bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B54: Type II interleukin 1 receptor-modulated SET/PP2A/p-ERK signaling is associated with regorafenib resistance in human colorectal cancer cells
Authors: Mar Ai-Chung , Chu Chun-Ho , Yang Shung-Haur , Jiang Jeng-Kai , Shiau Chung-Wai , Lee Te-Chang 
Published: May 2016

Abstract
Regorafenib, a newly approved multi-kinase inhibitor by US FDA, has recently demonstrated overall survival benefits in late-stage colorectal cancer (CRC) patients. We have observed that the expression type II interleukin 1 receptor (IL1R2), an IL-1 decoy receptor, were closely associated with regorafenib resistance in human CRC cells. In addition, IL1R2 expression was associated with poor prognosis of patients with CRC cancer. In this study, we conducted experiments to elucidate the roles of IL1R2 in regorafenib resistance. We first demonstrated that silencing of IL1R2 in HT29 cells by shRNA overcame their resistance to regorafenib, whereas ectopic expression of IL1R2 in HCT116 cells increased their resistance to regorafenib in either in vitro or in vivo systems. We further established regorafenib-resistant DLD-1 cells (DLD-1-R) by long-term culturing DLD-1 cells in the presence of regorafenib. Our results demonstrated increased expression of IL1R2 in DLD-1-R cells compared to parental DLD-1 cells. We observed that IL1R2 expression is associated with p-ERK level, which is crucial for survival of cancer cells. Pretreatment of HT29, IL1R2-overexpressing HCT116, and DLD-1-R cells with MEK/ERK inhibitor U0126 significantly reversed their resistance to regorafenib. Mechanistically, we revealed that SET/PP2A signaling plays crucial role on increasing p-ERK levels in IL1R2-overexpressing cells. Taken together, our present study suggested that enhanced IL1R2 mediates through SET/PP2A/p-ERK signaling to induce regorafenib resistance and, therefore, IL1R2 associated regorafenib resistance is overcome by combination treatment of CRC patients with regorafenib and MEK/ERK inhibitor.
Citation Format: Ai-Chung Mar, Chun-Ho Chu, Shung-Haur Yang, Jeng-Kai Jiang, Chung-Wai Shiau, Te-Chang Lee. Type II interleukin 1 receptor-modulated SET/PP2A/p-ERK signaling is associated with regorafenib resistance in human colorectal cancer 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 B54.
Abstract B67: Sarcoma cell line screen of oncology drugs and investigational agents identifies patterns associated with gene and microRNA expression
Authors: Teicher Beverly A. , Polley Eric , Kunkel Mark , Evans David , Silvers Thomas , Delosh Rene , Laudeman Julie , Ogle Chad , Reinhart Russell , Selby Michael , Connelly John , Harris Erik , Monks Anne , Morris Joel 
Published: May 2016

Abstract
The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA approved oncology agents and 345 investigational agents. The investigational agents library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at 9 concentrations in triplicate with an exposure time of 96 hrs using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community.
Citation Format: Beverly A. Teicher, Eric Polley, Mark Kunkel, David Evans, Thomas Silvers, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, John Connelly, Erik Harris, Anne Monks, Joel Morris. Sarcoma cell line screen of oncology drugs and investigational agents identifies patterns associated with gene and microRNA expression. [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 B67.
Abstract B68: Screening for the compound that induces cell death selectively in β-catenin mutant tumor cells
Authors: Shikata Yuki , Kiga Masaki , Tashiro Etsu , Imoto Masaya 
Published: May 2016

Abstract
The Wnt signal transduction pathway plays a central role for the cell proliferation, differentiation and apoptosis. β-catenin, a component of Wnt pathway, translocates to nucleus and forms an active complex with TCF4, leading to activate cell growth signaling, and this activity is tightly regulated by the “destruction complex” consisting of Axin, APC, GSK3β and CK1α. However, when β-catenin is actively mutated, this cell growth signaling would be hyperactive and drive oncogenesis. As β-catenin is mutated in up to 10% of all sporadic colon carcinomas resulting from point mutations or in-frame deletions of serine and threonine residues phosphorylated by GSK3β, mutated β-catenin has been considered as promising targets for therapeutic intervention.
Therefore, we screened the compound that induced cell death selectively in tumor cell lines harboring β-catenin mutation from an in-house natural product library, and finally we isolated and found that nonactin, a well-known antibiotics, exhibited this activity. To confirm its apoptosis-inducing ability selectivity in β-catenin mutated cell lines, we examined the effect of nonactin on cell viability in 15 human tumor cell lines. Nonactin potently induced PARP-cleavage in 5 cell lines harboring β-catenin mutation (A427, HCT116, LS-174T, SK-MEL-1, SW48 cells), whereas the others, which do not harbor a mutation of β-catenin activation, were resistant to nonactin. In addition, overexpression of actively mutated β-catenin accelerated apoptosis induced by nonactin in the nonactin-resistant A375 cells, and β-catenin knockdown by siRNA reduced nonactin-induced apoptosis in HCT116 cells. Furthermore, nonactin induced tumor regression only in β-catenin mutated HCT116 xenograft mice.
Taken together, these findings suggested that the β-catenin mutated tumor cell lines are highly sensitive to nonactin, and it would be potential drug-seed for tumor cells harboring β-catenin mutation.
Citation Format: Yuki Shikata, Masaki Kiga, Etsu Tashiro, Masaya Imoto. Screening for the compound that induces cell death selectively in β-catenin mutant tumor 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 B68.
Abstract C181: RRx-001 combined with anti-PD-L1 antibody increases the complete response rate in a preclinical myeloma model
Authors: Knox Susan J. , Ning Shoucheng , Peehl Donna , Oronsky Bryan , Scicinski Jan 
Published: May 2016

Abstract
BACKGROUND: RRx-001, a novel oxidizing and epigenetic agent, has shown promise as a single agent in a Phase I trial and is currently in Phase II trials, both alone and in combination with immunotherapy (Nivolumab), chemotherapy and radiation therapy.
OBJECTIVE: The primary objective of the experiments described here was to test the hypothesis that RRx-001 combined with the checkpoint inhibitor, anti-PD-L1 would increase the complete response (CR) rate in a preclinical model of myeloma.
METHODS and RESULTS: BALB/c mice with well established J558L myeloma tumors (100-150 mm3 in volume) were treated with anti-PD-L1 antibody alone (10 mg/kg, i.p., twice a week for two weeks), RRx-001 alone (10 mg/kg, i.p., two doses on Day 0 and day 4) or the combination of anti-PD-L1 + RRx-001. Tumors were measured every other day and tumor response as well as the tumor volume quadrupling time (4X TGT) were calculated. In an initial pilot experiment with 4 mice/group, the combined therapy group had the best response compared to either treatment alone or the untreated control group. In a larger duplicate experiment with 8-10 mice/group, the CR rate was 0%, 37.5%, 22.2% and 75% for the untreated control, anti-PD-L1, RRx-001, and combined group, respectively. In terms of a comparison of the 4X TGT, RRX-001 + anti-PD-L1 was more efficacious than the untreated control (P &lt; 0.01), RRx-001 alone (P = 0.01) and anti-PD-L1 alone (P = 0.1).
CONCLUSIONS: These results demonstrate that inhibition of the PD-1/PD-L1 axis in combination with RRx-001 can significantly increase the CR rate in a preclinical model of myeloma. Experiments are ongoing to optimize this treatment regimen, study the effects of the combined treatment on the tumor immune microenvironment, and the study the efficacy of this combined therapy in other tumor types. Results from this ongoing work will be presented, and have near term translational potential.
Citation Format: Susan J. Knox, Shoucheng Ning, Donna Peehl, Bryan Oronsky, Jan Scicinski. RRx-001 combined with anti-PD-L1 antibody increases the complete response rate in a preclinical myeloma model. [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 C181.
Abstract C28: The combination of Acetazolamide and Sulforophane targets the tumor initiating cells in human bronchial carcinoids
Authors: Baluch Narges , Bayat Mokhtari Reza , Homayouni Tina , Akbari Pedram , Heshmati Fatemeh , Islam Syed S , Kumar Sushil , Aitken Karen , Fitzpatrick Carrie , Yeger Herman 
Published: May 2016

Abstract
Bronchial carcinoids (BC) are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive. The AC form of BC possesses a higher degree of invasiveness and metastatic potential. It is important to understand how the BC tumor initiating cells (TIC) or cancer stem cells (CSC) in BC account for this phenotype. In order to functionally characterize the suspected BC stem cell fraction, BC cell lines (H727 and H720) were grown under a non-adhesive condition to form 3D spheroids favouring expansion of the TIC. The third generation of spheroids was assessed for clonogenicity, tumorigenicity (xenograft model), stem cell and hypoxia markers, drug resistance, karyotype and microarray analysis compared to parental cells. We previously showed that a pan-carbonic anhydrase inhibitor, acetazolamide (AZ) significantly potentiated the anti-tumor effects of sulforophane (SFN, a natural isothiocyanate with HDACi activity) on these lung carcinoid cell lines in vitro and subcutaneous xenografts. Here we developed an orthotopic lung model to study tumor progression and metastatic behaviour of the spheroid forming BC cells. Orthotopically grown tumors were treated with AZ, SFN and the AZ+SFN combination using previous doses within clinically available ranges. Results demonstrated that the spheroid grown BC cells showed increased clonogenic, tumorigenic, and drug resistance potential, with enhanced expression of stem cell, carbonic anhydrase and hypoxia markers as compared with the control non-spheroid cells, all suggesting selection for the TIC or CSC fraction. As in the subcutaneous model the combination of AZ with SFN was more effective than either single agent alone in inhibiting orthotopic tumor growth and survival. Taken together the evidence indicates that the novel AZ+SFN combination is likely targeting the TIC/CSC population. This offers increased value in terms of the management of BC tumor progression and possible metastasis in BC patients presenting with more aggressive variants.
Citation Format: Narges Baluch, Reza Bayat Mokhtari, Tina Homayouni, Pedram Akbari, Fatemeh Heshmati, Syed S Islam, Sushil Kumar, Karen Aitken, Carrie Fitzpatrick, Herman Yeger. The combination of Acetazolamide and Sulforophane targets the tumor initiating cells in human bronchial carcinoids. [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 C28.
Abstract C39: First-in-class inhibitors of the putatively undruggable DNA repair target Poly(ADP-ribose) glycohydrolase (PARG)
Authors: Waszkowycz Bohdan , James Dominic , Acton Ben , Fairweather Emma , Fritzl Sam , Hamilton Niall , Hamilton Nicola , Holt Sarah , Hitchen James , Hutton Colin , Jones Stuart , Jordan Allan , McGonagle Alison , Mould Daniel , Small Helen , Smith Kate , Stowell Alexandra , Waddell Ian D. , Ogilvie Donald 
Published: May 2016

Abstract
Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers, thereby reversing the effects of poly(ADP-ribose) polymerases (PARPs). PARG depletion, using RNAi, results in several effects such as PAR chain persistence, progression of single- to double-strand DNA lesions and NAD+ depletion. Given these findings, inhibition of PARG with a small molecule agent offers a potential opportunity to interfere with DNA repair mechanisms and induce cell death in those cells with increased susceptibility to DNA damage, such as tumour cells.
Previous efforts to develop small molecule inhibitors of PARG activity have generally been hampered by poor physicochemical properties, off-target pharmacology and a lack of cell permeability, leading some to suggest that PARG may be undruggable.
In contrast, we have now developed a series of first-in-class PARG inhibitors which display drug-like properties and attractive pharmacokinetic parameters. These compounds have proved to be useful biological tool compounds.
Moreover, displaying selective activity in both biochemical and, more importantly, cellular assays of PARG function, these derivatives have allowed an exploration of the phenotypes resulting from reversible, pharmacological PARG inhibition in both in vitro cell panels and in vivo models. Furthermore, our initial bioinformatic analysis suggests that deficiency of a known tumour suppressor confers sensitivity to PARG inhibition, suggesting patient populations that will potentially benefit from PARGi therapies.
Citation Format: Bohdan Waszkowycz, Dominic James, Ben Acton, Emma Fairweather, Sam Fritzl, Niall Hamilton, Nicola Hamilton, Sarah Holt, James Hitchen, Colin Hutton, Stuart Jones, Allan Jordan, Alison McGonagle, Daniel Mould, Helen Small, Kate Smith, Alexandra Stowell, Ian D. Waddell, Donald Ogilvie. First-in-class inhibitors of the putatively undruggable DNA repair target Poly(ADP-ribose) glycohydrolase (PARG). [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 C39.
Abstract C60: Pre-clinical efficacy of the ATR inhibitor AZD6738 in combination with the PARP inhibitor olaparib
Authors: Lau Alan , Brown Elaine , Thomason Andrew , Odedra Rajesh , Sheridan Victoria , Cadogan Elaine , Xu Shirlian , Cui Andy , Gavine Paul R. , O'Connor Mark 
Published: May 2016

Abstract
The PARP inhibitor olaparib acts through both inhibition of DNA single-strand-break repair and trapping of PARP-DNA complexes creating DNA lesions which cause replication fork stalling and collapsed fork DNA breaks. Cells which have lost BRCA-dependent homologous recombination repair are highly sensitive to olaparib treatment and this has led to its approval in patients with tumors carrying BRCA mutations. In addition, ATM (Ataxia telangiectasia mutated) and ATR (Ataxia telangiectasia mutated and Rad3 related) dependent DNA repair processes are hypothesized to be important survival pathways to PARP inhibitor treatment. In pre-clinical studies cancer cells which have defects in either ATM or ATR have been shown to be sensitive to PARP inhibitors. Here we present data that the orally bioavailable ATR inhibitor AZD6738 (in Phase-I clinial trials) combines synergistically with olaparib leading to cell death and anti-tumour activity in pre-clinical models. The combinations are effective across a panel of gastric and lung cancer cell lines in vitro. In addition results from isogenic ATM−/-/− knockout versus ATM+/+/+FaDu head and neck cancer cell line pairs show enhanced combination activity in ATM knockout cells versus ATM wild-type cells. Studies in vivo show that through intermittent dosing the combination is tolerated while demonstrating significant anti-tumour efficacy and regressions across multiple human patient derived primary explant models. Together, these data support the notion of development of AZD6738 and olaparib combinations for the treatment of ATM-deficient cancers.
Citation Format: Alan Lau, Elaine Brown, Andrew Thomason, Rajesh Odedra, Victoria Sheridan, Elaine Cadogan, Shirlian Xu, Andy Cui, Paul R. Gavine, Mark O'Connor. Pre-clinical efficacy of the ATR inhibitor AZD6738 in combination with the PARP inhibitor olaparib. [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 C60.
Abstract C85: Identification of a novel potent selective SMYD3 inhibitor with oral bioavailability
Authors: Mitchell Lorna H. , Boriack-Sjodin Paula A. , Smith Sherri , Thomenius Michael , Rioux Nathalie , Munchhof Michael , Mills James E. , Klaus Christine , Totman Jennifer , Riera Thomas V. , Raimondi Alejandra , Jacques Suzanne L. , Foley Megan , Waters Nigel J. , Kuntz Kevin W. , Wigle Tim J. , Porter Scott Margaret , Copeland Robert A. , Smith Jesse J. , Chesworth Richard 
Published: May 2016

Abstract
SMYD3 (Set and Mynd Domain containing 3) is a lysine methyltransferase overexpressed in several cancer types including breast, prostrate, pancreatic, and lung, and this overexpression is associated with poor clinical prognosis. Genetic knockdown of SMYD3 by shRNA has been shown to decrease proliferation in a range of cancer cell lines suggesting that inhibition of SMYD3 may have therapeutic utility.
In this presentation we describe the discovery and optimization of a novel series of oxindole sulfonamides and sulfamides with SMYD3 inhibitory activity. One of these compounds, EPZ030456, has a SMYD3 biochemical IC50 of 4 nM and is active in cells with an IC50 of 48 nM in a trimethyl MAP3K2 (MEKK2) in-cell western (ICW) assay. The crystal structure of this compound was solved with SMYD3 and the nucleotide substrate, S-adenosylmethionine and shows the oxindole portion of the molecule extends into the SMYD3 lysine binding channel. EPZ030456 shows &lt; 30% inhibition at a 10 uM screening concentration against 17 histone methyltransferase targets tested, including SMYD2.
Further optimization within the series resulted in EPZ031686 which has similar potency to EPZ030456 with a biochemical IC50 of 3 nM and an ICW IC50 of 36 nM and in addition exhibits good bioavailability following oral dosing in mice. Hence, EPZ031686 is a suitable tool to study the role of SMYD3 in cancer and other therapeutic areas, using both in vitro and in vivo models.
Citation Format: Lorna H. Mitchell, Paula A. Boriack-Sjodin, Sherri Smith, Michael Thomenius, Nathalie Rioux, Michael Munchhof, James E. Mills, Christine Klaus, Jennifer Totman, Thomas V. Riera, Alejandra Raimondi, Suzanne L. Jacques, Megan Foley, Nigel J. Waters, Kevin W. Kuntz, Tim J. Wigle, Margaret Porter Scott, Robert A. Copeland, Jesse J. Smith, Richard Chesworth. Identification of a novel potent selective SMYD3 inhibitor with oral bioavailability. [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 C85.
Abstract C88: HPV infections, hTERT methylation and hTERT expression in patients with invasive cervical cancer
Authors: Moreno-Acosta Pablo , Morales Nicolas , Burgos Marcela , Gamboa Oscar , Mejia Juan Carlos , Romero-Rojas Alfredo , Combita Alba Lucia , Molano Monica 
Published: May 2016

Abstract
Background: There is limited information of the role of hTERT methylation, hTERT expression and their association with type specific HPV infections in patients with invasive cervical cancer
Objective: To analyze the possible association between methylation status of the hTERT promoter gene, hTERT expression and HPV infection in patients with invasive cervical cancer.
Methodology: Eighty seven frozen samples of women with invasive cervical cancer were analyzed for type specific HPV infection using a GP5+/GP6+ mediated PCR- RLB. hTERT DNA methylation analysis was performed on bisulfite modified DNA using a new PCR-RLB-hTERT methylation assay targeting two regions flanking the hTERT [region 1 (nt -240 to -1) and region 2 (nt +1 to +120) relative to first ATG]. Expression of hTERT was detected by immunohistochemistry using an Anti-hTERT (348-358) rabbit pAb).
Results: All samples with HPV types belonging to the α7 species (HPV 18, 45 and 59) showed no hTERT methylation in region 1 (core promoter) and an increase in% of partial methylation in region 2. Samples with HPV types belonging to the α9 specie (16, 52, 35, 31 and 58) showed similar% of methylation in region 1 and region 2 according viral type but the percentages of methylation were different between them (ranging from 0% for HPV58 samples to 66.7% for HPV31). Strong expression of hTERT was observed in 77% of the samples independent of the HPV genotype.
Conclusion: hTERT methylation seems to be associated with specific genotype HPV infection; however expression of the hTERT protein seems to depend of additional molecular events and worth further investigation.
Citation Format: Pablo Moreno-Acosta, Nicolas Morales, Marcela Burgos, Oscar Gamboa, Juan Carlos Mejia, Alfredo Romero-Rojas, Alba Lucia Combita, Monica Molano. HPV infections, hTERT methylation and hTERT expression in patients with invasive cervical 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 C88.
Abstract CN02-03: Heterogeneity, drug resistance, and clonal dynamics in colorectal cancers
Authors: Bardelli Alberto 
Published: May 2016

Abstract
Colorectal cancers evolve by a reiterative process of genetic diversification and clonal evolution. Tissue and liquid biopsies can be used to define CRC molecular subtypes and to monitor clonal evolution during therapy. Using these approaches, CRC patients were found to respond selectively to targeted agents interfering with oncogenic nodes of the EGFR signaling pathway. Notably, the patient-specific responses can be recapitulated and paralleled in cellular and mouse clinical proxies (CRC-avatars). The inevitable development of acquired resistance to inhibitors of the EGFR signaling axis presently limits further clinical advances. Strategies to prevent or overcome resistance are therefore essential to design the next generation of molecularly-driven clinical trials for CRC patients.
Citation Format: Alberto Bardelli. Heterogeneity, drug resistance, and clonal dynamics in colorectal cancers. [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 CN02-03.