bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3030: CT179: A novel small molecule Olig2 inhibitor for the treatment of glioblastoma
Authors: Alton Gordon , Beaton Graham , Knowles Susan , Stein Greg , Mukthavaam Rajesh , Kesari Santosh 
Published: July 2016

Abstract
Glioblastoma (GBM) is an orphan disease with a high unmet medical need. Despite optimal treatment, the median survival is only 12 to 15 months in GBM patients of which only 4% achieve 5-year survival. OLIG2 is a transcription factor that is almost exclusively expressed in the CNS that has been linked to the tumorigenesis of GBM cells and their resistance to radiotherapy. Importantly OLIG2 is a key transcription factor that maintains the stemness of the glial stem cells, drives proliferation and invasion and recurrent tumor growth. Inhibitors of this pathway are therefore of interest as potential treatments for this unmet need.
CT-179 is a small molecule inhibitor that was initially designed to prevent homodimerization of Olig2. CT-179 is highly cytotoxic to OLIG2 expressing GBM cells with a high therapeutic index for non-OLIG2 expressing cell types. This inhibitor demonstrates functional inhibition of the OLIG2 pathway through specific reduction in nuclear Olig2 protein levels in treated cells. A cell pathway analysis indicates that CT-179 impacts GBM proliferation through cell cycle arrest and induction of apoptosis. Secondarily an immunosuppression mechanism-of-action may also be relevant. CT-179 penetrates the CNS to attain high brain concentrations at levels far in excess of its cytotoxicity to GBM cells. Efficacy studies reveal dose dependent reductions of tumor growth which is enhanced with radiotherapy. CT-179 demonstrates impressive extension of survival in orthotopic human PDX GBM. Safety studies indicate that there is a large therapeutic window. The compound has a long half-life, low metabolism and has excellent formulation properties and PK supporting once per day oral dosing. CT-179 show promise as both a cytotoxic agent and as potential radiosensitizer for use in the treatment of GBM.
Citation Format: Gordon Alton, Graham Beaton, Susan Knowles, Greg Stein, Rajesh Mukthavaam, Santosh Kesari. CT179: A novel small molecule Olig2 inhibitor for the treatment of glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3030.
Abstract 3039: Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II
Authors: Santamaria-Nunez Gema , Genes-Robles Carlos M. , Martínez-Leal Juan F. , Galmarini Carlos M. , Egly Jean Marc 
Published: July 2016

Abstract
Cancer cells are characterized for their avid demand for active transcription, which reaches the level of a real addiction in solid tumors as small cell lung cancer (SCLC) or triple-negative breast cancer. Pharmacological modulation of transcription may thus provide a therapeutic approach to treat tumor types that depend on deregulated transcription for the maintenance of their oncogenic state. Lurbinectedin, currently under evaluation in a Phase III clinical trial for platinum-resistant ovarian cancer patients, and with very promising activity in combination with doxorubicin in SCLC, inhibits active transcription. Here we demonstrate that, after binding to specific DNA triplets highly represented in the CG-rich region surrounding the promoter of genes, this drug induces a rapid degradation of RNA Polymerase II (Pol II). Our results show that the hyperphosphorylated form of Pol II, already engaged in transcription elongation and likely blocked during this process by the lurbinectedin-DNA adduct, is then specifically submitted to the ubiquitin/proteasome degradation process, which finally removes the majority of the Pol II protein pool in treated cells. Disappearance of Pol II is followed by the formation of DNA breaks, process in which the nucleotide excision repair (NER) machinery, specifically the endonuclease XPF, has an important role. Pol II degradation and subsequent DNA damage were not only abrogated by inhibitors of CDK7 and CDK9 cyclin dependent kinases (DRB and flavopyridol), ubiquitin ligation (PYR-41), or proteasome activity (MG132), but also correlated with the antiproliferative activity of lurbinectedin in different cancer cell line models. In summary, lurbinectedin exemplifies a prototype drug for targeting transcriptional dependency in tumor cells and, thus, it could represent a new therapeutic alternative for solid tumors with this addiction.
Citation Format: Gema Santamaria-Nunez, Carlos M. Genes-Robles, Juan F. Martínez-Leal, Carlos M. Galmarini, Jean Marc Egly. Lurbinectedin specifically targets transcription in cancer cells, triggering DNA breaks and degradation of phosphorylated Pol II. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3039.
Abstract 3049: Arachidonate 12-lipoxygenase contributes to radiation-induced type II pneumocyte senescence and fibrosis
Authors: Chung Eun Joo , Valle Luca F. , White Ayla O. , Citrin Deborah E. 
Published: July 2016

Abstract
Introduction: Ionizing radiation (IR) is commonly used in the treatment of thoracic malignancies. Exposure of adjacent normal lung may result in lung injury and fibrosis. Recently, we reported that accelerated senescence of type II pneumocytes, the alveolar stem cell, results in parynchymal depletion and precedes pulmonary fibrosis. Arachidonate 12-lipoxygenase (12-LOX) oxidizes arachidonic acid to form 12-Hydroxyeicosatetraeonic acid (12-HETE), a pro-inflammatory mediator. Increased expression of ALOX-12 has previously been associated with aging. We hypothesized that mice deficient in ALOX-12 would be resistant to IR induced fibrosis and senescence.
Methods: C57/Bl6J (WT) and Alox12 homozygous knockout (Alox12-KO) mice (n&gt;3 per group) were exposed to thoracic IR (0Gy, 5Gy, 17.5Gy, 5×5Gy, or 6×5Gy). Fibrotic foci were identified with aniline blue staining of fixed lung sections. Levels of 12-LOX mRNA and protein were assessed in WT lungs after IR with microarray, quantitative PCR, and western blotting. In vitro studies with primary murine pneumocyte cultures and A549 cells included staining for senescence associated β-galactosidase activity and western blotting for NOX4, p21, and PML following IR and 12-HETE treatment.
Results: A significant increase in 12-LOX mRNA and protein was observed in murine lungs exposed to fibrogenic doses of IR (17.5 Gy, 5×5 Gy and 5×6 Gy) compared to low dose IR (5 Gy) or controls (0 Gy). 12-LOX deficiency significantly reduced fibrotic foci in murine lungs receiving fibrogenic doses of thoracic IR (6×5 Gy) at 18 weeks. Treatment of murine primary pneumocytes with 12-HETE (1 and 150 nM) increased the rate of pneumocyte senescence (2.1 fold). Treatment of murine primary pneumocytes with 12-HETE increased the expression of NOX4 (a mediator of superoxide generation), p21, and PML (senescence markers), paralleling increases observed after IR. Similarly, human type II pneumocyte A549 cells exhibited increased 12-LOX expression in β-galactosidase-stained senescent cells at 3 days after IR.
Conclusion: These studies identify 12-LOX as a critical mediator in radiation lung fibrosis and type II pneumocyte senescence. 12-LOX may serve as a novel therapeutic target in mitigating IR-induced lung fibrosis.
Citation Format: Eun Joo Chung, Luca F. Valle, Ayla O. White, Deborah E. Citrin. Arachidonate 12-lipoxygenase contributes to radiation-induced type II pneumocyte senescence and fibrosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3049.
Abstract 3054: CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11)
Authors: Schwartz Anthony L. , Kaur Sukhbir , Tang Sai-Wen , Pommier Yves , Roberts David D. 
Published: July 2016

Abstract
Schlafen-11 (SLFN11) expression was recently shown to determine the sensitivity of human cancer cells to DNA damaging agents including topoisomerase inhibitors, DNA alkylating agents, and DNA synthesis inhibitors. High expression of SLFN11 in cancer cell lines results in increased sensitivity to these agents, whereas depletion of SLFN11 induces cellular protection. In addition, high expression of SHFN11 is associated with greater overall survival than low SLFN11 expression in ovarian patients treated with cisplatin. These observations suggest that SLFN11 may be an integral part of a critical DNA repair pathway. However, the pathways that regulate SLFN11 expression have not been reported. CD47 is an integrin-associated protein widely expressed on mammalian cells and frequently elevated in cancers. Its ligand, thrombospondin-1 (TSP1) induces CD47 signaling that regulates some growth factor receptors, cell fate, viability, and responses to cellular stresses such as radiation and chemotherapy. Our laboratory has previously shown that CD47 deficiency results in protection of nontransformed cells, whereas high CD47 expression sensitizes the same cells to ionizing radiation and DNA-damaging chemotherapy. We identified SLFN11 expression as a potential target of CD47 signaling by microarray analysis of a CD47-deficient mutant cell line and found that CD47 expression also correlates with that of SLFN11 in some human cancers. Thus, we sought to investigate the possible regulation of SLFN11 by CD47 by treating various cell lines with the function-modifying CD47 antibody B6H12 or its physiological ligands TSP1 and signal regulatory protein-α (SIRPα). qRT-PCR analysis revealed significant decreases in SLFN11 expression at 3 and 6 hours post-B6H12 treatment. Furthermore, treatment with TSP1 significantly decreased SHFN11 mRNA expression at the same time points, but SIRPα-Fc did not. Conversely, transient re-expression of CD47 in deficient cells elevated SLFN11 expression. These data demonstrate that pharmacological and physiological modulation of CD47 signaling acutely alters SLFN11 expression and suggests a potential mechanism by which CD47 modulates cellular sensitivity to DNA damaging chemotherapy agents. SLFN11 may in turn be a functional target and useful biomarker for the therapeutic CD47 antibodies currently in clinical trials.
Citation Format: Anthony L. Schwartz, Sukhbir Kaur, Sai-Wen Tang, Yves Pommier, David D. Roberts. CD47 signaling regulates a DNA damage response pathway by suppressing the expression of Schlafen-11 (SLFN11). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3054.
Abstract 3057: Synthetic novel Psammaplin A derivatives enhance radiation lethality in human cancer cells
Authors: Kim Jin Ho , Wee Chan Woo , Kim Hak Jae , Suh Soo Youn , Ma Eun Sook , Shin Boom Soo , Kim Il Han 
Published: July 2016

Abstract
DNA methyltransferase (DNMT) inhibitors show not only anticancer effects but radiosensitization activity. Psammaplin A (PsA), a known DNMT inhibitor, enhances radiation lethality of human cancer cells, but the chemical instability hampers in vivo application of PsA. The purpose of the present study was to synthesize novel radiosensitizers using PsA as the backbone structure. Eight novel PsA-based derivatives (MA2, MA3, MA5, MA6, MA7, MA8, MA9 and MA5M) were synthesized. They were tested for in vitro cytotoxicity and radiosensitizing effects in A549 (lung cancer) and U373MG (glioblastoma) cells using a clonogenic assay. A paired ratio t-test was used to test a statistical significance of sensitizer enhancement ratios of the compounds. All 8 PsA derivatives inhibited in vitro cell survival with 50% inhibitory concentrations ranging 16-150 μM (A549) and 15-50 μM (U373MG). MA7, MA9 and MA5M significantly enhanced radiation lethality in A549 cells, while compounds MA2, MA3 and MA7 showed a significant radiosensitization in U373MG cells (p&lt;0.05). MA3 and MA6 marginally radiosensitized A549 and U373MG cells, respectively (p&lt;0.10). For further investigation, we selected MA3 and MA7, because only these two compounds showed radiosensitization in both A549 and U373MG cell lines. A DNMT activity assay showed that MA3 inhibited DNMT1 activity, but that MA7 showed no inhibitory effect on DNMT1. Pharmacokinetic parameters were determined in mice by a validated LC-MS/MS assay method using a non-compartmental analysis. The average degradation half-life of MA3 and MA7 was under 10 minutes in mouse serum. In the present study, we synthesized two novel PsA-derived compounds that enhanced radiation lethality in two human cancer cell lines. However, they lacked chemical stability to allow for in vivo experiments. Based on the present study, a further study is necessary to improve bioavailability of PsA-derived radiosensitizers. [Supported by 2013M2A2A7043683]
Citation Format: Jin Ho Kim, Chan Woo Wee, Hak Jae Kim, Soo Youn Suh, Eun Sook Ma, Boom Soo Shin, Il Han Kim. Synthetic novel Psammaplin A derivatives enhance radiation lethality in human cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3057.
Abstract 3059: Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry
Authors: Warder Scott E. , McLoughlin Shaun M. , Hansen T. Matthew , Richardson Paul L. , Wilcox Denise M. , Addo Sadiya N. , Tang Hua , Sun Chaohong , Petros Andrew M. , Panchal Sanjay C. , Park Chang H. , Duggan M. Shannon , Patterson Melanie J. , Buchanan F. Greg , Cheng Dong , Davis Heather M. , Calderwood David J. , Elmore Steven W. , Shen Yu 
Published: July 2016

Abstract
As part of a multi-year technology integration strategy to identify unprecedented targets, AbbVie has committed to building broad-endpoint profiling assays to enable phenotypic screening campaigns and compound prioritization. Early on, phenotypic cell-based screening employing a panel of protein-fragment complementation assays (PCAs) identified A-1107604 as a hit with potent activity against a subset of endpoints. While its activity profile had some commonalities with known anti-cancer agents, the overall profile of PCAs that were significantly and concomitantly modulated represented a unique signature. Further analysis revealed A-1107604 to have potent and selective activity in a panel of human tumor cell lines. Inhibitor affinity capture from cellular lysates coupled with mass spectrometry identified the BET family of proteins as the putative cellular targets of A-1107604. Binding was localized to the bromodomain of the target proteins using affinity capture-protease digestion and was confirmed by thermal shift assay, solution
binding and X-ray crystallography. This binding was found to be highly selective when A-1107604 was counter-screened against a 150-member kinase panel and an 80-member receptor panel. To correlate target affinity with cellular efficacy, a series of analogs were prepared with affinities spanning 3 orders magnitude. Affinity for BRD4, a BET family member, strongly correlated with efficacy in human tumor cell lines. Finally, A-1107604 was evaluated in human tumor xenograft models where it demonstrated significant tumor growth inhibition. This discovery effort laid the foundation for our BET inhibitor program. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the
publication.
Citation Format: Scott E. Warder, Shaun M. McLoughlin, T. Matthew Hansen, Paul L. Richardson, Denise M. Wilcox, Sadiya N. Addo, Hua Tang, Chaohong Sun, Andrew M. Petros, Sanjay C. Panchal, Chang H. Park, M. Shannon Duggan, Melanie J. Patterson, F. Greg Buchanan, Dong Cheng, Heather M. Davis, David J. Calderwood, Steven W. Elmore, Yu Shen. Discovery of BET family proteins as cancer targets using phenotypic-based profiling and affinity capture mass spectrometry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3059.
Abstract 306: Analysis of differentially expressed exosomal genes from ibrutinib resistant diffuse large B cell lymphoma
Authors: Jain Neeraj , Sehgal Lalit , Khashab Tamer , Samaniego Felipe 
Published: July 2016

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) and approximately 30% of the patients develop relapsed/refractory disease that becomes a major cause of mortality and morbidity. Selective pressure provided by chemotherapy causes aberrant gene expression and selection of pre-existing population of chemo-resistant cells. These chemo-resistant cells can also transmit chemo-resistance to chemo-sensitive cells through exosomal transfer of molecules (miRNA, mRNA and proteins). In this study, we have analysed differentially expressed mRNA and miRNA from syngeneic ibrutinib (an irreversible BTK inhibitor, FDA approved) resistant DLBCL cells and from their isolated exosomes. Five DLBCL-GCB and five ABC subtype were analysed for their sensitivity with ibrutinib. We found three ABC subtype and one GCB subtype (OCL-LY1) were sensitive to ibrutinib. We have generated syngeneic ibrutinib drug resistant model from sensitive cells (at least 10 fold increase in IC50 value) by continuous culturing them in the presence of ibrutinib with gradual increase in drug concentration in each passage. Ibrutinib sensitive DLBCL cells when cultured with the syngeneic resistant cells in transwell apparatus, acquired resistance to ibrutinib. We also analysed the sensitivity of ibrutinib resistant cells with other conventional drugs for non-Hodgkin lymphomas. We further tested the expression of drug resistant genes in syngeneic resistant cells by real time PCR analysis. Later, we isolated the total RNA and miRNA species from DLBCL ibrutinib sensitive, their syngeneic resistant cells and from respective exosomes and analysed for differential expression by micro array analyses. Thus in conclusion, our study demonstrates that chemo-resistance can be transferred from resistant cells to sensitive cells via exosomal horizontal transmission of miRNA and mRNA in diffuse large B cell lymphoma cells. Moreover, our study identified potential targets that can be used to overcome chemo-resistance in diffuse large B cell lymphoma.
Citation Format: Neeraj Jain, Lalit Sehgal, Tamer Khashab, Felipe Samaniego. Analysis of differentially expressed exosomal genes from ibrutinib resistant diffuse large B cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 306.
Abstract 307: GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy
Authors: Houthuijzen Julia , Oosterom Ilse , Hudson Brian , Hirasawa Akira , Daenen Laura , McLean Chelsea , Hansen Steffen , van Jaarsveld Marijn , Peeper Daniel , Jafari Sadatmand sahar , Roodhart Jeanine , van de Lest Chris , Ulven Trond , Ishihara Kenji , Milligan Graeme , Voest Emile 
Published: July 2016

Abstract
Although chemotherapy is designed to eradicate tumor cells it also has a significant impact on normal tissues. These host-responses can have large effects on the efficacy of treatment and overall survival. Fatty acids are increasingly recognized to play important signaling roles. 12-S-HHT and 16:4(n-3) are two platinum-induced fatty acids (PIFAs) that induce systemic resistance to a broad range of DNA-damaging chemotherapeutics. PIFAs exert their chemoprotective effect on tumor cells via an indirect mechanism involving splenic F4/80+/CD11blow macrophages. Here we identified GPR120 on mouse and human splenic macrophages as the relevant receptor for 16:4(n-3). GPR120 (FFAR4) is a free fatty acid receptor that binds medium- to long-chain fatty acids and omega-3 fatty acids and is involved in anti-inflammatory response and metabolic control. Although both GPR40 (FFAR1) and GPR120 can be activated by 16:4(n-3) in vitro, only inhibition or genetic loss of GPR120 was able to block 16:4(n-3)-mediated chemoresistance in vivo. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA2 activity in splenic macrophages resulting in the production and secretion of resistance-inducing lysophosphatidylcholine 24:1 (LPC(24:1)). Taken together, we identified a novel function for GPR120. Activation by 16:4(n-3) leads to enhanced cPLA2 activity and production of LPC(24:1) resulting in chemotherapy resistance.
Citation Format: Julia Houthuijzen, Ilse Oosterom, Brian Hudson, Akira Hirasawa, Laura Daenen, Chelsea McLean, Steffen Hansen, Marijn van Jaarsveld, Daniel Peeper, sahar Jafari Sadatmand, Jeanine Roodhart, Chris van de Lest, Trond Ulven, Kenji Ishihara, Graeme Milligan, Emile Voest. GPR120/FFAR4 activation by fatty acid 16:4(n-3) plays a key role in resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 307.