bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5273: Role of methylation of Wnt target genes in tumorigenesis and effect of re-expression with demethylating agent decitabine in colon cancer
Authors: Linnekamp Janneke , Kandimalla Raju , Vermeulen Louis , van Laarhoven Hanneke , Medema Jan Paul 
Published: August 2015

Abstract
Colon cancer is the fourth leading cause of cancer-related death worldwide. Extensive studies of the Wnt signal cascade have determined its role in colon cancer development and progress. Several targets of the Wnt-cascade like APCDD1, ASCL2, AXIN2 or DKK1 are thought to reduce Wnt activity by negative feedback. As a result, expression of these genes prevents pathway activation and silencing of these targets can cause proliferation of the tumor. Recently, we have shown that silencing of Wnt target genes by DNA-methylation predicts poor prognosis in colon cancer patients. Moreover, demethylation of those genes results in reexpression and is associated with reduced tumor growth in mice. Hence, treatment with demethylating agents can be beneficial for a subgroup of colon cancer patients with high methylation of Wnt target genes. The aim of this study is to clarify whether Wnt target gene methylation is an important driver in development of colon cancer and can be an effective target in colon cancer.
To determine the role of Wnt target genes in colon cancer more extensively, we study the effect of selective expression of these genes via an inducible vector system in established colorectal cell lines and in patient derived cultures that display CpG island methylation on these genes. In that way, we can monitor the effect of induced overexpression on tumor growth, tumor invasion and sensitivity towards chemotherapeutic agents. As a control, baseline expression in the same cell population, but in an uninduced state will be used.
Furthermore, we are also studying the effect of the demethylating agent decitabine on Wnt target gene methylation in a clinical trial in stage II/III colon cancer patients. Patients are pre-operatively treated with decitabine. Tumor material prior to decitabine treatment obtained during endoscopy is compared to resection material after treatment. Differences in methylation and expression of Wnt target genes are determined by respectively pyrosequencing and q-PCR.
We hypothesize that reexpression of Wnt target genes via an inducible vector results in lower Wnt pathway activity through negative feedback. As a result, tumor growth and invasion will be reduced and might be more sensitive towards chemotherapeutics.
To translate this into the clinic, demethylation of Wnt target genes by decitabine will hopefully give a similar effect in patients.
Citation Format: Janneke Linnekamp, Raju Kandimalla, Louis Vermeulen, Hanneke van Laarhoven, Jan Paul Medema. Role of methylation of Wnt target genes in tumorigenesis and effect of re-expression with demethylating agent decitabine in colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5273. doi:10.1158/1538-7445.AM2015-5273
Abstract 5275: Association of TERT polymorphism with acute myeloid leukemia risk and prognosis
Authors: Lotfi Kourosh , Mosrati Mohamed Ali , Willander Kerstin , Jakobsen Falk Ingrid , Hermanson Monica , Höglund Martin , Stockelberg Dick , Wei Yuan , Söderkvist Peter 
Published: August 2015

Abstract
Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNPs in 256 acute myeloid leukemia (AML) patients. A significant association for increased risk of AML was found for TERT SNPs, rs2853669 (OR = 2.45, p = 0.00006) and rs2736100 (OR = 1.52, p = 0.02). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 (respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, age and treatment. No hot spot TERT promoter mutations at -228C&gt;T or -250C&gt;T or POT1 mutations could be identified in this AML cohort. We show for the first time that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify relative high risk NK-AML patients, for treatment guidance.
Note: This abstract was not presented at the meeting.
Citation Format: Kourosh Lotfi, Mohamed Ali Mosrati, Kerstin Willander, Ingrid Jakobsen Falk, Monica Hermanson, Martin Höglund, Dick Stockelberg, Yuan Wei, Peter Söderkvist. Association of TERT polymorphism with acute myeloid leukemia risk and prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5275. doi:10.1158/1538-7445.AM2015-5275
Abstract 5280: A polymorphism of VEGFA is associated with susceptibility to extrathyroidal invasion of papillary thyroid cancer
Authors: Eun Young Gyu , Lee Young Chan , Lee Jung-Woo 
Published: August 2015

Abstract
Background: Vascular endothelial growth factor A (VEGFA) has pivotal roles in angiogenesis, vascular permeability, vasculogenesis, cellular growth, and cell migration. We investigated whether single nucleotide polymorphisms (SNPs) of the VEGFA gene are associated with the development of papillary thyroid cancer (PTC). We also assessed the relationships between VEGFA SNPs and the clinicopathologic characteristics such as the size of cancers (&lt; 1 cm and ≥ 1 cm), numbers of cancers (unifocality and multifocality), location of cancers (one lobe and both lobe), extrathyroidal invasion (present and absent), and cervical lymph node metastasis (present and absent).
Methods: One promoter SNP (rs699947, -2578A/C) and one 5′-untranslation region (5′UTR) SNP (rs2010963, +405C/G) in VEGFA were genotyped using direct sequencing in 94 PTC patients and 213 healthy controls. SNPStats, SNPAnalyzer, Helixtree, and Haploview version 4.2 were used to analyze genetic data. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p values.
Results: Two SNPs of VEGFA were not associated with the development of PTC. Also, haplotypes were not associated with PTC??. However, we found a relationship between the 5′UTR SNP rs2010963 and PTC with the extrathyroidal invasion (p = 0.0060 in codominant model, p = 0.0258 in dominant model, p = 0.0057 in recessive model, and p = 0.0060 in log-additive model). Allele frequencies of rs2010963 were different between the extrathyroidal invasion (-) and extrathyroidal invasion (+) groups (p = 0.0050). In Bonferroni correction, these correlations were also significant except the recessive model.
Conclusion: Our results suggest that the 5′UTR SNP rs2010963 (+405C/G) of VEGFA may be associated with susceptibility to extrathyroidal invasion of PTC in Korean population.
Note: This abstract was not presented at the meeting.
Citation Format: Young Gyu Eun, Young Chan Lee, Jung-Woo Lee. A polymorphism of VEGFA is associated with susceptibility to extrathyroidal invasion of papillary thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5280. doi:10.1158/1538-7445.AM2015-5280
Abstract 5310: Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients
Authors: Toft Anders , Urup Thomas , Grunnet Kirsten , Christensen Ib J. , Michaelsen Signe R. , Broholm Helle , Larsen Vibeke A. , Kosteljanetz Michael , Lassen Ulrik , Poulsen Hans S. 
Published: August 2015

Abstract
Background: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has proven activity in treatment of recurrent high-grade glioma. High response rates have been demonstrated, but particularly in WHO grade 3 malignant gliomas, efforts to identify predictors of clinical response have been limited. Predictive biomarkers and prognostic models are required in order to individualize treatment for this patient population. The primary end-point of this study was identification of prognostic and potentially predictive clinical and paraclinical factors of response. The secondary end-point was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS).
Materials and methods: A total of 64 recurrent grade 3 glioma patients treated with bevacizumab and irinotecan were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol.
The possibly relevant prognostic baseline factors screened for included: Age, gender, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, performance status, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, Mib-1, MGMT, IDH-1 and ATRX.
Candidate factors were subjected to univariate analysis and factors with P-values below 0.10 were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modeling response and survival end-points. P-values below 0.05 were considered statistically significant.
Results will be presented.
Citation Format: Anders Toft, Thomas Urup, Kirsten Grunnet, Ib J. Christensen, Signe R. Michaelsen, Helle Broholm, Vibeke A. Larsen, Michael Kosteljanetz, Ulrik Lassen, Hans S. Poulsen. Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5310. doi:10.1158/1538-7445.AM2015-5310
Abstract 5319: Apoptotic properties of platinum antitumor agents phosphaplatins
Authors: Dezvareh Homa 
Published: August 2015

Abstract
Phosphaplatins, a group of non-DNA binding platinum compounds, exhibit excellent in vivo and in vitro efficacies against a variety of cisplatin- and carboplatin-sensitive and resistant ovarian cancers. Although, combinations of cis- or carbo-platin and paclitaxel therapies continue to be the choice of treatment for many ovarian cancer patients, many develop resistance to treatment. Phosphaplatins are pyrophosphate bound platinum-(II) and (IV)-platinum complexes that bi-negatively charged at or near neutral pH. Both Platinum (II) and platinum (IV) complexes did not overexpress any DNA repair genes consistent with the no-DNA binding property of phosphaplatins. In this report, we show the apoptotic properties of two representative compounds, (R,R-1,2-cyclohexanediamine)-(dihydrogen pyrophosphato)platinum (II) (RRD2) and (R,R-1,2-cyclohexanediamine)-trans-dihydroxo(dihydrogen pyrophosphato)platinum (IV) (RRD4) through a variety of experiments as described below.
Phosphaplatins activate and upregulate death receptors on cell surface such as FAS, DR5, and TNFR1. These three death receptors follow the common signaling path to trigger apoptosis by an extrinsic pathway via Death Inducing Signaling Complex (DISC) by recruiting FADD and procaspase-8 and activating caspase-8. A direct binding of FAS by platinum is implicated as the platinum compound was found to be co-localized in the lipid rafts.
The PTEN-PI3K pathway involvement was confirmed by the down regulation of both PI3K and p-AKT. Phosphoplatins also upregulate tumor suppression genes P53 and PTEN. Apoptosis by p53 signaling follows intrinsic pathways involving BCL-proteins. In particular up regulation of BAX, PUMA, and downregulation of BCL2 were observed. To further confirm p53-signailng, we have identified a number of p53 target genes that include AEN, CYFIP2, TP53I3, TP53INP1, DPYSL4, LRDD, DRAM1, and a few others.
Our data shows that phosphaplatins have the potential to not only treat resistant but also advanced metastatic ovarian cancers.
Citation Format: Homa Dezvareh. Apoptotic properties of platinum antitumor agents phosphaplatins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5319. doi:10.1158/1538-7445.AM2015-5319
Abstract 5323: Targeting PIM1 and CDK4/6 kinases in renal cell carcinoma
Authors: Small Jeffery S. , Holder Sheldon L. 
Published: August 2015

Abstract
In this study we examine the hypothesis that combination therapy targeting the VEGFR, PIM1, and CDK4/6 kinases improves the efficacy of VEGFR-directed monotherapy in renal cell carcinoma (RCC).
Two RCC cell lines, 786-O and Caki-1 (chosen for differences in VHL), were evaluated and the ED50s of SGI-1776 (PIM1 inhibitor), PD0332991 (CDK4/6 inhibitor), and LY2835219 (dual PIM1 and CDK4/6 inhibitor) assessed with an MTT assay. Cell Titer-Glo® was used to determine the effects of each of the inhibitors on cellular viability alone and in combination with sunitinib (VEFGR tyrosine kinase inhibitor). The effect of LY2835219 on phosphorylation of BAD, a PIM1 substrate, was assessed by Western blot.
PIM1 and dual PIM1-CDK4/6 inhibition showed more potent effects on cellular viability than CDK4/6 inhibition. ED50 values of each inhibitor for RCC cells are reported in Table 1. Further assays showed greater decreased cellular viability in cells treated with the combination of a PIM1 inhibitor and sunitinib than in cells treated with either a PIM1 inhibitor or sunitinib alone. When combined with sunitinib, dual PIM1-CDK4/6 inhibition was more effective than PIM1 inhibition in 786-O cells. Sunitinib in combination with a CDK4/6 inhibitor was not as effective as in combination with either a PIM1 inhibitor or a dual PIM1-CDK4/6 inhibitor. Western blot analysis showed a decrease in phospho-BAD in cells treated with a dual PIM1-CDK4/6 inhibitor.
Table 1.Potency of Kinase Inhibitors Against RCC Cell LinesInhibitorED50 (786-O; uM)ED50 (Caki-1; uM)SGI-17768.67 (8.13 - 9.25)6.94 (5.05 - 9.53)PD0332991Indeterminate*Indeterminate*LY28352197.46 (6.32 - 8.81)1.18 (1.02 - 1.36)95% confidence intervals are presented in parenthesis. *Highest dose level did not result in a sufficient response to allow for reliable curve fitting to determine the ED50
Our data reveal that targeting PIM1 in combination with sunitinib is superior to sunitinib alone in RCC cell lines. Additionally, in 786-O cells, added CDK4/6 inhibition further improves the efficacy of the combination therapy. Dual PIM1-CDK4/6 kinase targeted therapy in combination with sunitinib is an attractive therapeutic regimen with good potential for translation to the clinic. Ongoing studies include further characterization of the molecular events involved including apoptosis, cell cycle regulation, PIM1 kinase and CDK4/6 kinase activity, and evaluation of the combination therapy in a mouse xenograft model of RCC.
Citation Format: Jeffery S. Small, Sheldon L. Holder. Targeting PIM1 and CDK4/6 kinases in renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5323. doi:10.1158/1538-7445.AM2015-5323
Abstract 5327: Simultaneous inhibition of ATR and PARP greatly sensitizes colon cancer cell lines to irinotecan
Authors: Davidson David , Abu-Sanad Atlal , Wang Yunzhe , Hasheminasab Fatemeh , Panasci Justin , Aloyz Raquel , Panasci Lawrence 
Published: August 2015

Abstract
Enhanced DNA damage repair is one mechanism behind colon cancer drug resistance. Thus, targeting molecular components of repair pathways with specific small molecule inhibitors may improve the efficacy of chemotherapy. ABT-888 and VE-821, inhibitors of poly-ADP-ribose-polymerase (PARP) and the serine/threonine-kinase Ataxia telangiectasia related (ATR), respectively, were used to treat colon cancer cell lines in combination with the topoisomerase-I inhibitor irinotecan (SN38). Our findings show that each of these molecules at nontoxic single agent concentrations synergized with SN38 to produce a 2.2 to 3 fold reduction in the 50% inhibitory concentration (IC50) of SN38 (Table 1). When combined, nontoxic concentrations of ABT-888 and VE-821 produced a 4.5 to 27 fold reduction in the IC50 of SN38. Furthermore, the combination of all three agents was associated with maximal G2-M arrest and enhanced DNA-damage (γH2AX). The mechanism of this enhanced synergy was associated with maximal suppression of SN38 induced PARP activity in the presence of both inhibitors. Furthermore, VE-821 enhancement of SN38 induced DNA-PK phosphorylation was abrogated by ABT-888, resulting in more unrepaired DNA damage. This novel combination of DNA repair inhibitors may be useful to enhance the activity of DNA damaging chemotherapies such as irinotecan and help circumvent resistance to this drug in colon cancer.
Cell LineVE-821 (μM)ABT-888 (μM)SN38 (IC50) ± SE (nM)I valueP valueLoVo13.5±1.214.5±1.90.30.020.55.8±2.00.40.030.59.4±1.00.70.0610.53.0±1.20.20.010.50.54.7±1.90.40.02HCT-1168.1±0.713.5±0.50.50.010.55.2±0.60.70.030.53.9±1.10.50.0310.50.3±0.030.10.010.50.52.1±0.40.30.01HT-2920.5±1.819.3±0.60.60.010.512.2±1.30.70.020.512.9±0.70.60.0210.53.9±0.50.30.010.50.56.1±0.20.40.01
Table 1 Colon cancer cell lines LoVo, HCT-116 and HT-29 were treated with SN38 alone or in combination with various concentrations of the ATR inhibitor VE-821 and/or the PARP inhibitor ABT-888. The IC50 values of SN38 were significantly reduced in the presence of VE-821 and/or ABT-888 for all cell lines. Drug synergy (I) values were determined, according to Berenbaum (1978), by calculating the ratio:
(IC50 SN38 with inhibitors/IC50 SN38 alone) + (inhibitor concentration used/IC50 inhibitor alone); I less than 1 = synergism, I equal to 1 = additive effect and I greater than 1 = antogonism.
Citation Format: David Davidson, Atlal Abu-Sanad, Yunzhe Wang, Fatemeh Hasheminasab, Justin Panasci, Raquel Aloyz, Lawrence Panasci. Simultaneous inhibition of ATR and PARP greatly sensitizes colon cancer cell lines to irinotecan. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5327. doi:10.1158/1538-7445.AM2015-5327
Abstract 5337: An in silico platform for characterizing ADC bystander effects
Authors: Burton Jackson , Teng Shu-Wen , Zopf Christopher J. , Nolan Ryan , Chakravarty Arijit 
Published: August 2015

Abstract
Introduction
The “bystander effect” is the hypothesized process by which neighboring cancer cells are killed when free drug is released into the tumor environment by dying cells. The extent to which an antibody drug conjugate (ADC) elicits the bystander effect can have significant impact on the magnitude and dynamics of efficacy. Understanding the bystander effect though experimental methods (e.g. video-microscopy) are challenging; however, when supplemented with in silico modeling, mechanistic details can be elucidated. The purpose of this work is to develop a spatial-temporal in silico platform describing tumor cell progression in the presence of an ADC in order to quantify the bystander effect.
Methods
The model employs spatial-stochastic methods to simulate the time evolution of cell death resulting from ADCs and freely diffusing payload based on following parameters: drug to antibody ratio (DAR), linker stability, antigen concentration, ADC cell membrane permeability, ADC-antigen internalization, payload permeability, and payload potency. Specifically, a 2-D rectangular grid of tumor cells, ADCs, and payload are numerically implemented through binary pixel occupation of the grid. Governing rules are then assigned for: mobility for freely diffusing ADCs and payload, reaction rate for ADC binding to antigen-expressing cells, rate of cell death dependent on payload concentration, and internalization rate of payload into non-antigen expressing cells. The simulation is run until stopping criteria are met, e.g. all cells are killed. Baseline parameters can be optimized by fitting the model to in vitro experimental video-microscopy data.
Results
Experimental conditions were simulated with the model to characterize the influence of the aforementioned ADC and biological parameters on the bystander effect.
Conclusions
By incorporating the spatial aspect of ADC mechanics, spatially dependent metrics can be formulated to quantify the bystander effect. The model allows for wide adjustability of the ADC design parameters as well as relevant biological parameters. Thus, by understanding the relative parameter sensitivities, the model can explore design optimization of ADCs that maximize the bystander effect. Through such optimization, the magnitude and dynamics of drug exposure at the site of action can be controlled to maximize efficacy and improve the therapeutic window.
Citation Format: Jackson Burton, Shu-Wen Teng, Christopher J. Zopf, Ryan Nolan, Arijit Chakravarty. An in silico platform for characterizing ADC bystander effects. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5337. doi:10.1158/1538-7445.AM2015-5337
Abstract 5362: Andrographolide inhibits prostate cancer by modulating chemokine and cytokines
Authors: Mir Hina , Kapur Neeraj , Singh Rajesh , Sonpavde Guru , Lillard James W. , Singh Shailesh 
Published: August 2015

Abstract
Treatment options for androgen independent prostate cancer (PCa) are limited. Hence, new treatment strategies are needed to treat/prevent hormone refractory advance disease. Major focus of this study was to develop non-toxic therapeutic/preventive option for PCa. Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata showed dose and time dependent inhibition of PCa cells (PC3, DU145 and LNCaP). This inhibition in growth was due to selective modulation of chemokines and cytokines required for PCa cell growth and proliferation. Specifically, CXCR3 and CXCR7 expression was reduced after AG treatment. Interestingly, AG inhibited IL-6 expression, which is known to be associated with advance PCa and also highly produced by the aggressive PCa cell compared to less aggressive or normal prostatic epithelial cells. Hence, AG may be offered as a new therapeutic/preventive agent against PCa due to its ability to inhibit key chemokines and cytokines required for PCa progression and supporting hormone refractory PCa.
Citation Format: Hina Mir, Neeraj Kapur, Rajesh Singh, Guru Sonpavde, James W. Lillard, Shailesh Singh. Andrographolide inhibits prostate cancer by modulating chemokine and cytokines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5362. doi:10.1158/1538-7445.AM2015-5362