bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1717: Downregulation of miR-217 correlates with resistance of ph+ leukemia cells to ABL tyrosine kinase inhibitors
Authors: Ikezoe Takayuki , Nishioka Chie , Yang Jing , Yokoyama Akihito 
Published: May 2015

Abstract
This study found that long-term exposure of chronic myelogenous leukemia (CML) K562 cells to BCR/ABL thyrosine kinase inhibirors (TKIs) caused drug-resistance in association with an increase in levels of DNA methyltransferases (DNMTs) and a decrease in levels of microRNAs (miRNAs) miR-217. These observations are clinically relevant; an increase in levels of DNMT3A in association with downregulation of miR-217 were noted in leukemia cells isolated from individuals with BCR/ABL TKI-resistant philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) and CML. Further studies with TKI-resistant K562 cells found that forced expression of miR-217 inhibited expression of DNMT3A through a miR-217-binding site within the 3′-untranslated region of DNMT3A and sensitized these cells to growth inhibition mediated by the TKI. Of note, long-term exposure of K562 cells to dasatinib (10 nM) together with 5-Aza-2′-deoxycytidine (5-AzadC) (0.1 μM) potently inhibited proliferation of these cells in association with upregulation of miR-217 and downregulation of DNMT3A in vitro. In addition, a decrease in levels of DNMT3A and an increase in levels of miR-217 were noted in K562 tumors growing in immune deficient mice that were treated by the combination of 5-AzadC and dasatinib. Taken together, Ph+ leukemia cells acquire TKI-resistance via downregulation of miR-217 and upregulation of DNMT3A. Inhibition of DNMT3A by forced expression of miR-217 or 5-AzadC may be useful to prevent drug resistance in individuals who receive TKIs.
Citation Format: Takayuki Ikezoe, Chie Nishioka, Jing Yang, Akihito Yokoyama. Downregulation of miR-217 correlates with resistance of ph+ leukemia cells to ABL tyrosine kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1717. doi:10.1158/1538-7445.AM2014-1717
Abstract 1718: Schlafen 11 (SLFN11) is a critical determinant of cellular sensitivity to PARP inhibitors
Authors: Murai Junko , Josse Rozenn , Doroshow James H. , Pommier Yves 
Published: May 2015

Abstract
Poly(ADP-ribose)polymerases (PARP) are DNA damage sensors and major repair factors for DNA single-strand breaks. Since the discovery of the synthetic lethality of PARP inhibitors in homologous recombination-deficient cells, the mechanism by which PARP inhibitors exert their cytotoxicity has been dominantly interpreted as an accumulation of unrepaired single-strand breaks resulting from catalytic PARP inhibition. We recently reported that several PARP inhibitors have an additional cytotoxic mechanism by trapping PARP-DNA complexes (1). BMN 673 is the most potent PARP inhibitor to date in terms of cytotoxicity and PARP trapping potency (2). Nevertheless, the NCI60 data show that half of the 60 cell lines are tolerant to BMN 673. To elucidate the mechanisms of tolerance, we searched for genes with expression levels correlated to BMN 673 sensitivity, and found that Schlafen 11 (SLFN11) is one of the most positively correlated genes. Most cells without SLFN11 expression were tolerant to BMN 673. To examine the involvement of SLFN11 in BMN 673 sensitivity, we disrupted the SLFN11 gene in DU145 prostate cancer cells and EW8 Ewing's sarcoma cells where SLFN11 expression levels and BMN 673 sensitivities are high. Knocking out SLFN11 in DU145 and EW8 did not affect their cell growth or cell cycle progression under normal conditions, but diminished their hypersensitivity to BMN 673 and another PARP inhibitor, olaparib. Cell cycle analyses revealed that SLFN11-proficient cells arrested at S phase while SLFN11 deficient cells were able to progress to G2 phase in the presence of BMN 673. Interestingly, arresting points at S phase in SLFN11 proficient cells were earlier when more PARP-DNA complexes were induced, suggesting that SLFN11 inhibits DNA replication under DNA damage. Differential kinetics of DNA repair and PARP-DNA complex formation were observed between SLFN11 proficient versus deficient cells. Our data suggest that the expression of SLFN11 may be a novel genomic biomarker for PARP inhibitor sensitivity.
1. Murai J, Huang S-yN, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Research. 2012;72:5588-99.
2. Murai J, Huang SN, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014; Submitted.
Citation Format: Junko Murai, Rozenn Josse, James H. Doroshow, Yves Pommier. Schlafen 11 (SLFN11) is a critical determinant of cellular sensitivity to PARP inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1718. doi:10.1158/1538-7445.AM2014-1718
Abstract 1719: Down-regulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma
Authors: Kang Zhigang , Yu Yunkai , Zhu Yuelin J. , Helman Lee , Meltzer Paul , Cao Liang 
Published: May 2015

Abstract
Agents targeting the insulin-like growth factor-1 receptor (IGF1R) are in clinical development, but, despite some initial success of single agents in sarcoma, response rates are low with brief durations. Thus, it is important to identify markers predictive of response, to understand mechanisms of resistance, and to explore combination therapies. In this study, we found that, while associated with PAX3-FKHR translocation, increased IGF1R level is an independent prognostic marker for worse overall survival, particularly in patients with PAX3-FKHR-positive rhabdomyosarcoma (RMS). IGF1R antibody-resistant RMS cells were generated using an in vivo model. Expression analysis indicated that IGFBP2 is both the most affected gene in the IGF signaling pathway and the most significantly down-regulated gene in the resistant lines, indicating that there is a strong selection to repress IGFBP2 expression in tumor cells resistant to IGF1R antibody. IGFBP2 is inhibitory to IGF1R phosphorylation and its signaling. Similar to antibodies to IGF1/2 or IGF2, the addition of exogenous IGFBP2 potentiates the activity of IGF1R antibody against the RMS cells, and it reverses the resistance to IGF1R antibody. In contrast to IGF1R, lower expression of IGFBP2 is associated with poorer overall survival, consistent with its inhibitory activity found in this study. Finally, blocking downstream AKT activation with PI3K- or mTOR-specific inhibitors significantly sensitized the resistant cells to the IGF1R antibody. These findings show that constitutive IGFBP2 down-regulation may represent a novel mechanism for acquired resistance to IGF1R therapeutic antibody in vivo and suggest various drug combinations to enhance antibody activity and to overcome resistance.
Citation Format: Zhigang Kang, Yunkai Yu, Yuelin J. Zhu, Lee Helman, Paul Meltzer, Liang Cao. Down-regulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1719. doi:10.1158/1538-7445.AM2014-1719
Abstract 1722: Investigating resistance to AZD9291
Authors: Eberlein Cath , Ratcliffe Laura , O'Brien Lucy , Al-Khadimi Katie , Brown Henry , Fisher Paul , Stetson Daniel , Lai Zhongwu , Marshall Gayle , Barnes Claire , Thress Kenneth , Dougherty Brian , Pao William , Cross Darren 
Published: May 2015

Abstract
First- and second-generation EGFR TKIs are established first line therapy for patients with NSCLC with activating mutations in EGFR. Unfortunately, patients ultimately develop disease progression with acquisition of a second-site EGFR T790M mutation in more than half of cases. This has led to the development of third generation EGFR TKIs which inhibit both the EGFRm+ and T790M mutations in preclinical models and are showing activity in TKI-resistant patients in Phase I studies. Despite the potential improvements brought by third generation EGFR-TKIs, advanced EGFRm+ tumor cells will still remain highly adaptable and the inevitability of further resistance will limit the effectiveness of these drugs. As such, the identification of resistance mechanisms to these agents is essential to guide future therapeutic strategies and identify novel:novel combinations.
To interrogate resistance to AZD9291, we have generated panels of EGFRm+ cell lines resistant to gefitinib (first generation TKI) and EGFRm+ and EGFRm+/T790M cell lines resistant to afatinib and AZD9291 (second and third generation TKIs, respectively). Subsequently, we characterised the cell lines using a variety of molecular profiling techniques including Next Generation Sequencing (NGS), Affymetrix gene expression analysis, and phenotypic profiling following pharmacological modulation by small molecule inhibitors of canonical signaling pathways.
The effects on cell survival across the range of resistant models by a panel of pathway inhibitors indicated that resistance to the EGFR inhibitors, in particular AZD9291, is frequently associated with increased sensitivity to selumetinib (AZD6244; ARRY-142886) (MEK1/2 inhibitor), suggesting that ERK signaling is commonly reactivated to circumvent inhibition of the EGFR pathway. Molecular characterisation of the panel of cell lines suggests a range of different resistance mechanisms may be responsible for reactivation of ERK signaling, including a decrease in negative regulators of ERK such as DUSP6 or an epithelial to mesenchymal transition consistent with previous observations.
Collectively, these data suggest that combining an EGFR TKI with a MEK inhibitor could prevent or delay resistance and drive superior duration of benefit from these agents.
Citation Format: Cath Eberlein, Laura Ratcliffe, Lucy O'Brien, Katie Al-Khadimi, Henry Brown, Paul Fisher, Daniel Stetson, Zhongwu Lai, Gayle Marshall, Claire Barnes, Kenneth Thress, Brian Dougherty, William Pao, Darren Cross. Investigating resistance to AZD9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1722. doi:10.1158/1538-7445.AM2014-1722
Abstract 1734: In vitro characterization of EGF816, a third-generation mutant-selective EGFR inhibitor
Authors: Jia Yong , Juarez Jose , Manuia Mari , Lelais Gerald , Kasibhatla Shailaja , Long Oliver , McNeill Matthew , DiDonato Michael , Bursulaya Badry , Liao Debbie , Murphy Eric , Epple Robert , Marsilje Thomas , Pathan Nuzhat , Michellys Pierre-Yves , Bender Steven , Harris Jennifer 
Published: May 2015

Abstract
EGFR is a major oncogene in NSCLC. Patients with the oncogenic mutations L858R and Ex19Del are responsive to the first generation pan-EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. The associated dose-limiting toxicities (DLTs) are severe rash and GI tolerability due to WT EGFR inhibition. However, therapy is universally limited by the development of acquired drug resistance where EGFR gatekeeper mutation T790M accounts for 50% of incidence. Second generation irreversible pan-EGFR TKI afatinib was developed to overcome T790M resistance. Though effective in animal models, the efficacy of afatinib on T790M patients is largely limited by its DLTs due to potent inhibition of WT EGFR. A strong medical need still exists for better tolerated therapy to treat NSCLC patients harboring EGFR mutations. Here we report the discovery and development of a potent third generation, irreversible mutant-selective EGFR TKI that is expected to improve/maintain efficacy on oncogenic EGFR mutant patients while demonstrating reduced side effects. EGF816 potently inhibits both activating (L858R and Ex19Del) and T790M resistant mutations in various cellular assays; it is selective against a large panel of kinases in both Ambit and BaF3 profiling, and more importantly is selective against WT EGFR. EGF816 is efficacious in mutant EGFR-driven xenograft models, is well tolerated in IND-enabling toxicology studies, and is entering phase 1 trials.
Citation Format: Yong Jia, Jose Juarez, Mari Manuia, Gerald Lelais, Shailaja Kasibhatla, Oliver Long, Matthew McNeill, Michael DiDonato, Badry Bursulaya, Debbie Liao, Eric Murphy, Robert Epple, Thomas Marsilje, Nuzhat Pathan, Pierre-Yves Michellys, Steven Bender, Jennifer Harris. In vitro characterization of EGF816, a third-generation mutant-selective EGFR inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1734. doi:10.1158/1538-7445.AM2014-1734
Abstract 1753: GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer
Authors: Pujuguet Philippe , Beirinckx Filip , Delachaume Carole , Huck Jacques , Aar Ellen Van der , Brys Reginald , Rompaey Luc Van , Wigerinck Piet , Saniere Laurent 
Published: May 2015

Abstract
Receptor tyrosine kinases define a clinically relevant class of targets in the field of cancer. Here we report the discovery of a pre-clinical drug candidate directed against the EPH receptor family. Members of this family of receptor tyrosine kinases are over-expressed in diverse cancer types. GLPG1790 is a small molecule, nanomolar inhibitor of various EPH receptors kinases. The compound displayed a remarkable efficacy by once-daily oral administration in a mouse EPHA2 expressing xenograft model (MDA-MB-231). A rapid dose-dependent reduction of tumor growth was achieved, with full inhibition at the oral dose of 30 mg/kg/d. GLPG1790 efficacy at this dose was similar to that of Paclitaxel administered at its maximum tolerated dose. A series of experiments was initiated to confirm the mechanism of action of this compound. GLPG1790 inhibits human EPHA2 kinase activity with an IC50 of 11 nM in a biochemical assay. In the human MDA-MB-231 breast cancer cell line, that expresses a high level of EPHA2 protein, GLPG1790 inhibits receptor phosphorylation with an IC50 of 260 nM, and anchorage-independent growth with similar potency. In addition, in vivo target engagement was demonstrated in the mouse MDA-MB-231 xenograft model. GLPG1790 inhibited EPHA2 receptor phosphorylation after single oral administration of 30 and 100 mg/kg doses. The extent of the effects observed on EPHA2 phosphorylation correlated with intra-tumoral GLPG1790 concentration. Moreover, the MAPK pathway, known to be a major driver of proliferation of this cell line, was inhibited both in in vitro cellular assays and in xenograft target engagement studies. Flow cytometric analyses revealed a cell cycle arrest at the G0/G1 phase for MDA-MB-231 cells treated with GLPG1790. EPHA2 knock-down-based experiments further support the EPH-driven mode of action of GLPG1790. All together these data stimulate the development of GLPG1790 in triple negative breast cancer. This novel mechanism of action is under investigation in other cancer types overexpressing EPH's (melanoma, pancreatic, ovarian, prostatic and colorectal cancers).
Citation Format: Philippe Pujuguet, Filip Beirinckx, Carole Delachaume, Jacques Huck, Ellen Van der Aar, Reginald Brys, Luc Van Rompaey, Piet Wigerinck, Laurent Saniere. GLPG1790: The first Ephrin (EPH) receptor tyrosine kinase inhibitor for the treatment of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2014-1753
Abstract 1762: Phosphodiesterase 10, a novel target for colorectal cancer therapeutics
Authors: Lee Kevin J. , Li Nan , Chen Xi , Zhu Bing , Yet Larry , Piazza Gary 
Published: May 2015

Abstract
Phosphodiesterase 10 (PDE10) is a newly characterized PDE isozyme that is expressed in regions of the brain affecting cognition and psychomotor activity. Inhibitors are currently being developed for the treatment of schizophrenia and Huntington's disease, one of which, Pf-2545920 (MP-10), is in clinical trials. Although PDE10 is not expressed in most peripheral tissues, we recently found high levels in colon tumor cells compared with normal colonocytes and that genetic silencing by siRNA selectively suppressed colon tumor cell growth. These observations suggest that PDE10 may represent a novel anticancer target. Pf-2545920 was found to selectively inhibit colon tumor cell growth. Here we show that PDE10 knockdown reduced the sensitivity of colon tumor cells to Pf-2545920. Consistent with the ability of PDE10 to degrade cGMP and cAMP, Pf-2545920 activated both PKG and PKA as determined using site-specific phospho-VASP antibodies. Treatment of colon tumor cells with Pf-2545920 induced caspase activation as well as cytotoxicity. A novel PDE10 inhibitor, MCI-030, was found to potently inhibit colon tumor cell lines with IC50 values in the 0.3μM range without significantly affecting the growth of normal colonocytes. MCI-030 appears to exhibit selectivity for cGMP PDE10 signaling over cAMP shown by the activation of PKG but not PKA at doses that match those which inhibit growth. PDE10 knockdown cells were appreciably less sensitive to MCI-030 as well. These findings support a novel role of PDE10 as a therapeutic target for the treatment or prevention of colorectal cancer.
Citation Format: Kevin J. Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Gary Piazza. Phosphodiesterase 10, a novel target for colorectal cancer therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1762. doi:10.1158/1538-7445.AM2014-1762
Abstract 1768: A novel PDE10 inhibitor suppresses tumor growth in an orthotopic mouse model of lung cancer
Authors: Ramirez-Alcantara Veronica , Schuler Michele A. , Zhu Bing , Li Nan , Gurpinar Evrim , Canzoneri Joshua , Keeton Adam , Gary Bernard , Russo Suzanne , Coward Lori , Gorman Gregory S. , Grizzle William , Chen Xi , Piazza Gary A. 
Published: May 2015

Abstract
Background: Conventional chemotherapy and radiation cannot distinguish between cancer and normal cells resulting in dose-limiting toxicity. Molecular targeted drugs hold greater promise, but few targets are unique to cancer cells and drugable. Our laboratory discovered that the cyclic nucleotide phosphodiesterase, PDE10, is elevated in human lung tumor cells and essential for their growth. A novel PDE10 inhibitor, MCI-020 was designed to achieve high lung concentrations and found to selectively inhibit the growth of human lung tumor cells in vitro. Objective: Evaluate pharmacokinetics, tissue distribution and antitumor efficacy of MCI-020 in mice. Material and Methods: MCI-020 (100 mg/kg) was formulated as a suspension and administrated orally to C57BL/6 female mice. Free levels of MCI-020 were quantified in plasma and tissues by reverse-phase chromatography with tandem mass spectrometry detection. For efficacy evaluation, athymic nude-Foxn1nu female mice were treated with MCI-020 (150 mg/kg bid) for 5 days before inoculation with 1x106 A549 cells/mouse into the left lung. After inoculation, MCI-020 treatment continued for 4 weeks. Anti-tumor efficacy of MCI-020 was evaluated by gross and histological grading of the lungs. Results: MCI-020 displayed attractive oral bioavailability and reached appreciably higher concentrations in lungs compared with plasma. MCI-020 treatment showed strong anti-tumor efficacy in the orthotopic mouse model of lung cancer and was well tolerated. Compared with the vehicle group in which 85% of the mice formed lung tumors, only 25% of the mice in the treatment group developed tumors. Histological grading of the extent of tumor formation revealed a score of 0.83 ± 0.3 (low involvement) for the treatment group, compared with 2.6 ± 0.4 (high involvement) for the vehicle group. Conclusions: These observations support a critical role of PDE10 in lung tumor growth and suggest that PDE10 inhibitors will be useful for the prevention or treatment of lung cancer. This project is supported by NIH grant 1R01CA148817.
Citation Format: Veronica Ramirez-Alcantara, Michele A. Schuler, Bing Zhu, Nan Li, Evrim Gurpinar, Joshua Canzoneri, Adam Keeton, Bernard Gary, Suzanne Russo, Lori Coward, Gregory S. Gorman, William Grizzle, Xi Chen, Gary A. Piazza. A novel PDE10 inhibitor suppresses tumor growth in an orthotopic mouse model of lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1768. doi:10.1158/1538-7445.AM2014-1768
Abstract 1785: Distinct effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae
Authors: Miles Jana Sharrae , Mazu Tryphon , Darling-Reed Selina , Flores-Rozas Hernan 
Published: May 2015

Abstract
Anthracyclines are common chemotherapeutic agents used in many cancers which are refractory to other therapeutic alternatives. In triple negative breast cancer which is commonly observed in African-American women (AA) and tend to be more aggressive, carry worse prognoses and are harder to manage because they lack the molecular targets required for therapies, anthracyclines are some of the few therapeutic alternatives. Although effective, resistance to this agent usually arises and serious side-effects like the development of cardiomyopathy limits their use. To increase our knowledge of the pathways that protect cells from anthracyclines we carried out a genome-wide genetic screening in the eukaryotic model organism S. cerevisiae to identify gene defects that generate cells hypersensitive to doxorubicin. A total of 71 deletion strains displayed varying levels of sensitivity to anthracyclines. Among these, mutants of HOM6 confer significant increased sensitivity to doxorubicin. This effect appears to be due to the accumulation of the threonine intermediate L-aspartate-semialdehyde and can be abolished by the inactivation of a prior step, involving HOM3, which prevents the accumulation of the intermediate. In order to further characterize the synergism of aldehydes and doxorubicin, we have tested the effect of different aldehydes on the cytotoxicity of cells exposed to anthracyclines.
Our data show that treatment with formaldehyde (2 mM) reduced the survival of the wild type strain to 78%. However, in the presence of doxorubicin, formaldehyde reduced the viability of the strain by between 31 to 39-fold (with 10 µM doxorubicin) relative to doxorubicin and formaldehyde alone and by ∼110-fold relative to doxorubicin at 150 µM concentration.
Co-treatment with formaldehyde and doxorubicin of anthracycline-resistant strains siz1 and msh2 also shows increased toxicity. However, the synergistic effect is not as pronounced in these strains compared to the wild type. Among the aldehydes tested, formaldehyde was most effective. Glutaraldehyde and acetaldehyde displayed distinct effect on strains siz1, and ald5. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy. This possibility will be discussed, as well as the targeting of aldehydes in relevant human pathways.
Research supported by NIH/NCRR RCMI grant #RR03020 at Florida A&M University.
Citation Format: Jana Sharrae Miles, Tryphon Mazu, Selina Darling-Reed, Hernan Flores-Rozas. Distinct effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1785. doi:10.1158/1538-7445.AM2014-1785