bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B205: EphA10 targeted antibody therapy is a potential as a novel option for management of breast cancers including triple negative breast cancer
Authors: Takahide Mori , Kazuya Nagano , Tsunoda Shin-ichi , Tsutsumi Yasuo 
Published: May 2016

Abstract
Introduction: Triple negative breast cancer (TNBC) is defined by the absence of receptors for Her2, estrogen and progesterone and is often referred to as a refractory disease, because it is resistant to treatment with anti-Her2 antibody and anti-hormone drugs. Thus, new targets for therapeutic agents are urgently required. Using a proteomic approach, we have identified EphA10, which is more highly expressed in breast cancer, including TNBC, than in normal breast tissues. Moreover, we previously revealed that EphA10 is expressed in testis, but not in other normal tissues. This suggests that EphA10 could become a promising therapeutic target in breast cancer patients. Here, we describe a novel monoclonal antibody (mAb) against the extracellular region of EphA10 showing tumor accumulation and anti-tumor effects against EphA10-positive breast cancer.
Materials and Methods: Tumor accumulation analysis of anti-EphA10 mAb; Alexa647-conjugated anti-EphA10 mAb or control mAb were administrated intravenously and observed daily using an in vivo imaging system. Tumor accumulation was quantified as the fluorescence intensity ratio of the tumor compared to that of the contralateral side. Anti-EphA10 mAb treatment in a mouse xenograft model; A mouse model was constructed by orthotopic transplantation of EphA10 stably expressing MDA-MB435 cells. When the tumor size reached approximately 100 mm3, anti-EphA10 mAb and control mAb were administrated intraperitoneally twice a week.
Results and Discussion: Anti-EphA10 mAb we have developed by hybridoma methods displayed an affinity against EphA10 in the nanomolar range and specificity for EphA family proteins. Administration of the fluorescein-labeled mAb to EphA10-positive breast tumor-bearing mice showed that the mAb specifically accumulated in tumors, but not in normal organs. Furthermore, tumor growth was significantly suppressed in the mAb-treated mice in a dose-dependent manner. These data indicate that EphA10 targeted antibody therapy have a potential as a novel option for management of EphA10-positive breast cancer. We are currently generating human anti-EphA10 mAb by phage human antibody library method toward the clinical application.
Conclusion: EphA10 targeted antibody therapy is effective for a mouse xenograft model. We hope that these findings will contribute to the development of a novel drug for refractory breast cancer patients.
Citation Format: Mori Takahide, Nagano Kazuya, Shin-ichi Tsunoda, Yasuo Tsutsumi. EphA10 targeted antibody therapy is a potential as a novel option for management of breast cancers including triple negative 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 B205.
Abstract B36: Human serum albumin and affibody fusion proteins for targeted drug delivery to HER2 positive cells
Authors: Dong Daoyuan , Li Zhijun , Li Zhiyu 
Published: May 2016

Abstract
Human Epidermal growth factor Receptor 2 (HER2) has been reported to be over-expressed in 20-30% of the breast cancer patients and related to poor prognosis. Affibody ZHER2 is a small protein which has high affinity to HER2 screened by phage display. Human Serum Albumin (HSA), as the main protein in plasma, has been commonly used to extend the small peptides serum half-life. Its high solubility, stability and excellent ability to carry multiple ligands in blood stream make it a good candidate for drug delivery. In this presentation, we report the development of albumin-affibody fusion proteins in the aim of targeted delivering chemotherapeutics to HER2 positive cells.
Two HSA fusion proteins have been successfully constructed, expressed and purified, one with a single ZHER2 domain at the albumin C terminus (rHSA-ZHER2) and the other has two tandem copies of ZHER2 (rHSA-(ZHER2)2). Both of the fusion proteins maintained the HER2 and fatty acid (FA) binding ability inherited respectively from the two parental proteins demonstrated by in vitro assays. Upon binding to the HER2, rHSA-ZHER2 only showed mild effect on HER2 positive SK-BR-3 cells, while rHSA-(ZHER2)2 significantly inhibited the proliferation of SK-BR-3 cells. More interestingly, a strong activation of both MAPK and AKT signaling was observed. Our results prove the feasibility of the fusion proteins to be used as drug carriers. Currently two formulations are under investigation, one is to complex the fusion protein with FA modified chemo drugs, and the other is to make them into nanoparticles. These two proteins not only can be explored as a potential drug delivery vehicle, but also may provide us with a good molecular tool to study the HER2 signaling pathway.
Citation Format: Daoyuan Dong, Zhijun Li, Zhiyu Li. Human serum albumin and affibody fusion proteins for targeted drug delivery to HER2 positive cells. [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 B36.
Abstract B64: Schlafen 11 (SLFN11) irreversibly blocks cell cycle recovery independently of ATR following replicative damage by poly(ADPribose) polymerase inhibitors
Authors: Murai Junko , Pommier Yves 
Published: May 2016

Abstract
PARP inhibitors kill cancer cells by trapping PARP-DNA complexes, with talazoparib the inhibitor with the highest PARP trapping activity. Genomic analyses across the 60 cancer cell lines of the National Cancer Institute (NCI-60) revealed a highly significant correlation between SLFN11 expression and sensitivity to talazoparib. The causal role of SLFN11 was established after generating four SLFN11-knockout cell lines (prostate DU145, Ewing EW8, leukemia CCRF-CEM and MOLT4) by CRISPR/Cas9 system, and finding that SLFN11 inactivation conferred high resistance to both talazoparib and olaparib. Resistance was caused neither by impaired drug penetration nor by hyperactivation of homologous recombination, as demonstrated in BRCA2-inactivated cells. SLFN11-proficient cells were irreversibly arrested in S phase by talazoparib treatment. Although ATR is the key regulator of the intra-S phase checkpoint, the addition of the ATR inhibitor (VE-821) did not release the replication arrest in SLFN11-proficient cells. By contrast, SLFN11-deficient cells treated with talazoparib reached G2, and their cell cycle and replication arrest was reversed by ATR inhibition. The combination of VE-821 with talazoparib or olaparib was highly synergistic with the greater synergy in the SLFN11-deficient cells. Our study reveals that SLFN11 acts as a novel DNA damage response gene for replicative DNA damage, and that SLFN11 inactivation, which is common in cancer cells, is a novel mechanism of resistance for PARP inhibitors, which can be mitigated by combining PARP and ATR inhibitors.
Citation Format: Junko Murai, Yves Pommier. Schlafen 11 (SLFN11) irreversibly blocks cell cycle recovery independently of ATR following replicative damage by poly(ADPribose) polymerase inhibitors. [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 B64.
Abstract B72: Cell-based DNA demethylation detection system for screening of epigenetic drugs in 2D, 3D and xenograft models
Authors: Agrawal Khushboo , Das Vishwanath , Otmar Miroslav , Krecmerova Marcela , Dzubak Petr , Hajduch Marian 
Published: May 2016

Abstract
Aberrant DNA methylation that turns ‘off’ the gene expression has remained a significant interest in cancer research. Despite major advances, the success of epigenetic therapy is prevented due to narrow therapeutic window. A wide variety of naturally occurring epigenetic agents and artificially synthesized molecules which can alter methylation patterns exists, but their usefulness in epigenetic therapy remains unknown. This underlines the need for large scale screening of epigenetic drugs with potent hypomethylation activity. In this ‘quest’ for more potent drugs targeting methylation, we present a cell-based DNA demethylation detection system, suitable for high content screening of epigenetic drug libraries in two-dimensional and three-dimensional culture systems. The detection system is fluorescence based and exploits the dominant ability of DNA methylation to inhibit gene transcription, and utilizes FLJ32130 gene which was discovered to be silenced on account of promoter hypermethylation in human colorectal cancer. In addition to demethylation screening, the detection system further incorporates the ability to monitor induced cytostatic/cytotoxic drug effects, in live cells, in a time dependent manner. Furthermore, our detection system also supports the in vivo determination of demethylation drug efficacy of potential hits selected on in vitro screening. Here, we describe the development of our cell-based DNA demethylation detection system, the anticipated results on screening of well-established DNA methylation inhibitors in two-dimensional versus three-dimensional cell cultures, and as well the efficacy of the system for monitoring demethylation in xenograft models.
Acknowledgements
The authors are grateful to Dr. Toshikazu Ushijima, Carcinogenesis Division, National Cancer Center Research Institute for his kind gift of FLJ32130 targeting vector. This study was supported by the grants awarded by the Ministry of Industry and Trade of the Czech Republic (MPO TIP FR-TI4/625), Ministry of Education, Youth and Sports (CZ09 / 7F14009 and LO1304; CZ.1.07/2.3.00/30.0041 to VD), Grant Agency of the Czech Republic (14-02652S and 14-03636S), and the Internal Grant Agency of Palacky University (IGA UP LF-2013/016).
Citation Format: Khushboo Agrawal, Vishwanath Das, Miroslav Otmar, Marcela Krecmerova, Petr Dzubak, Marian Hajduch. Cell-based DNA demethylation detection system for screening of epigenetic drugs in 2D, 3D and xenograft models. [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 B72.
Abstract B84: Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 significantly enhance the activity of the DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML)
Authors: Min Chengyin , Quayle Steven N. , Huang Pengyu , Shearstone Jeffrey R. , Jones Simon S. , Yang Min 
Published: May 2016

Abstract
AML is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. There is a great need for novel approaches to treat AML due to limited improvements in the treatment of patients over the past several decades. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and the DNA methyltransferase inhibitor azacitidine is approved for the treatment of myelodysplastic (MDS), which frequently progresses to AML, and is commonly used in AML patients. Numerous clinical studies are ongoing to investigate the benefit of combining azacitidine with other investigational agents in AML.
HDAC inhibitors are promising agents for the treatment of AML. Selective HDAC inhibitors are predicted to reduce combination drug toxicity and other side effects observed with pan-HDAC inhibitors, while still enabling therapeutic benefits. In this work, we demonstrate that potent and selective inhibitors of HDAC1/2 are highly efficacious both as single agents and in combination with azacitidine in preclinical models of AML, including established AML cell lines and bone marrow samples freshly derived from AML patients. Combination treatment in vivo demonstrated good tolerability, and ongoing efficacy studies in AML xenograft models will be discussed. At the molecular level, gene expression profiling and DNA methylation mapping were performed on MV4-11 cells treated with an HDAC1/2 inhibitor, azacitidine, or the combination. Molecular signatures were analyzed by GSEA. Significantly more genes and signatures were upregulated than downregulated by the single agent and combination treatments, consistent with the transcription activation mechanism of these compounds. Signatures and genes involved in myeloid cell differentiation, apoptosis and cell cycle arrest were identified as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML and potentially MDS patients.
Citation Format: Chengyin Min, Steven N. Quayle, Pengyu Huang, Jeffrey R. Shearstone, Simon S. Jones, Min Yang. Novel and selective inhibitors of histone deacetylases (HDAC) 1 and 2 significantly enhance the activity of the DNA methyltransferase inhibitor azacitidine in acute myeloid leukemia (AML). [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 B84.
Abstract B90: HSP90 inhibitor NVP-AUY922 sensitizes intrinsic MEK inhibitor Trametinib-resistant NSCLC cells harboring KRAS mutation
Authors: Lee Dae Ho , Park Kang-Seo , Oh Bora , Lee Mi-Hee , Yang Hannah 
Published: May 2016

Abstract
Introduction: Mutant KRAS is feature of more than 25% of non-small cell lung cancers (NSCLC) and exemplifies one of the most popular oncogenic drivers. Ras-driven tumors are often hard to cure with conventional therapies and are necessary novel treatment strategies.
Experiment: Using the HSP90 inhibitor NVP-AUY922, we investigated the potential of HSP90 inhibition to overcome the resistance to Trametinib, MEK inhibitor, in lung cancers harboring K-RAS mutant cell lines (H23, H358, H647, H1944, and A549). The synergistic effect of AUY-922 and trametinib was determined by analysis of the combination index (CI). After performing western blotting, we underwent following xenograft study with 6-week-old Balb/c-nu/nu female using H649 and H1944 cell lines. The mice were randomized into groups of 5, and NVP-AUY922 (5 mg/kg) was administered 3 days/week and GSK1120212 (300 μg/kg) was administered 5 days/week for up to 21 days in total.
Result: NSCLC cells harboring G13D KRAS mutation showed intrinsic MEK inhibitor resistance via PI3K activation by highly expressed AKT as a bypass pathway. And then, HSP90 inhibitor AUY-922 suppresses both PI3K-AKT-mTOR and RAF-MEK-ERK reactivated by MEK inhibitor GSK1120212 and finally AUY-922 renders intrinsic MEK inhibitor resistant NSCLC cells sensitive to GSK1120212 with significant synergy. Furthermore, we showed this synergistic effect is occurred on sub-effective dose of either drug.
Conclusion: The dual inhibition of HSP90 and MEK signaling pathways on sub-effective dose may constitute a potent therapeutic strategy to treat intrinsic MEK inhibitor resistant G13DKRAS mutant NSCLCs for resolving toxicity problem of dual inhibition of AKT and MEK in clinical trials.
Citation Format: Dae Ho Lee, Kang-Seo Park, Bora Oh, Mi-Hee Lee, Hannah Yang. HSP90 inhibitor NVP-AUY922 sensitizes intrinsic MEK inhibitor Trametinib-resistant NSCLC cells harboring KRAS mutation. [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 B90.
Abstract C110: Evaluation of immune cell populations in checkpoint inhibitor responsive syngeneic models
Authors: Barnes Sheri , Lasaro Marcio , Hauser Jacob , Mullin Robert J. , Synnott Aidan 
Published: May 2016

Abstract
Given the increasing success of cancer immunotherapies, we recognized a growing need for well-characterized preclinical models to enable drug discovery efforts. Syngeneic mouse tumor models offer advantages over conventional xenograft models for immunotherapy studies due to the presence of a fully functional immune system. We recently completed a comparative evaluation of the responsiveness of a collection of syngeneic models to two antibody based immunocheckpoint inhibitor therapeutics (anti-CTLA4, anti-PD1). This body of work resulted in the identification of several models responsive to checkpoint inhibition; CT26, Colon26, MC38, EMT-6, and A20. Our results clearly show differential tumor growth responses across this set of models following treatment with CTLA-4 and PD-1 targeted therapy. To further characterize these responses, we have performed a series of studies to identify and track immune cell populations by flow cytometry in blood, spleen, and tumor samples from mice harboring each responsive model. In these studies, we have investigated whether the modulation of CD4+, CD8+, regulatory CD4+ T cells (Treg), and myeloid derived suppressor cells (MDSC) populations correlates with the impact of immunocheckpoint inhibitors on tumor growth over time in untreated and challenged animals. These correlations of flow analyses with our antitumor data can point to the utility of cell-based endpoints as additional tools for evaluating combination outcomes.
Citation Format: Sheri Barnes, Marcio Lasaro, Jacob Hauser, Robert J. Mullin, Aidan Synnott. Evaluation of immune cell populations in checkpoint inhibitor responsive syngeneic models. [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 C110.
Abstract C115: Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations
Authors: Wang Zhenghe John , Hao Yujun 
Published: May 2016

Abstract
Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is the most frequently mutated oncogene in human cancers. However, whether PIK3CA mutations reprogram cancer metabolism is an important unaddressed question. Here we show that oncogenic PIK3CA mutations render colorectal cancers (CRCs) more dependent on glutamine to growth. As a metabolite, glutamine is first converted glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. Calithera Biosciences recently developed a potent GLS inhibitor called CB-839, which is currently in phase I clinical trials in cancer patients. Using isogenic colorectal cancer cell lines with either WT or mutant PIK3CA allele knockout, we demonstrated that CRCs with PIK3CA mutations are more sensitive to growth inhibition by CB-839. Remarkably, combination of CB-839 with 5-FU induces regression xenograft tumors from a CRC with a PIK3CA mutation, suggesting that this combinational therapy may be effective approach to treat CRC patients whose tumors harbor PIK3CA mutations.
Mechanistically, mutant p110α up-regulates gene expression of glutamate pyruvate transaminase 2 (GPT2) in CRC cells, thereby facilitate conversion of glutamate to α-KG. Using [13C5-]glutamine isotope-tracing technology, we showed that PIK3CA mutant CRCs produce more α-KG from glutamine to α-KG to replenish the tricarboxylic acid (TCA) cycle to generate ATP. Moreover, aminooxyacetate, which inhibits enzymatic activity of transaminases including GPT2, suppresses xenograft tumor growth of CRCs with PIK3CA mutations, but not CRCs with WT PIK3CA. Mutant p110α up-regulates the transcription of GPT2 through an AKT-independent PDK1-RSK2-ATF4 signaling axis. We showed that ATF4 is a transcription factor that activates GPT2 gene expression. We further demonstrated that mutant p110α activates RSK2 kinase through PDK1. Activated RSK2 then phosphorylates ATF4 at the serine residue 245, which in turn recruits deubiquitinase USP8 and protects ATF4 from ubiquitin-mediated degradation. Together, our data establish oncogenic PIK3CA mutations as a cause of glutamine addiction in CRCs and that targeting glutamine metabolism may be effective approach to treat CRCs with PIK3CA mutations.
Citation Format: Zhenghe John Wang, Yujun Hao. Targeting glutamine metabolism in colorectal cancers with PIK3CA mutations. [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 C115.
Abstract C136: Identification of selective cancer cytotoxic modulators of phosphodiesterase 3a by predictive chemogenomics
Authors: de Waal Lucian , Lewis Timothy A. , Rees Matthew G. , Tsherniak Aviad , Wu Xiaoyun , Choi Peter S. , Gechijian Lara , Hartigan Christina , Faloon Patrick W. , Hickey Mark J. , Tolliday Nicola , Carr Steven A. , Clemons Paul A. , Munoz Benito , Wagner Bridget K. , Shamji Alykhan F. , Koehler Angela N. , Schenone Monica , Burgin Alex B. , Schreiber Stuart L. , Greulich Heidi , Meyerson Matthew 
Published: May 2016

Abstract
High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identify phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrate that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased sensitivity to DNMDP. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.
Citation Format: Lucian de Waal, Timothy A. Lewis, Matthew G. Rees, Aviad Tsherniak, Xiaoyun Wu, Peter S. Choi, Lara Gechijian, Christina Hartigan, Patrick W. Faloon, Mark J. Hickey, Nicola Tolliday, Steven A. Carr, Paul A. Clemons, Benito Munoz, Bridget K. Wagner, Alykhan F. Shamji, Angela N. Koehler, Monica Schenone, Alex B. Burgin, Stuart L. Schreiber, Heidi Greulich, Matthew Meyerson. Identification of selective cancer cytotoxic modulators of phosphodiesterase 3a by predictive chemogenomics. [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 C136.