bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B111: Efficacy of AKT inhibitor ARQ 092 compared with Sorafenib in a cirrhotic rat model with hepatocellular carcinoma
Authors: Roth Gael S. , Zeybek Ayca , Macek-Jilkova Zusana , Abbadessa Giovanni , Yu Yi , Marche Patrice , Leroy Vincent , Decaens Thomas 
Published: May 2016

Abstract
Background and aim: Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. PI3K/AKT pathway is activated in 50% of HCC. The aim of this study was to assess toxicity and efficacy of a new AKT inhibitor (ARQ 092) compared to sorafenib.
Method: In vitro experiments were realized with viability, apoptosis and migration assays in 5 different cell lines to analyze the effects of ARQ 092 and sorafenib on the different mechanisms of carcinogenesis. Furthermore, an in vivo study with a diethylnitrosamine (DEN)-induced rat model of HCC on cirrhosis was performed. After 14 weeks of DEN, rats were randomized in 3 groups: control, sorafenib, or ARQ 092 and treated during 6 weeks. Tumor volume and progression were assessed by MRI before treatment, after 3 and 6 weeks of treatment. After euthanasia, pathological analysis of livers was performed assessing tumor numbers and volumes.
Results: ARQ 092 showed a dose-dependent decrease in cell viability, induction of apoptosis, and inhibition of migration. In vivo study on 26 rats showed a significantly lower tumor volume in ARQ 092 group: 45.9% of the control versus 60.4% of the control with sorafenib (p = 0.022). Number of tumors per liver was also significantly lower in ARQ 092 group with a mean of 53.9 tumors versus 96.3 tumors in control group (p = 0.001) and 96.8 tumors in sorafenib group (p = 0.015). MRI analysis showed a lower tumor progression in ARQ 092 group with 57.0% versus 155.3% in control group (p&lt;0.0001), and 80.2% in sorafenib group (p = 0.08).
Conclusion: ARQ 092 was more significantly control tumor progression in a DEN-induced cirrhotic rat model with HCC compared to sorafenib.
Citation Format: Gael S. Roth, Ayca Zeybek, Zusana Macek-Jilkova, Giovanni Abbadessa, Yi Yu, Patrice Marche, Vincent Leroy, Thomas Decaens. Efficacy of AKT inhibitor ARQ 092 compared with Sorafenib in a cirrhotic rat model with hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B111.
Abstract B131: Chemical array screen identifies a novel MMP inhibitor NPDK-18 that suppresses tumor cell migration
Authors: Kawatani Makoto , Kondoh Yasumitsu , Honda Kaori , Sekine Tomomi , Osada Hiroyuki 
Published: May 2016

Abstract
Background and Purpose: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade extracellular matrix components and that have been implicated in a wide range of pathological processes including tumor metastasis. Although many small-molecule MMP inhibitors have been developed, there are some problems related to specificity and side effects. In addition, recent studies have shown that several MMPs have nonproteolytic and tumor-suppressing functions depending upon the stage of cancer progression. Thus, much work remains for the elucidation of each MMP function and the development of new MMP inhibitors. Small-molecule microarrays represent a powerful new platform for facilitating target-based screens. Thousands of small molecules are arrayed on a slide glass and used to screen for protein-small molecule interactions in a high-throughput manner. We have developed unique photo-cross-linked chemical arrays, which enable the immobilization of a variety of small molecules on a solid support in a functional group-independent manner using a photoaffinity reaction. In this study, we screened MMP-9 inhibitors using the photo-cross-linked chemical arrays.
Methods and Results: The array slides with compounds of the RIKEN NPDepo chemical library were probed sequentially with His-Myc-tagged human recombinant MMP-9, anti-His antibody, and a Cy5-labeled secondary antibody, and then scanned with a microarray scanner. The fluorescence signals from two slides treated with and without His-Myc-tagged MMP-9 were quantified. We obtained 27 hit compounds among 24,275 compounds; 2 of the identified compounds (isoxazole compound NPDK-1 and naphthofluorescein) inhibited MMP-9 enzyme activity in vitro. We further explored 17 analogs of NPDK-1 and found that NPDK-18 showed the strongest inhibitory activity against MMP-9, with an IC50 value of 3.8 μM. NPDK-18 inhibited the enzyme activities of MMP-2, MMP-12 and MMP-13, as well as MMP-9 and MMP-9/ΔHemopexin, with almost identical potency, but showed no inhibition against MMP-1 and MMP-7. The biological potency of NPDK-18 was confirmed in a wound-healing scratch assay, where NPDK-18 significantly inhibited cell migration of human fibrosarcoma HT1080 cells with no cell toxicity at 10 μM.
Conclusion: These results suggest that NPDK-18 is a broad-spectrum MMP inhibitor. Our study has shown that the photo-cross-linked chemical arrays are useful for high-throughput drug screening.
Citation Format: Makoto Kawatani, Yasumitsu Kondoh, Kaori Honda, Tomomi Sekine, Hiroyuki Osada. Chemical array screen identifies a novel MMP inhibitor NPDK-18 that suppresses tumor cell migration. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B131.
Abstract B155: The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα
Authors: Ying Meidan , Zhou Qian , Shao Xuejing , Cao Ji , Zhu Hong , Yang Bo , He Qiaojun 
Published: May 2016

Abstract
Retinoic acid receptor alpha (RARα) plays a critical role in the differentiation process of osteosarcoma cells induced by all-trans retinoic acid (ATRA). However, degradation of RARα through ubiquitin proteasome pathway weakens the differentiation efficiency of osteosarcoma cells. In this study, we discover that murine double minute-2 (MDM2) acts as an E3 ubiquitin ligase to target RARα for degradation. We observe that MDM2 is required for RARα polyubiquitination and proteasomal degradation because downregulation of MDM2 by shRNA results in the accumulation of RARα, and MDM2 overexpression promotes the degradation of RARα. We also demonstrate that the N-terminal domain of MDM2 (amino acids 1-109) is the major RARα-binding site. Importantly, endogenous MDM2 levels are not only upregulated in human primary osteosarcoma blasts, but they are also inversely correlated with the level of OPN, which is a marker of bone differentiation. Moreover, MDM2 impairs the ATRA-induced osteoblastic differentiation of osteosarcoma cells, whereas an inhibitor of the MDM2 ubiquitin ligase synergises with ATRA to enhance the differentiation of osteosarcoma cells and primary osteosarcoma blasts. Therefore, our study indicates that MDM2 serves as an E3 ubiquitin ligase to regulate the degradation of RARα and suggests that MDM2 is a novel therapeutic target for ATRA-based differentiation therapeutic approaches in osteosarcoma.
Citation Format: Meidan Ying, Qian Zhou, Xuejing Shao, Ji Cao, Hong Zhu, Bo Yang, Qiaojun He. The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B155.
Abstract B157: YAP is a promising target in cutaneous melanoma
Authors: Tang Jian zhong , Zhang Xiaomeng , Vergara Ismael , Papenfuss Anthony , Harvey Kieran , Shackleton Mark 
Published: May 2016

Abstract
The transcriptional regulator YAP (Yes-associated protein) has been implicated in tissue development and homeostasis and in cancer growth (Harvey et al. 2013). In uveal melanoma, YAP mediates oncogenic signaling of mutated G-proteins, driving tumor growth in a therapeutically exploitable manner (Yu et al. & Feng et al. 2014). The role of YAP in cutaneous melanoma (CM) is less well defined, although previous studies implicating YAP in metastasis and disease maintenance/progression (Nallet-Staub et al. 2014; Menzel et al. 2014), and encouraging data suggesting synergism between combination targeting of YAP and the Mitogen-Activated Protein Kinases (MAPK) pathway (Lin et al. 2015).
Here we show that YAP is a critical mediator of disease maintenance and progression in some but not all CMs. In a primary CM we identified novel YAP mutations, which are rare in human cancer but are predicted to relieve YAP from inhibition by the Hippo pathway. By quantifying YAP expression by immunofluorescence, we found YAP was increased early in human melanocytic transformation, being elevated in nevi and in over 50% of primary CMs. Gene targeting of YAP with inducible shRNAs induced profound proliferative arrest and death in cultured CM cells (measured by MTT assay, EdU incorporation and propidium iodide staining respectively). The dependency on YAP of melanoma maintenance was validated in vivo using xenograft models of cell lines and of early passage patient-derived melanomas. Further, efficacy of YAP targeting synergized with MAPK inhibition in BRAF mutant CMs. However, some CMs were resistant to YAP targeting independent of BRAF/NRAS genotype and of levels of YAP protein expression or activation.
These data compel the development of anti-YAP therapies in CM and the identification of biomarkers that predict response to YAP targeting.
Citation Format: Jian zhong Tang, Xiaomeng Zhang, Ismael Vergara, Anthony Papenfuss, Kieran Harvey, Mark Shackleton. YAP is a promising target in cutaneous melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B157.
Abstract B166: A RNA helicase siRNA screen to identify potential therapeutic targets in castration-resistant prostate cancer
Authors: Wang Hannah , de Billy Emmanuel , de Bono Johann , Workman Paul 
Published: May 2016

Abstract
Castration-resistant prostate cancers (CRPC) are resistant to androgen-deprivation therapies commonly used to treat carcinoma of the prostate, resulting in death from this disease. CRPC can remain AR-driven through upregulation of the expression of wild-type, mutated or alternatively spliced constitutively active AR. Targeting both full-length AR and AR splice variants may overcome endocrine resistance. Since RNA helicases play crucial roles in various aspects of RNA metabolism including transcription, pre-mRNA splicing, translation, RNA export and RNA decay, we evaluated potentially druggable RNA helicases implicated in the regulation of AR and AR-V7 expression. We performed an siRNA screen targeting RNA helicases in which the readout was the expression of AR and AR-V7 mRNA as determined by quantitative RT-PCR. Out of the 75 human RNA helicases silenced, we identified 11 that induced a 50% or greater decrease in both AR and AR-V7 mRNA expression. These included 3 RNA helicases that have no known described function, 2 that regulate ribosomal RNA transcription, 3 required in nuclear export of spliced and unspliced mRNA, 2 in translation initiation and the DEAD-box helicase EIF4A3 involved in nonsense-mediated decay. Among these, only EIF4A3 reduced cell numbers by 40% in addition to decreasing AR and AR-V7 expression. Silencing EIF4A3 resulted in a 50-80% inhibition of cell proliferation and between 2- to 11-fold induction of apoptosis in a panel of 6 prostate cancer cell lines. Inhibiting EIF4A3 in CRPC may block the expression of important oncogenes including AR and counteract the emergence of splice variants involved in resistance mechanisms.
Citation Format: Hannah Wang, Emmanuel de Billy, Johann de Bono, Paul Workman. A RNA helicase siRNA screen to identify potential therapeutic targets in castration-resistant prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B166.
Abstract B194: Tivantinib in combination with erlotinib vs erlotinib alone for EGFR mutant NSCLC: Subgroup results from the phase 3 MARQUEE study
Authors: Scagliotti Giorgio V. , Orlov Sergey , von Pawel Joachim , Shepherd Frances A. , Akerley Wallace , Ross Jeffrey S. , Shuster Dale , Wang Qiang , Schwartz Brian , von Roemeling Reinhard 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 10:00 AM ET Saturday, November 7.
Citation Format: Giorgio V. Scagliotti, Sergey Orlov, Joachim von Pawel, Frances A. Shepherd, Wallace Akerley, Jeffrey S. Ross, Dale Shuster, Qiang Wang, Brian Schwartz, Reinhard von Roemeling. Tivantinib in combination with erlotinib vs erlotinib alone for EGFR mutant NSCLC: Subgroup results from the phase 3 MARQUEE study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B194.
Abstract B48: Identification of potent, cell active MTH1 inhibitors and their use in target validation studies
Authors: Leo Elisabetta , Petrocchi Alessia , Bardenhagen Jennifer , Alimova Maria , Shi Xi , Parker Connor , Reyna Naphtali , Hamilton Matthew , Felix Edward , Mazan Andrzej , Dillon Christian , Mseeh Faika , Marszalek Joseph R. , Toniatti Carlo , Draetta Giulio , Jones Phil , Lewis Richard T. 
Published: May 2016

Abstract
MTH1 is a protein that sanitizes oxidized dNTPs in the cell. It preferentially hydrolyzes 8-oxo-dGTP and 2-OH-dATP to their corresponding monophosphates and thereby prevents the incorporation of oxidized nucleotides into DNA or RNA. The functional result is a reduction in down-stream mutations, or DNA damage, thus preventing cell death. Recent publications suggest that MTH1 is a non-essential enzyme in normal cells, but is required for the survival of cancer cells as a consequence of being subjected to high levels of oxidative stress; hence its relevance as an oncology target. Gad et al., 2014
The interesting target rationale combined with a perceived high chemical tractability of the target resulting from availability of x-ray crystallographic information for the protein, led to a decision to undertake, in parallel, target validation, assay development and drug discovery. This effort resulted in the structure-based design of potent, cell active MTH1 small molecule inhibitors. This poster will describe the discovery and optimization of these inhibitors, and their use to evaluate the potential of MTH1 as an oncology target. This work was complemented by parallel genetic studies. Pharmacodynamic evaluation of target engagement using proximal biomarkers will be presented, as will phenotypic responses across a range of cancer cell lines.
Citation Format: Elisabetta Leo, Alessia Petrocchi, Jennifer Bardenhagen, Maria Alimova, Xi Shi, Connor Parker, Naphtali Reyna, Matthew Hamilton, Edward Felix, Andrzej Mazan, Christian Dillon, Faika Mseeh, Joseph R. Marszalek, Carlo Toniatti, Giulio Draetta, Phil Jones, Richard T. Lewis. Identification of potent, cell active MTH1 inhibitors and their use in target validation studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B48.
Abstract B55: High expression of CDK6 protects breast cancer cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant treatment in estrogen receptor-positive metastatic breast cancer
Authors: Alves Carla L. , Elias Daniel , Lyng Maria , Bak Martin , Lykkesfeldt Anne , Ditzel Henrik J. 
Published: May 2016

Abstract
Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are also being investigated in clinical trials in combination with different endocrine treatments, including fulvestrant. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains to be defined. We evaluated the expression of genes of the cyclin D/CDK4-6/p16INK4A/Rb pathway in a panel of endocrine-resistant breast cancer cell lines by gene array and found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression by specific gene knockdown impaired fulvestrant-resistant cells growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. Evaluation of CDK6 expression levels in metastatic samples from breast cancer patients treated with fulvestrant (N = 45) showed that high levels of CDK6 correlated significantly with shorter progression-free survival (PFS) (p = 0.0006), while no association was observed between CDK6 levels and PFS in patients receiving other endocrine treatments (N = 41, p = 0.874). Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.
Citation Format: Carla L. Alves, Daniel Elias, Maria Lyng, Martin Bak, Anne Lykkesfeldt, Henrik J. Ditzel. High expression of CDK6 protects breast cancer cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant treatment in estrogen receptor-positive metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B55.
Abstract B65: High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide
Authors: Guertin Amy D. , O'Neil Jennifer , Stoeck Alexander , Reddy Joseph A. , Cristescu Razvan , Haines Brian B. , Hinton Marlene C. , Dorton Ryan , Bloomfield Alicia , Nelson Melissa , Vetzel Marilynn , Lejnine Serguei , Nebozhyn Michael , Zhang Theresa , Loboda Andrey , Picard Kristen L. , Schmidt Emmett V. , Dussault Isabelle , Leamon Christopher P. 
Published: May 2016

Abstract
Targeting surface receptors overexpressed on cancer cells is one way to specifically treat cancer versus normal cells. Vintafolide (EC145), which consists of folate linked to a cytotoxic small molecule, desacetylvinblastine hydrazide (DAVLBH), takes advantage of the overexpression of folate receptor (FR) on cancer cells. Once bound to FR, vintafolide enters the cell by endocytosis, and the reducing environment of the endosome cleaves the linker, releasing DAVLBH to destabilize microtubules. Vintafolide has shown efficacy and improved tolerability compared to DAVLBH in FR-positive preclinical models. As the first FR-targeting drug to reach the clinic, vintafolide has achieved favorable responses in Phase II clinical trials in FR-positive ovarian and lung cancer. However, some FR-positive patients in these clinical trials do not respond to vintafolide. We sought to identify potential biomarkers of resistance to aid in the future development of this and other FR-targeting drugs. Here, we confirm in both in vitro and in vivo preclinical models that high P-glycoprotein (P-gp) expression was the strongest predictor of resistance to DAVLBH in a panel of 359 cancer cell lines. Furthermore, targeted delivery of DAVLBH via the FR as in vintafolide fails to overcome P-gp mediated efflux of DAVLBH as seen in FR-expressing engineered cell lines and in vivo models. Therefore, we suggest that patients whose tumors express high levels of P-gp be excluded from future clinical trials for vintafolide as well as other FR-targeted therapeutics bearing a P-gp substrate.
Citation Format: Amy D. Guertin, Jennifer O'Neil, Alexander Stoeck, Joseph A. Reddy, Razvan Cristescu, Brian B. Haines, Marlene C. Hinton, Ryan Dorton, Alicia Bloomfield, Melissa Nelson, Marilynn Vetzel, Serguei Lejnine, Michael Nebozhyn, Theresa Zhang, Andrey Loboda, Kristen L. Picard, Emmett V. Schmidt, Isabelle Dussault, Christopher P. Leamon. High levels of expression of P-glycoprotein/multidrug resistance protein result in resistance to vintafolide. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B65.
Abstract B95: PDL-1 is more frequently expressed on circulating epithelial tumor cells (CETCs) in metastatic than in non-metastatic breast cancer patients and could be a crucial factor in the inhibition of immune response to CETCs during metastasis formation
Authors: Pizon Monika , Zimon Dorothea , Pachmann Ulrich , Pachmann Katharina 
Published: May 2016

Abstract
Background:
Analysis of CETCs is a promising diagnostic field for estimating the risk for metastatic relapse and progression. The phenotypic characterization of CETCs may provide real time information and can be of great value in therapy monitoring. Programmed cell death ligand 1 (PDL-1) is an important protein frequently upregulated in a number of different cancers. Cancer cells expressing PDL-1 inhibit immune-modulatory T-cell activation allowing disease progression. Therefore this immune checkpoint has emerged as an important target for immune therapy. The purpose of the current study was to identify potential patients who may benefit from PDL-1 targeted immunotherapies.
Methods:
CETCs were determined from blood of 22 (69%) non-metastatic and 10 (31%) metastatic breast cancer patients. The number of vital CETCs and the expression of PDL-1 were investigated using the maintrac® method.
Results:
PDL-1 expressing CETCs were detected in 94% of breast cancer patients; however the fraction varied between 30 to 100% in individual patients. There was no association between the frequency of PDL-1 positive CETCs and chemotherapy. Interestingly, we found a relationship between the frequencies of PDL-1 positive CETCs and progression of disease. Patients with metastatic disease had more PDL-1 positive CETCs as compared to patients without metastasis.
Conclusion:
Metastatic breast cancer patients have an elevated fraction of PDL-1 positive CETCs as compared to non-metastatic patients. These cells have the capacity to block the immune system and therefore may be a promising target for anticancer therapies. Monitoring the frequency of PDL-1 positive CETCs could contribute to individual patient's response for to anti-PDL-1 therapy.
Citation Format: Monika Pizon, Dorothea Zimon, Ulrich Pachmann, Katharina Pachmann. PDL-1 is more frequently expressed on circulating epithelial tumor cells (CETCs) in metastatic than in non-metastatic breast cancer patients and could be a crucial factor in the inhibition of immune response to CETCs during metastasis formation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B95.