bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT319: Determination of FGF-19, 21, and 23 protein levels in a phase I clinical trial of ARQ 087, an oral pan-FGFR inhibitor
Authors: Hall Terence , Kazakin Julia , Schwartz Brian , Savage Ronald 
Published: August 2015

Abstract
Background: Early biomarker development is vital in the current clinical landscape of targeted oncology therapies. Biomarkers that can be used to assess target engagement are increasingly being developed in parallel with novel agents. Fibroblast growth factors (FGFs) represent a potentially useful biomarker for use with pan-FGFR inhibitors such as ARQ 087. To evaluate this possibility, levels fibroblast growth factors 19, 21, and 23 were monitored using during the phase I trial of ARQ 087.
Study Design: Plasma was collected from 61 pts (dose range 25-425mg QOD or QD). FGF levels were quantified using commercially available ELISA kits for FGF-19 and 21 (R&D Systems, Minneapolis, MN), and FGF-23 (EMD-Millipore, Billerica, MA). The kits were validated at ArQule for use with human clinical samples. Experiments were designed based on the FDA guidance for bioanalytical method development, and conducted using standard curves and quality control samples prepared in plasma. Performance parameters included selectivity, specificity, precision, accuracy, stability, and effect of sample collection tube additives on measured protein levels.
Results: The kits were successfully validated for all three FGFs. Changes from baseline levels of all three FGFs were observed in patients. Full data tables and results from our evaluation, along with clinical and preclinical data will be presented.
Conclusions: Although there are previous reports of altered FGF-23 levels in patients treated with an FGFR inhibitor, FGF-19 and 21 represent novel biomarkers, which have not previously been reported in the literature. These biomarkers may assist in identifying ARQ 087 activity in patients, and contribute to defining an optimal clinical development strategy.
Citation Format: Terence Hall, Julia Kazakin, Brian Schwartz, Ronald Savage. Determination of FGF-19, 21, and 23 protein levels in a phase I clinical trial of ARQ 087, an oral pan-FGFR inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT319. doi:10.1158/1538-7445.AM2015-CT319
Abstract LB-010: Hijacking the E3 ubiquitin ligase cereblon to create efficient BRD4 degraders
Authors: Lu Jing , Qian Yimin , Altieri Martha , Dong Hanqing , Wang Jing , Raina Kanak , Winkler Jim , Crew Andy , Coleman Kevin , Hines John , Crews Craig 
Published: August 2015

Abstract
BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as an attractive target in multiple pathological settings. For example, recent studies have demonstrated its importance in driving the proliferation of several cancers including NUT midline carcinoma, acute myelogenous leukemia (AML), multiple myeloma, Burkitt's Lymphoma (BL), and prostate cancer. Thus, BET bromodomain inhibitors have showed promising effects in certain preclinical settings, particularly in MYC-driven hematological malignancies, such as BL. Interestingly, we found that BRD4 inhibitors lead to a rapid and robust accumulation of BRD4 that, together with the reversible nature of binding to BRD4, may account for their moderate suppression of MYC expression and inhibition of cell proliferation. To circumvent these limitations, we designed a Proteolysis Targeting Chimera (PROTAC) compound, containing a BRD4 binding moiety and an E3 ubiquitin ligase cereblon ligand. By actively engaging the E3 ligase-proteasome degradation machinery, BRD4 PROTAC leads to fast and efficient degradation of BRD4. Consequently, it is more effective than small molecule BRD4 inhibitors in suppressing MYC levels and downstream signaling, which are associated with proliferation and survival of malignant cells. More importantly, we also demonstrated that BRD4 PROTAC is more effective in inhibiting BL cell proliferation and inducing apoptosis compared to BRD4 inhibitors. Our findings strongly demonstrate that a degrader of BRD4, in the form of a cereblon-based PROTAC, provides a better and more efficient strategy in targeting BRD4 than traditional small molecule inhibitors.
Citation Format: Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, Jim Winkler, Andy Crew, Kevin Coleman, John Hines, Craig Crews. Hijacking the E3 ubiquitin ligase cereblon to create efficient BRD4 degraders. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-010. doi:10.1158/1538-7445.AM2015-LB-010
Abstract LB-022: Aptamer-mediated inhibition of EGFRvIII mutant in glioblastoma cells
Authors: Camorani Simona , Crescenzi Elvira , Colecchia David , Carpentieri Andrea , Amoresano Angela , Chiariello Mario , Cerchia Laura 
Published: August 2015

Abstract
High-grade glioblastoma multiforme (GBM) is the most aggressive and common of gliomas in human populations, accounting for 55% of primary brain tumors. The prognosis of GBM is very poor and most patients die of tumor recurrence.
The epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor β (PDGFRβ) are hallmarks in GBM since they influence multiple aspects of tumor biology including cell proliferation, migration, invasiveness and resistance to treatment. In approximately half of the tumors with amplified EGFR, the EGFRvIII truncated extracellular mutant is detected. EGFRvIII does not bind ligand, is highly oncogenic and appears to be relatively resistant to treatment with conventional anti-EGFR agents such as ligand blocking monoclonal antibodies or EGFR tyrosine kinase inhibitors (TKIs). Recently, it has been demonstrated that EGFRvIII-dependent cancers may escape targeted therapy by developing dependence on PDGFRβ signaling, thus providing a strong rationale for combination therapy aimed at blocking both EGFRvIII and PDGFRβ signaling.
We have generated two nuclease resistant 2′F-Py RNA aptamers, CL4 and Gint4.T, as high affinity ligands and inhibitors of human wild-type EGFR (EGFRwt) and PDGFRβ, respectively. Thanks to their unique characteristics (low size, good target affinity, no immunogenicity, high stability) aptamers represent a new class of molecules with a great potential to rival monoclonal antibodies in both therapy and diagnosis.
Herein, by different approaches we demonstrate that CL4 aptamer binds to the EGFRvIII mutant even though it lacks amino acids 6-273 in the extracellular domain. As a consequence of binding, the aptamer inhibits EGFRvIII activation by hampering receptor homodimerization and downstream STAT3 pathway, thus confirming the critical role of EGFRvIII dimerization for signaling. Further, we show that targeting EGFRvIII by CL4, as well as by erlotinib and gefitinib, causes upregulation of PDGFRβ as a compensatory response to support cancer cell survival. Importantly, CL4 and EGFRTKIs cooperate with the anti-PDGFRβ aptamer in inhibiting survival and proliferation of EGFRvIII-overexpressing glioblastoma cells.
Given the paucity of selective inhibitors for receptor tyrosine kinases, this study could have impact in the fields of targeted molecular cancer therapeutics and may result in progress against GBM.
Citation Format: Simona Camorani, Elvira Crescenzi, David Colecchia, Andrea Carpentieri, Angela Amoresano, Mario Chiariello, Laura Cerchia. Aptamer-mediated inhibition of EGFRvIII mutant in glioblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-022. doi:10.1158/1538-7445.AM2015-LB-022
Abstract LB-023: Caspase-9b directly interacts with cIAP1 to drive agonist-independent NF-κB activation and tumorigenesis in non-small cell lung cancer
Authors: Vu Ngoc T. , Park Margaret A. , Shultz Michael D. , Ladd Amy C. , Chalfant Charles E. 
Published: August 2015

Abstract
Caspase-9 has two isoforms with opposing functions, pro-apoptotic caspase-9a (C9a) and anti-apoptotic caspase-9b (C9b). C9b expression has been reported to augment the anchorage-dependent growth (AIG) and tumorigenic capacity of non-small cell lung cancer (NSCLC) cells. The mechanism of this biological observation was revealed in this study. Specifically, C9b was demonstrated to have a dual caspase-9a-independent function in regulating the survival/oncogenic nuclear factor κB (NF-κB) pathway. In particular, C9b was shown to activate the canonical arm and inhibit of the non-canonical arm of the NF-κB pathway by destabilizing NF-κB inhibitor alpha (IκB-α) and NF-κB-inducing kinase (NIK). Importantly, this new role for C9b contributes to the enhanced survival and AIG of NSCLC cells conferred by C9b expression. The link between C9b expression and NF-κB activation was also validated in human NSCLC tumors. Further mechanistic studies revealed a direct association of C9b with the cellular inhibitor of apoptosis 1 (cIAP1), a regulatory factor in both arms of the NF-κB network, via its IAP-binding motif (IBM). Through this interaction, C9b induces the E3 ligase activity of cIAP1, which regulates NF-κB activation, and promotes the viability, AIG and tumorigenicity of NSCLC cells. Hence, C9b/cIAP1 interaction is a new attractive molecular target for developing therapeutics to treat NSCLC.
Citation Format: Ngoc T. Vu, Margaret A. Park, Michael D. Shultz, Amy C. Ladd, Charles E. Chalfant. Caspase-9b directly interacts with cIAP1 to drive agonist-independent NF-κB activation and tumorigenesis in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-023. doi:10.1158/1538-7445.AM2015-LB-023
Abstract LB-025: Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism
Authors: Kreger Bridget T. , Antonyak Marc , Cerione Richard 
Published: August 2015

Abstract
Cell-cell communication plays important roles in promoting tumor growth and metastasis, and these events are frequently targeted by therapies. The generation of extracellular vesicles (EVs), including exosomes and microvesicles (MVs), are beginning to be appreciated as one such form of communication that has important consequences in cancer. MVs are small vesicular structures (0.1-2 μm) that are derived from plasma membranes and are shed into the cell's surroundings; exosomes (30-100 nm) are rerouted endosomes that are released by the fusion of multi-vesicular bodies with the plasma membrane. Both types of EVs influence the behavior of recipient cells through the transfer of their cargo, which includes oncogenic factors, signaling proteins, RNA transcripts, and cytoskeletal components. However, the mechanism through which cargo is selectively trafficked to EVs has not yet been elucidated. We have discovered that disrupting microtubule dynamics in the MDAMB231 breast cancer cell line using the microtubule inhibitor nocodazole has the intriguing effect of significantly increasing the amount of the anti-apoptotic factor survivin that is contained within the EVs shed by these cells. This finding has been replicated in several additional human cancer cell lines and also when using the chemotherapy agent Paclitaxel (Taxol), which also inhibits microtubule dynamics. When MVs were separated from exosomes using procedures that were developed to resolve these two classes of EVs from MDAMB231 cell conditioned medium, survivin was found to be a specific cargo of exosomes and was absent from MVs. Moreover, the exosomes containing survivin enhanced the survival of recipient cells exposed to serum-starvation. Overall, these results show how a specific protein (e.g. survivin) can be selectively packaged into exosomes, as well as shed light on a novel mechanism that underlies Paclitaxel resistance.
Citation Format: Bridget T. Kreger, Marc Antonyak, Richard Cerione. Survivin is trafficked into cancer cell-derived exosomes via a microtubule-dependent mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-025. doi:10.1158/1538-7445.AM2015-LB-025
Abstract LB-026: Pin1 negatively regulated Grb7 protein stability via the ubiquitin-proteasome cascade requires the peptidyl-prolyl cis/trans isomerase activity of Pin1
Authors: Tai Yu-Ling , Shen Tang-Long 
Published: August 2015

Abstract
Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein in cooperation with numerous tyrosine kinases to regulate various cellular signaling and functions. Although the regulatory mechanisms on the activation of Grb7 have been documented, the molecular mechanism governing Grb7 stability and its functional consequence is still not clearly understood. Here, we observed a novel negative regulatory mechanism of Grb7 by peptidyl-prolyl cis/trans isomerases Pin1 at the post-translational level. The Grb7 phosphorylation on the Ser194-Pro motif facilitated its binding to the WW domain of Pin1 and subsequently ubiquitination on Grb7, which, in turn, enhanced the process of proteosome-dependent proteolysis. Moreover, the interaction between Grb7 and Pin1 is dependent on the phosphorylation that is mediated by c-Jun N-terminal kinases MAPK. Both the phosphorylated Ser/Thr-Pro motif binding module and the peptidyl-prolyl cis/trans isomerase activity of Pin1 is essentail for Pin1-mediated Grb7 ubiquitin-proteasome proteolysis. By contrast, inhibition of Pin by lentiviral-mediated gene silencing resulted in accumulation of Grb7 protein as well as prolonged Grb7 protein stability. A stable Grb7S194A mutant that cannot be bound to and modulated by Pin1 utilize its potential to influence cell cycle progression. Our finding revealed that the Pin1/Grb7 complex formation enables negatively regulating Grb7-mediated cell proliferation due to the influence of Grb7 protein stability.
Note: This abstract was not presented at the meeting.
Citation Format: Yu-Ling Tai, Tang-Long Shen. Pin1 negatively regulated Grb7 protein stability via the ubiquitin-proteasome cascade requires the peptidyl-prolyl cis/trans isomerase activity of Pin1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-026. doi:10.1158/1538-7445.AM2015-LB-026
Abstract LB-028: Cell density sensing alters TGF-beta signaling in a cell type-specific manner, independent from Hippo pathway activation
Authors: Nallet-Staub Flore , Yin Xueqian , Gilbert Cristèle , Marsaud Véronique , Ben Mimoun Saber , Javelaud Delphine , Leof Edward B. , Mauviel Alain 
Published: August 2015

Abstract
Cell-cell contacts inhibit cell growth and proliferation in part by activating the Hippo pathway that drives the phosphorylation and nuclear exclusion of the transcriptional coactivators YAP and TAZ. Cell density and Hippo signaling have also been reported to block TGF-β responses, based on the ability of phospho-YAP/TAZ to sequester TGF-β-activated SMAD complexes in the cytoplasm. Herein, we provide evidence that epithelial cell polarization interferes with TGF-β signaling well upstream and independent of cytoplasmic YAP/TAZ. Rather, polarized basolateral presentation of TGF-β receptors I and II deprives apically delivered TGF-β of access to its receptors. Basolateral ligand delivery nonetheless remains entirely effective to induce TGF-β responses. These data demonstrate that cell type-specific inhibition of TGF-β signaling by cell density is restricted to polarized epithelial cells and reflects the polarized distribution of TGF-β receptors, which thus impacts SMAD activation irrespective of Hippo pathway activation.
Citation Format: Flore Nallet-Staub, Xueqian Yin, Cristèle Gilbert, Véronique Marsaud, Saber Ben Mimoun, Delphine Javelaud, Edward B. Leof, Alain Mauviel. Cell density sensing alters TGF-beta signaling in a cell type-specific manner, independent from Hippo pathway activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-028. doi:10.1158/1538-7445.AM2015-LB-028
Abstract LB-040: mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation
Authors: He Kan , Zheng Xingnan , Li Mei , Zhang Lin , Yu Jian 
Published: August 2015

Abstract
The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. We now show that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by TRAIL and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, upon rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results establish activation of ER stress and the death receptor pathway as a novel anticancer mechanism of mTOR inhibitors.
Citation Format: Kan He, Xingnan Zheng, Mei Li, Lin Zhang, Jian Yu. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-040. doi:10.1158/1538-7445.AM2015-LB-040
Abstract LB-043: Highly specific and sensitive nanoimmunoassay of PARP1 as cell death measurement toolkit
Authors: Pontikos Michael A. , Zimmermann Amos , Moncada Camilo , Abarca Heidemann Karin V. , Miller Jordan B. , Birabaharan Jonathan , Boyer Michael , Zuck Robin M. , Lorenzi Philip L. , Ascoli Carl 
Published: August 2015

Abstract
We developed and validated a highly specific toolkit to analyze PARP1 in a panel of control and siRNA knockdown cell lysates by multiple immunoassays. We can specifically and quantitatively distinguish PARP1 from 17 other PARP family members using highly specific antibodies and optimized methods.
Poly (ADP-ribose) polymerase-1 (PARP1) is a chromatin associated, ADP-ribosylating enzyme essential for multiple cellular functions, including
cardiac remodeling, vasoconstriction, regulation of astrocyte and microglial
function, long term memory, aging, transcription regulation, and DNA repair. More recently, it has been implicated in a new form of cell death termed parthanatos. PARP1 can also promote tissue survival by shifting the balance of cell death programs between autophagy and necrosis. Since PARP1 can promote tumorigenicity, it has gained traction as a therapeutic target in cancer. In that regard, clinical studies have shown vulnerability to PARP inhibitors in DNA repair defective cancers. One of the difficulties in analyzing PARP1 activity is the promiscuity of the reagents toward other PARP family members. Furthermore, the ability to examine
multiple tissue samples in parallel has been limited.
In this study we developed highly sensitive and specific antibodies against PARP1 fragments. Using siRNAs against 18 PARP family members, we validated antibody specificity by western blotting and nanoimmunoassay (NIA). NIA is a highly sensitive platform capable of screening up to 96 cancer samples at sub-microliter volume. Moreover, this platform permits quantitative analysis of non-modified PARP1 as well as post-translational modifications such as PARylation and phosphorylation using a single antibody for the measurement of all species. We anticipate this workflow will be amenable to a wide range of protein targets, ushering in a new frontier in diagnostic analysis.
Citation Format: Michael A. Pontikos, Amos Zimmermann, Camilo Moncada, Karin V. Abarca Heidemann, Jordan B. Miller, Jonathan Birabaharan, Michael Boyer, Robin M. Zuck, Philip L. Lorenzi, Carl Ascoli. Highly specific and sensitive nanoimmunoassay of PARP1 as cell death measurement toolkit. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-043. doi:10.1158/1538-7445.AM2015-LB-043
Abstract LB-047: Single-cell genomics reveals the genesis of cancer: copy number variation precedes single nucleotide variation
Authors: Xie Sunney , Huang Lei , Ma Fei , Wang Jingran , Ding Shigang , Gu Fang , Wang Wenjing , Zhang Jing 
Published: August 2015

Abstract
Recent advances in single cell whole genome amplification methods, such as MALBAC [1], have allowed accurate determination of copy number variation (CNV) as well as single nucleotide variation (SNV) of a single cancer cell [2]. In a bulk tissue sample at an early stage of cancer development, detection of abnormal CNV is often difficult, especially when the number of cells with abnormal CNV is small. Single cell genomic analysis is essential in evaluating the relation, if any, between CNV and SNV.
We have carried out for the first time single cell genomic analyses of colonoscopy biopsy at different adenoma stages. Some single cells in the Stage II adenoma have CNVs in the tumor suppresser gene APC (the copy number loss reduced from two to one) as well as SNVs in numerous cancer related genes. Interestingly, we found that while some single cells exhibited CNV reduction in APC without SNVs, all single cells with SNVs in COSMIC genes showed the CNV reduction in APC. Moreover we did not see a single cell that has SNVs but not CNVs in an adenoma. These data indicates that the CNV of APC precedes the SNVs in colon cancer development.
Furthermore, we found that the single cells from the same adenoma exhibited CNV patterns reproducible among all the cells, indicating that these cells were derived from the same stem cell, in which CNVs resulted from double strand breaks that could not be repaired perfectly.
Thus, we have established for the first time a correlation between SNVs and CNVs and propose that SNVs are generated as a consequence of abnormal CNVs in the genome. Therefore, our results could have a significant implication on the genesis of cancer.
References
(1) Zong, et al. Science 338: 1622-1626 (2012).
(2) Ni et al. PNAS 110, 21083 (2013).
Note: This abstract was not presented at the meeting.
Citation Format: Sunney Xie, Lei Huang, Fei Ma, Jingran Wang, Shigang Ding, Fang Gu, Wenjing Wang, Jing Zhang. Single-cell genomics reveals the genesis of cancer: copy number variation precedes single nucleotide variation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-047. doi:10.1158/1538-7445.AM2015-LB-047