer (PCa) we then coupled fragment-diversification and novel synthetic routes to upfront positive selection screens (inhibition of cell motility) and negative selection screens (cell toxicity) in an iterative fashion. We thereby efficiently synthesized a new class of bioactive compounds that inhibits systemic PCa metastasis at low nanomolar concentrations. Efficacy against other cancer types was demonstrated. Extensive investigations indicate high specificity and no toxicity. Target validation studies point to inhibition of protein-protein interaction motifs. Together, these studies support the notion that this approach is powerful, can be broadly applied across biological systems, and constitutes a paradigm. Specifically, they have led to the discovery of a novel acting drug that inhibits human cancer metastasis.
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 C177.
Abstract C199: Sorafenib targets BCR kinases and blocks migratory and microenvironmental survival signals in CLL cells.
Authors: Lopez-Guerra Monica , Xargay-Torrent Silvia , Perez-Galan Patricia , Saborit-Villarroya Ifigenia , Rosich Laia , Villamor Neus , Aymerich Marta , Roue Gael , Campo Elias , Montserrat Emili , Colomer Dolors 
Published: June 2012

Abstract
Targeting deregulated kinases has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL). Here, we report that the multikinase inhibitor sorafenib selectively induces apoptosis in the majority of CLL cases, with preference for the IGVH unmutated cases and for lymph node-derived CLL cells. We also show that ERK inhibition by sorafenib in CLL cells is an early but not sustained event, thus downregulation of RAF/MEK/ERK pathway is not a crucial effect of this agent in CLL. Among all the different kinases modulated by sorafenib in CLL cells, the blockage of BCR-associated tyrosine kinases, SRC and SYK, is particularly relevant for its action. In line with this, we demonstrate a strong synergy when combining sorafenib with two pharmacological BCR inhibitors, R406 and dasatinib. Importantly, sorafenib overcomes BCR stimulation as well as the protective effect of the stromal coculture. This compound resensitizes CLL cells cultured with stroma to fludarabine- and bendamustine-induced apoptosis. Furthermore, sorafenib inhibits CLL migration toward CXCL12 and blocks both CXCL12- and BCR-induced FAK activation. All these results indicate that sorafenib could overcome the tumoral microenvironment and might be particularly effective in BCR signaling inhibition in CLL cells with higher migratory potential, especially in high risk 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 C199.
Abstract C2: Selection for combinational studies through biomarker stratification in colorectal patient-derived explant models.
Authors: Alferez Denis G. , Dry Jonathan R. , Holt Sarah V. , Weston Susie L. , McWalter Gael , Beran Garry J. , Revill Mitch , Smith Paul D. , Guichard Sylvie , Wedge Stephen R. , Hedge Phillip , Wilkinson Robert W. 
Published: June 2012

Abstract
Patient-derived explant models (PTX) show a higher genetic and pathological heterogeneity than cell line derived xenograft models, and may have greater clinical relevance in cancer drug development and personalised oncology treatments than cell line derived xenograft models. Therefore PTX models can potentially be used to provide additional confidence in patient stratification hypotheses for novel therapies or combination approaches.
To examine comparative pharmacological responses in PTX models, the monotherapy activity of the MEK inhibitor selumetinib was determined in colorectal cancer PTX models that were stratified according to a MEK pathway “functional activation” mRNA signature, originally derived using a broad human tumor cell line panel (1). Tumor passage, immunohistochemical and genetic markers of target pathway activity were also assessed to collectively select 6 models of high interest for examining response to treatment. In addition, to monotherapy treatment, 3 models were also used to examine the combination of selumetinib with the mTORC1/2 kinase inhibitor AZD8055.
The results suggest that the MEK pathway mRNA signature is applicable in colorectal PTX models and enables selumetinib responsive versus non-responsive models to be identified. Combination therapy of selumetinib and AZD8055 has also shown additional therapeutic benefit, similar to that observed in selected cell line derived xenografts.
These data illustrate that use of PTX panels can be applied to substantiate in-vitro derived biomarker-led hypotheses for a given therapeutic approach. In addition, biomarker stratification has focused experimental design to test novel:novel combinations and may enable stratification for prospective patient subsets. Collectively this approach to disease modelling could significantly reduce wide screening in vivo studies and steer more refined clinically relevant hypotheses, whilst allowing for a reduction in animal usage.
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 C2.
Abstract C215: Depletion of the resistance-associated βIII tubulin isotype enhances eribulin's potency in suppressing microtubule dynamic instability and promotes inhibition of both microtubule growth and shortening.
Authors: Lopus Manu , Miller Herbert , Azarenko Olga , Joseph Silja , Nomoto Kenichi , Wilson Leslie , Jordan Mary Ann 
Published: June 2012

Abstract
Eribulin mesylate (Halaven®) is a synthetic analog of the microtubule-targeted natural product halichondrin B, originally isolated from the marine sponge, Halichondria okadai. Recently, the US FDA approved eribulin mesylate for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Seven β-tubulin isotypes have been identified, and they are differentially expressed in a variety of tissues and tumors. A high level of βIII-tubulin often correlates with poor clinical outcome in several human tumors and with resistance to microtubule-targeted agents in certain human cancer cell lines and tumors. Here, we report the strong preferential suppression by eribulin of microtubule dynamic instability of purified microtubules depleted of βIII-tubulin in vitro. Tubulin was purified from bovine brain by cycles of temperature-dependent assembly and disassembly followed by phosphocellulose chromatography, and depleted of III-tubulin by immunoaffinity chromatography. Depletion of βIII-tubulin did not affect the inherent dynamic instability of the microtubules. Eribulin (100 nM) suppressed dynamic instability of βIII-tubulin-depleted microtubules significantly more strongly than it suppressed dynamic instability of microtubules assembled from unfractionated tubulin. Specifically, with microtubules composed of unfractionated tubulin, eribulin significantly suppressed only the growth rate (by 27%) and dynamicity (by 36%). The shortening rate and the catastrophe and rescue frequencies were suppressed only insignificantly (by 14%, 17%, and −2%, respectively). However, with βIII-tubulin-depleted microtubules, eribulin significantly suppressed almost all dynamic instability parameters including the growth rate (40%), shortening rate (42%), and the catastrophe and rescue frequencies (by 49% and 33%, respectively) leading to an overall suppression of microtubule dynamicity of 58%. Determination of the binding of eribulin to βIII- tubulin-depleted microtubules and to unfractionated microtubules is in progress. Acknowledgment: Supported by a grant from Eisai Inc.
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 C215.
Abstract C222: Diverting Hsp70 trafficking as a tool for stimulating anticancer immunity.
Authors: Juhasz Kata , Thuenauer Roland , Spachinger Andrea , Duda Erno , Horvath Ibolya , Vigh Laszlo , Sonnleitner Alois , Balogi Zsolt 
Published: June 2012

Abstract
The stress-inducible heat shock protein 70 (Hsp70) is normally destined for cytosolic localization. In tumors, Hsp70 is frequently localized to the cell surface and released from cells, unusual features that stimulate the immune system against cancer cells. Interestingly, it has been shown that overexpression of Hsp70 enhances the immunogenicity of tumor cells in animal models. Here we investigated potential mechanisms by which overexpression of Hsp70 in B16 melanoma cells may increase surface expression and release. Flow cytometry measurements revealed an increased cell membrane concentration upon elevated level of intracellular Hsp70. Hsp70 was detectable in subcellular fractions enriched in endosomes/ lysosomes. An accumulation of excess Hsp70 was seen in high Hsp70 expressing cells, in particular in the purified lyosomal fractions. In low expressing cells apparent trafficking of Hsp70 was confined to the endosomal system. In contrast, high intracellular Hsp70 concentration was associated with a predominant lysosomal routing. Remarkable changes were observed in Hsp70 trafficking upon heat stress, a common approach used to facilitate Hsp70 release. In control cells a dramatic depletion of surface-exposed Hsp70 was paralleled with increased endosomal recycling of internalized protein. In contrast, excess intracellular Hsp70 prevented the membrane transport from heat-induced depletion, and allowed transport of surface-exposed Hsp70 to lysosomes secreting their cargo in a soluble form. Therefore excess Hsp70 appears to be decisive in terms of both trafficking to the plasma membrane and stress-induced active release. Altogether, our findings demonstrate a vesicular trafficking system bringing excess intracellular Hsp70 to fulfill its immunostimulatory role.
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 C222.
Abstract C29: Elevated CDKN1A (p21) expression in human cancer cell variants selected for resistance to the novel microtubule depolymerizing agent BAL27862 (active moiety of BAL101553).
Authors: Duran George E. , Lane Heidi , Bachmann Felix , Sikic Branimir I. 
Published: June 2012

Abstract
BAL27862 is a synthetic small molecule that induces tumor cell apoptosis due to inhibition of tubulin polymerization via a potentially new mechanism of action. Administered as the prodrug BAL101553, BAL27862 is currently undergoing Phase I evaluation in advanced cancer patients. We have previously demonstrated that BAL27862 retains activity in a broad panel of MDR1(+) and MDR1(−) human breast and ovarian cancer cell variants selected for resistance to taxanes (Abstract 4412, AACR 2010). In this current study, we established five variants selected for stable drug resistance in cell lines from human lung cancer (H460 and A549), acute T-cell leukemia (Jurkat), ovarian cancer (SK-OV-3) and cervical cancer (HeLa). These variants are approximately 3- to 24-fold resistant to BAL27862. The resistance is not transporter mediated, with no activation of ABCB1 (MDR1/P-glycoprotein) following drug selection, no change in activity in cells co-incubated with known P-glycoprotein inhibitors (PSC-833, 2 μM) and no difference in either accumulation or retention of [14C]-BAL27862 relative to parental controls. Tubulin polymerization assays indicated a higher proportion of tubulin in the polymerized fraction from resistant lines, indicating microtubule stabilization. Consistently, most lines exhibited increased sensitivity to microtubule stabilizers (e.g. resistance factors [RF = antiproliferative IC50 resistant line/parental line] for paclitaxel: H460=0.4; Jurkat=0.7). Strikingly, differential responses to standard microtubule-destabilizing agents were evident. For example, RFs for Jurkat cells were lower for both vincristine (2.5) and colchicine (10) as compared to BAL27862 (24); whereas, similar RFs were measured in SK-OV-3 (3, 5 and 4, respectively). Finally, relative to parental controls, altered tubulin isoform content was observed in some BAL27862-selected lines, but elevated CDKN1A (p21) protein expression was observed in 4 out of 5 of the resistant variants (SK-OV-3, H460, A549 and HeLa). Q-PCR analysis indicated an associated elevation in p21 mRNA levels only in lines with enhanced protein expression. As aberrant p21 expression has been previously related to poor prognosis and chemotherapy resistance in cancer patients, the potential of using this biomarker to support patient stratification efforts in future trials is worthy of further study. The functional significance of p21 to the resistance phenotype, and other key alterations identified through more detailed genomic profiling (Stanford's HEEBO microarrays), will be studied by gene transfer and gene silencing experiments.
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 C29.