bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3577: A decade of changed behavior: Trends in screening adherence and incidence 2000-2010
Authors: Clarke Tainya C. , Ocasio Manuel A. , Caban-Martinez Alberto J. , Lee David J. , Arheart Kristopher L.
Published: August 2012

Background: Cancer is still one of the most prominent diseases of all times claiming more than 569,490 lives in 2010. Over the past decade the United States (U.S.), like many other industrialized and developed nations have seen a significant decrease in the incidence of cancers and have experienced an increase in the number of cancer survivors. The decrease in incidence can be attributed to an increase in the number of persons adhering to recommended cancer screenings. In 2012, there will be an estimated 1 million newly diagnosed Americans, 75% of who would have adhered to recommended cancer screening in the previous year. Methods: We used incidence data from the Surveillance Epidemiology and End Results database (2000 -2008) to assess the trend in incidence rates of some of the most common cancers in the United States. Using SAS version 9.2, we pooled data from the National Health Interview Survey (NHIS) - Cancer Supplements (2000, 2005 and 2010) and analyzed adherence to recommended screening (n= 90,959). The guidelines provided by the American Cancer Society were used to guide analyses. Screening compliance was measured among the appropriate age and sex cohort within the U.S. population. Results: There has been a 17.22% decrease in the incidence of colorectal cancers and a11.06% decrease in lung cancer incidence between 2000 and 2008. While Bladder and Cervical cancer showed no significant time trends, gender specific cancers, namely prostate and breast also showed significant decreases; 16.21% and 6.78% respectively. There was an 18.12% increase in the incidence of Melanoma cases. There was a significant increase in adherence to recommended screening between 2000 and 2010. Adherence to mammography screening guidelines increased two fold between 2000 and 2010 as represented by women interviewed in the NHIS. Similar trends were observed for pap smears and colorectal screenings; 2010 analyses showed 70.48% compliance for mammography, 72.80% for colorectal screening and 68.19% for pap smears. Conclusion: Though screening compliance is below the preferred level, there has been an increase in adherence to recommended screening in the U.S. population over the past decade. This has translated into decreased cancer incidence and an increased prevalence as more persons live beyond the five year survivor mark. Identification of cancers with high incidence rates is needed to direct targeted interventions and public health campaigns.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3577. doi:1538-7445.AM2012-3577
Abstract 359: Longitudinal monitoring of autotaxin-expressing tumors in vivo using an activatable near-infrared fluorescent probe
Authors: Madan Damian
Published: August 2012

Autotaxin (ATX) and its product lysophosphatidic acid are involved in numerous biological functions that generally involve cell proliferation and motility. Their dysregulation is associated with several diseases, including many cancers, with ATX reportedly being among the forty most upregulated genes in highly metastatic cancers. Until now there have been no methods to visualize or measure the activity of ATX in living organisms. Here, we monitor tumor progression in vivo using ATX-Red, a biosensor that reports on ATX activity. We show that ATX-Red is specifically activated by ATX to fluoresce in the near-infrared, the optimal spectral window for in vivo fluorescence imaging. While minimal fluorescence activation is seen when ATX-Red is administered systemically to healthy mice, ATX-Red is strongly activated in MDA-MB-231 xenografts, which are known to over-express ATX. Longitudinal imaging of mice bearing these xenografts shows that ATX-Red fluorescence correlates with tumor size. Our data demonstrate that ATX-Red is an effective and non-invasive in vivo imaging tool that enables real time visualization and quantitation of ATX-expressing tumor progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 359. doi:1538-7445.AM2012-359
Abstract 3594: Impact of metformin on HCC prognosis
Authors: Akmal Khan , Hassabo Hesham , Botrus Gehan , Shah Neeraj , Soliman Khalid , Khalaf Rossa , Li Donghui , Kaseb Ahmed , Hassan Manal
Published: August 2012

Concurrent with the increase in hepatocellular carcinoma (HCC) incidence, the prevalence of metabolic syndrome has increased in the USA. Metabolic syndrome is currently considered a major health problem. Moreover, long term diabetes mellitus is an independent risk factor for HCC. We have previously shown that use of metformin among diabetics was associated with 70% risk reduction of HCC as compare to the use of other types of antidiabetic treatment. It is not known, however, if diabetic patients with HCC who used metformin had a better prognosis. Between 2001 and 2010 we interviewed 438 patients with pathologically confirmed HCC for multiple risk factors of HCC including prior history of diabetes and type of antidiabetic treatment. Survival times were calculated from the date of pathology diagnosis and were censored for patients who were alive at the last follow up. Median survival was calculated using Kaplan Meier product-limit method and survival rates were compared using the log rank test. Cox proportional hazards model (CPHM) was used to estimate the multivariate Hazard Risk Ratios (HRR) and 95% Confidence Interval (CI). Total of 130 HCC patients (29.7%) recalled prior history of diabetes with more than 1 year prior to HCC diagnosis. Most subjects were considered to have type 2 diabetes mellitus and were on an oral antidiabetic regimen. The survival duration for HCC patients with diabetes did not significantly differs from those without diabetes in men and women. However, HCC diabetic men who received metformin had a better survival outcome. The median survival was 14.9 months (95% CI, 1.3-28.9) for metformin users compared to 12.7 months (95% CI. 6.2-10.1) among HCC diabetic men who received other treatments, Log Rank p value=.04. CPHM, which included age, hepatitis C virus infection, alcohol consumption, treatment of HCC (chemotherapy and surgical treatment), history of cirrhosis, and Liver Italian Program (CLIP) staging score yielded 40% improvement of overall survival in HCC men with diabetes who received metformin as compared to other treatments. The estimated HRR (95% CI) was 0.56 (.35-.91), P =.02. These results suggest a possible beneficial role of metformin in diabetic men with HCC. Such observations need to be confirmed in other populations and with correlation with duration of metformin intake.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3594. doi:1538-7445.AM2012-3594
Abstract 360: Tumor specific imaging by L-5-F-18-ethoxy-Tryptophan mediated by LAT1 and IDO1
Authors: Borkowski Sandra , Siebeneicher Holger , Gekeler Volker , Brumby Thomas , Dinkelborg Ludger
Published: August 2012

Purpose Radiolabeled tryptophan is capable of visualizing the amino acid metabolism of tumor cells. We investigated the indirectly labeled derivative L-5-F-18-ethoxy-Trp for its potential to differentiate tumors from inflammation by Positron-Emission-Tomography (PET) and for its possible intracellular trapping after catabolism by indoleamine-2,3-dioxygenase 1 (IDO1). Methods Human NCI-H460 lung cancer and PC-3 prostate cancer cells were used for in vitro studies. Cellular influx and efflux of L-5-F-18-ethoxy-Trp at 37°C was measured by a gamma-counter and via HPLC. Blocking studies were carried out under similar conditions to examine the transporter family being relevant for Trp uptake. The effect of IDO1 was investigated after stimulation of cells with 100 IU interferon-gamma (IFN-γ). Human plasma stability of 5-F-18-ethoxy-Trp was measured by radio-HPLC. The imaging potential was examined in tumor-bearing rodents and inflammation models. NCI-460 tumors in rats and PC-3 tumors in mice were subcutaneously inoculated. A sterile inflammation was induced by Complete Freund's Adjuvant (CFA) and an infection inflammation was induced by E.coli injection into rats. PET/CT imaging after 1 hour was conducted by an Inveon microPET camera. Results High cellular uptake of L-5-F-18-ethoxy-Trp was found in NCI-H460 and PC-3 cells with 10% of the applied radioactive dose per 100,000 cells and 30% per 100,000 cells, respectively. Uptake could be blocked by an excess of L-Trp, L-Leu and bicycloheptan-carboxylic acid indicating transport by the heterodimeric amino acid transporters of the SLC7 family with predominant transport by LAT-1. Both cellular uptake and retention were increased after stimulation of IDO1 activity by IFN-γ. HPLC of the efflux supernatant showed strict IDO1 dependence of the intracellular Trp catabolism. The tracer was rather instable in human plasma in vitro and degraded already after 15 min incubation. Nevertheless, PET imaging revealed good uptake of L-5-F-18-ethoxy-Trp in NCI-H460 and PC-3 tumors in rodents with low background. No uptake was found in both inflammation models in rats. Conclusion Tryptophan derivatives are promising tracers for cancer imaging utilizing enhanced metabolism by IDO1 which has been shown to be overexpressed in tumors to suppress the immune response of their microenvironment. Differentiation between malignant lesions and inflammation seems to be possible which would give this PET tracer an advantage over the currently used FDG.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 360. doi:1538-7445.AM2012-360
Abstract 3604: Elevated sigma-2 receptor/Pgrmc1 (progesterone receptor membrane component 1) levels as a potential cancer biomarker in tumors and plasma
Authors: Mir Shakeel UR , Jin Ling , Craven Rolf J.
Published: August 2012

Cancers of the lungs and head and neck are one of the leading causes of death, particularly in Kentucky, which leads the nation in multiple categories related to smoking. Thus, there is an urgent need for new biomarkers and therapeutic targets for airway cancers. The sigma-2 receptor is an intracellular receptor for numerous drugs and metabolites and was recently found to be identical to Pgrmc1 (progesterone receptor membrane component 1), a cytochrome-related protein implicated in metabolism and hormone signaling. S2RPgrmc1 is up-regulated in multiple types of cancer and is required for tumor cell proliferation and motility in vitro and tumor formation and metastasis in vivo. Furthermore, small molecule inhibitors of S2RPgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. In the present study, we have analyzed S2RPgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SqCLC), lung adenocarcinomas, head and neck cancers and others. S2RPgrmc1 levels were increased in tumors throughout and correlated with survival in lung cancer (n=43, p=0.02) and with grade in head and neck cancer (higher in grade 2 versus 1, p=0.007). One of the cancer types with highest S2RPgrmc1 expression was squamous cell lung cancer (SqCLC), and treatment options for SqCLC are limited. S2RPgrmc1 was highly expressed in SqCLC cell lines, and SqCLC cell survival was inhibited by siRNA knockdown of S2RPgrmc1 or the S2RPgrmc1 inhibitor AG-205. S2RPgrmc1 is part of a family of secreted cytochromes, and we found that S2RPgrmc1 was significantly elevated in the plasma of 42 lung cancer patients compared to non-cancer patients and was significantly higher in the plasma of stage I lung cancer patients compared to stage 2-4 patients. Purified, recombinant S2RPgrmc1 increased the proliferation of NSCLC cell lines, suggesting that secreted S2RPgrmc1 may contribute to lung tumor growth. Together, the results demonstrate that S2RPgrmc1 correlates with key clinical endpoints in tumors and is a therapeutic target in some cancers with few therapeutic options, particularly squamous cell lung cancer. Furthermore, S2RPgrmc1 is a potential plasma biomarker for early stage lung cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3604. doi:1538-7445.AM2012-3604
Abstract 3607: Differential protein expression and miR content of sorted subsets of circulating microvesicles from cancer patients and healthy controls
Authors: Smith Shannon E. , Holterman Daniel A. , Brown Kirk M. , Duncan Janet E. , Zhong Jason , Stark Adam , Millis Meredith , Tinder Teresa , Spetzler David
Published: August 2012

MicroRNAs (miRs) are small non-coding RNAs that are 20 to 25 nucleotides in length and regulate expression of entire families of genes. A major source of circulating miRs in cancer patients is believed to be circulating microvesicles (cMV) within biologic fluids such as blood. The transfer of these modifiers of RNA translation from diseased cells into the bloodstream can have broad impacts on disease detection, progression and/or prognosis. The goal of these studies was to determine whether there are differences in miR composition within different subpopulations of cMV based on surface protein composition. We used flow cytometry to phenotype and sort plasma-derived cMV from 20 individuals (3 breast cancer, 2 lung cancer, 6 prostate cancer, 1 bladder cancer and 6 non-cancer controls). cMV were stained for proteins associated with membranes such as tetraspanins (CD9, 63, 81) Ago2 and/or GW182 using a Beckman Coulter MoFlo XDP. For phenotypic analysis, events were gated on tetraspanin expression to distinguish cMV from nano-sized irrelevant debris, and co-expression of GW182 and Ago2 was determined. Quadrant-based sorting was performed for single- and double-positive events. miR content was determined using conventional Taqman probes with the ABI 7900 thermal cycler on extracted RNA from the sorted cMV. The results of these studies demonstrate that unfractionated cMV were not able to discriminate cancers from non-cancers using miRs-let-7a, -16, -22, -148a or -451 in this population of patients. When sorted tetraspanin+, Ago2+ and/or GW182+ populations of cMV were compared, miR expression was generally 5-fold higher in cancer patients than in healthy controls. These studies demonstrate that cMV can be consistently phenotyped, analyzed and sorted using a flow cytometer and that subpopulations of cMV contain unique miR profiles which can be useful in distinguishing cancer plasma from non-cancer plasma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3607. doi:1538-7445.AM2012-3607
Abstract 3617: A novel competition-based antibody array technology as a potential platform for cancer biomarker discovery
Authors: Jiang Weidong , Chen Yunru , Wu Lisha , Zhang Ying , Jones Valerie , Huang Ruopan
Published: August 2012

A novel competition-based antibody array assay has been developed. This assay, which is named the EIA array, adopts the principle of competition-based enzyme immunoassay (cEIA), in which an endogenous antigen and a labeled antigen competitively bind to a capture antibody fixed on a matrix. In this EIA array platform, 11 anti-adipokine antibodies are spotted onto membranes in an array format. After blocking, the capture antibodies can interact with either the endogenous adipokines in the sample or with the biotinylated adipokines spiked into the sample. Antibody-bound biotinylated adipokines are then detected by streptavidin-horseradish peroxidase (SA-HRP), which catalyzes a color development reaction. The intensity of colorimetric signal is directly proportional to the amount of biotinylated peptide-SA-HRP complex and inversely proportional to the amount of adipokines in the standards or samples. The signal is standardized against a cocktail of unlabeled adipokine peptides, allowing the unknown concentrations to be quantified. All 11 adipokines were detected at pg/ml and ng/ml levels with a CV of less than 20%, indicating that the EIA array has high sensitivity and reproducibility. Furthermore, no cross-reactivity was found among the 11 adipokine markers, indicating high specificity. Using this novel competition-based antibody array, we screened adipokine expression profiles in cancer cell lines HepG2 and MCF-7 with and without treatment of 100µM H2O2 and 100ng/ml EGF. Among these adipokine markers, visfatin was significantly increased in culture supernatants of both cell lines after H2O2 treatment, but not increased in cell lysates. The upregulation of visfatin after H2O2 treatment was confirmed by both EIA array and Western blot. Currently, studies investigating the role of visfatin in liver carcinogenesis are underway using serum samples from clinically diagnosed pre-operative hepatocellular carcinoma patients with age and sex-matched controls. In summary, our results suggest that the novel competition-based EIA array has great potential for cancer biomarker discovery.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3617. doi:1538-7445.AM2012-3617
Abstract 3621: Polymorphisms in genes related to DNA repair and to apoptosis: Link with the outcome after radiochemotherapy in head and neck cancer patients
Authors: Borchiellini Delphine , Etienne-Grimaldi Marie-Christine , Thariat Juliette , Chateau Yann , Formento Jean-Louis , Formento Patricia , Llorca Laurence , Milano Gerard
Published: August 2012

Background For patients with locally-advanced head and neck cancer (LAHNC), treatment with irradiation (RT), associated or not with chemotherapy (CT), remains a valuable alternative to surgery and is currently being actively investigated. Identification of individual factors able to discriminate good candidates for radiochemotherapy (RCT) would allow optimal handling of RCT (doses, associated drugs). We examined whether functional single nucleotide polymorphisms (SNPs) in genes related to DNA repair and to apoptosis could be related to the outcome of patients with LAHNC treated with RCT. Methods A homogeneous group of 90 patients with LAHNC were treated by either RT (29%) or cisplatin-based RCT (71%). For all study patients, we used DNA extracted from tumor samples stored in liquid nitrogen from 1992 to 2006. The following SNPs (rs) were analysed by PCR-RFLP: ERCC2 (XPD) 751Lys≫Gln (rs13181), XRCC1 399Arg≫Gln (rs25487), TP53 72Arg≫Pro (rs1042522) and MDM2 309T>G (rs2279744). The SNPs ERCC1 259Lys≫Thr (rs735482) and ERCC5 46His C>T (rs1047768) were investigated by Single Base Extension. Results Univariate analyses showed no link between the studied SNPs and overall response rate evaluated at 3 months or 6 months from the end of the treatment. In contrast, there was a significant association between the polymorphism MDM2 309T>G and the occurrence of cutaneous toxicity, since G/G subjects had a higher risk of severe radiation dermatitis (p=0.047). Similarly, the Gln allele of ERCC2 751Lys≫Gln was specifically related to a risk of acute radiation dermatitis following exclusive RT (p=0.009). Also, homozygous patients for XRCC1 399Arg≫Gln (Arg/Arg or Gln/Gln) had an increased risk of developing early osteoradionecrosis, particularly for patients receiving RCT (p=0.032). The occurrence of late toxicities (cervical fibrosis, p=0.011 or xerostomia, p=0.043) was associated with the genotype T/T of ERCC5 46His C>T. Conclusion Individually-based decision criteria are eagerly needed in the context of concurrent chemoradiation in LAHNC, especially with the introduction of anti-EGFR targeted therapies, which increase both anti-tumor efficacy and side-effects (radiation dermatitis). We believe that analyses of gene polymorphisms such as MDM2 and ERCC2 could be of clinical value in establishing the necessary guidelines.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3621. doi:1538-7445.AM2012-3621
Abstract 3637: Loss of prostate derived Ets (E-twenty six) transcription factor (PDEF) predicts patients at the highest risk of metastatic prostate cancer
Authors: Haller Andrew C. , Morrison Carl , Tan Wei , Payne-Ondracek Rochelle , Underwood Willie , Poch Michael , Tian Lili , Mohler James , Li Fengzhi
Published: August 2012

PSA has ability to detect prostate cancer (CaP) at an early stage, but many CaP tumors are slow to progress, and many patients are overtreated for a disease that will not become life-threatening. Since there remains no reliable way to distinguish indolent from aggressive disease, doctors who advise and patients on active surveillance worry about progression to incurable disease. Therefore, new prognostic tools must be developed to identify patients with potentially metastatic, life threatening CaP. Prostate derived Ets transcription factor (PDEF) has shown to be a master negative regulator of transcriptional networks controlling migration and invasion in many cancer tissues, including CaP. Therefore we studied the expression of PDEF in radical prostatectomy specimens to determine retrospectively whether PDEF expression is predictive of clinical outcome. Patients’ tumor PDEF expression was determined by immunohistochemical staining of a 724 patient tissue microarray (TMA). CaP patients were stratified into groups based on PDEF expression (high, mid, low, null) and a Cox proportional hazards model was used to compare clinical outcomes. Univariate analysis showed that loss of PDEF expression significantly increased risk of metastatic disease (HR = 5.38, PDEF mid; to HR = 43.48, PDEF null; p=0.0059), although it did not correlate with incidence of biochemical failure detected using the American Urological Association (AUA) or National Comprehensive Cancer Network (NCCN) definitions. This result was confirmed in the Kaplan-Meier survival analysis that showed that patients whose CaP were PDEF low/null had significantly shorter metastases-free survival (p=0.0151). Multivariate analysis also demonstrated CaP with low/null PDEF expression were associated with increased risk of developing metastatic disease (HR = 6.21/10.53), although it was not statistically significant, in part due to the low incidence of patients with metastatic disease in the TMA. Therefore, we studied PDEF and vimentin (stem-like marker, repressed by PDEF) tumor expression in a cohort of patients matched for Gleason score, stage, age, and follow-up who developed metastatic disease versus those who did not. Patients that developed metastatic disease had a significantly lower PDEF (3.9 vs 1.7, p<0.0001) and higher vimentin (0.43 vs. 4.1, p<0.0001) expression compared to matched controls. We propose that intact PDEF expression in CaP can be used to distinguish patients who are suitable for active surveillance from those who require aggressive treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3637. doi:1538-7445.AM2012-3637
Abstract 3645: Integrative molecular profiling in serous epithelial ovarian cancer for identification of biomarkers of chemoresistance
Authors: Koti Madhuri , Vidal Ricardo , Nuin Paulo , Haslehurst Alexandria , Weberpals Johanne , Childs Timothy , Bryson Peter , Dharsee Moyez , Evans Ken , Feilotter Harriet E. , Park Paul C. , Squire Jeremy A.
Published: August 2012

Ovarian cancer is the fifth leading cause of death due to gynecological cancers in women in the western world. Development of primary resistance to carboplatin and paclitaxel poses a major challenge in the management of serous epithelial ovarian cancer. To identify the molecular mechanisms underlying the development of instrinsic resistance upon exposure to standard first-line therapy for ovarian cancer, we used microarrays to profile the 1) copy number alteration and SNP, 2) mRNA, 3) miRNA and 4) methylation signatures in a cohort comprising 11 chemoresistant and 14 chemosensitive tumour samples. Copy number analysis showed significant copy number alterations in the chemoresistant group (gains on chromosomal regions, 4q, 6q, 8p, 8q, 19q, 7q and 22q; losses on 8p and 10q) compared to the sensitive group. Gene expression data analysis using R/bioconductor revealed a set of 248 discriminating genes in the two cohorts. Pathway analysis of these genes using Ingenuity Pathway Analysis revealed enrichment in genes primarily involved in epithelial to mesenchymal transition and PI3 Kinase pathway. Additionally, genes related to the pro-inflammatory cytokine pathways, as well as drug transport demonstrated significant differential expression between the two groups. Ongoing concurrent comparative analyses of miRNA profiles within this cohort have also identified several differentially expressed transcripts including mir-34b, mir-155, mir-214, mir-200c and mir-143. Some of these miRNAs have been earlier reported to be associated with tumour progression. Further integrated analysis will elucidate the synergistic roles that the genetic and epigenetic alterations in the deregulation of these and other pathways involved in primary chemoresistance. Our research findings will yield diagnostic and prognostic biomarkers that will lead to development of specific treatment regimens for the improved control of serous epithelial ovarian cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3645. doi:1538-7445.AM2012-3645
Abstract 3688: Akt pathway genes classify GBM into 6 prognostic subgroups with different clinical and molecular features
Authors: Joy Anna M. , Ramesh Archana , Smirnov Ivan , Misra Anjan , Shapiro William , Phillips Heidi , Aldape Ken , Mills Gordon , Kim Seungchan , Feuerstein Burt
Published: August 2012

The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known if akt pathway variations exist in GBM tumors. To investigate we developed a list of Akt pathway genes and investigated expression subgroups in a set of human GBM. Akt classification divides GBM into 6 subgroups with differing survivals and clinical/molecular features. Median survival of patients in the longest surviving subgroup (subgroup 5) was 3.9 yr vs 0.75 yr for patients in the shortest surviving subgroup (p < 0.01 Bonferroni corrected log rank). Patients in the long surviving subgroup were younger than the rest (median age = 38 vs 49 respectively; p = 0.05 corrected for multiple comparisons), but survival differences were independent of age (p = 0.027; subgroup 5 vs the rest). Tumors in short surviving subgroups were characterized by chr7 gain, chr10 loss and high ser473 phosphorylated-akt (p-akt) staining. The long surviving subgroup tumors were enriched for chr19q loss, low p-akt staining, elevated Notch staining and had no DNA copy number alterations in chr7 or chr10. Previously described subgroups (Phillips et.al.) were enriched in akt subgroups (all with p<0.001). These results suggest that tumors with a pathological diagnosis of GBM are a collection of molecular subgroups with fundamental differences in biology and clinical behavior. We hypothesize that Akt subgroups will enhance drug discovery and help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation (BGF and AMJ), Halle Family Foundation (BGF), and NIH 1 K01 NS064952-01A1 (AMJ).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3688. doi:1538-7445.AM2012-3688
Abstract 370: Tetrazine trans-cyclooctene ligation: An efficient 18F labeling method for cysteine containing peptides and proteins
Authors: Li Zibo , Liu Shuanglong , Hassink Matt , Selvaraj Ramajeyam , Yap Li-peng , Chen Xiaoyuan , Fox Joseph M. , Conti Peter S.
Published: August 2012

18F PET has a number of attributes that make it clinically attractive, including almost 100% positron efficiency, very high specific radioactivity, and short half-life of ∼110 min. However, the short half-life of 18F and the poor nucleophilicity of fluoride make it difficult to incorporate 18F in complex molecules. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a novel 18F labeling method that proceeds with fast reaction rates without any catalysis. To further explore the scope of this reaction, herein we reported an efficient method for 18F-lableing of free cysteine-containing bioligands based on the tetrazine-trans-cyclooctene ligation. The newly developed method was tested for site specific labeling of both c(RGDyC) and VEGF-SH protein. Starting with 4 mCi of 18F-trans-cyclooctene and only 10 μg of tetrazine-RGD (80-100 µM) or 15 μg of tetrazine-VEGF (6.0 µM), the 18F labeled RGD peptide or VEGF protein could be obtained in 95% yield and 75% yield within five minutes. The obtained tracers were then evaluated in small animals. In conclusion, a highly efficient method has been developed for site-specific 18F labeling of cysteine containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize 18F-labeled probes with high specific activity for PET applications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 370. doi:1538-7445.AM2012-370
Abstract 3701: Phase II study of BIBF1120 in recurrent glioblastoma multiforme
Authors: Lassen Ulrik , Mau-Soerensen Morten , Muhic Aida , Ehrnrooth Eva , Poulsen Hans S.
Published: August 2012

Background: BIBF 1120, a potent, orally available triple angiokinase inhibitor targeting VEGFR 1-3, PDGFR- α/-α, and FGFR 1-3, has shown promising clinical activity with a good safety profile in patients with advanced non-small cell lung cancer or ovarian cancer. The specific and simultaneous abrogation of these three pathways results in effective growth inhibition of both endothelial and perivascular cells. This may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. In addition, signalling via FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the VEGF pathway is disrupted. Recurrent glioblastomas (GBM) have an extremely poor prognosis and consequently new and innovative therapies are still needed. Accordingly, the purpose of this study was to assess the efficacy and safety of BIBF 1120 in two parallel groups of patients with recurrent GBM after radiotherapy and temozolomide (STD) or the same regimen and subsequent bevacizumab based therapy (BEV). Methods: Patients were included in one of two parallel groups depending of prior exposure to bevacizumab (STD or BEV). Inclusion critieria included recurrent GBM, PS 0-1, normal organ function, available archival tissue blocks, and measurable disease according to RANO guidelines. A total of 32 patients were to be enrolled in each group in a two-stage design including a stopping rule if less than 4/16 patient responded. BIBF-1120 was administered orally 200 mg bid, with weekly plasma sampling for the first 4 weeks and MRI assessement every 8 weeks. Primary endpoint was objective response rate. Secondary endpoints were safety, PFS and plasma and tissue biomarkers. Results: The study was prematurely stopped for after inclusion of 13 patients in the STD arm and 12 patients in the BEV arm. No objective responses were seen in either arm. One patient in the BEV arm has had stable disease for 8 months while the remainder of the patients in both arms progressed within the first 4 cycles. BIBF-1120 was very well tolerated with no observed grade III or IV adverse events. Most frequent adverse events were grade I-II hypertension, diarrhoea and fatigue, with a frequency of < 10%. Conclusion: BIBF-1120 was well tolerated, but did not show anti-tumor activity in recurrent GBM at the dose of 200 mg bid in this patient population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3701. doi:1538-7445.AM2012-3701
Abstract 3707: Captopril inhibits colorectal cancer liver metastases following 70% partial hepatectomy in a mouse model
Authors: Koh Shir Lin , Ager E. I. , Malcontenti-Wilson C. , Costa P L. , Muralidharan V. , Christophi C.
Published: August 2012

Background: Blockade of the renin-angiotensin system (RAS) with the angiotensin-converting enzyme inhibitor, Captopril, has been shown to inhibit CRCLM. Partial hepatectomy (PH) for colorectal cancer liver metastases (CRCLM) can stimulate tumour recurrence. Aim: This study investigated the effects of Captopril on liver regeneration (LR), as well as on CRCLM in the regenerating liver. Methods: Male CBA mice were used for 70% PH as well as 70% PH following CRCLM induction. Mice were randomly assigned to control or Captopril-treated groups. Liver and tumour samples were collected on days 1, 2, 4, 6 and 8, 16 and 21 post-surgery. The rate of LR was measured by liver-to-body weight (LBW) ratio. The percentage of liver metastases was quantified using quantitative stereology and immunohistochemistry was performed to quantify hepatocyte and tumour cell proliferation (anti-Ki67) and apoptosis (anti-caspase-3). Results: Captopril increased LBW (0.57 ± 0.02 Captopril, 0.49 ± 0.02 control, p = 0.027) compared to controls on day 2 following 70% PH. At day 6, Captopril had decreased LBW (0.5 ± 0.03, 0.73 ± 0.06, p = 0.006). However, by day 8, LBW was not different between the control and Captopril groups. At day 21, Captopril decreased the percentage of liver metastases compared to controls (24.4 ± 6.2%; 48.7 ± 4.7%, p = 0.008) in the regenerating liver. Tumour volume (388.3 ± 150.4; 1046.2 ± 200.2mm3, p = 0.02) and tumour nodule count per image field (68 ± 17.6; 181.1 ± 28.5, p = 0.005) were also decreased by Captopril. In contrary, Captopril did not significantly alter liver volume compared to controls (886.1 ± 65.2; 1044.1 ± 115.8, p = 0.254). Furthermore, LBW during LR in the presence of CRCLM at day 2 (0.53 ± 0.01; 0.51 ± 0.02, p = 0.449) and day 6 (0.71 ± 0.01; 0.73 ± 0.03, p = 0.51) were not different between Captopril and control groups. Conclusion: Captopril enhanced the early stage of LR following 70% PH. Captopril inhibits CRCLM in the regenerating liver without inhibiting LR. Understanding the mechanisms of actions of Captopril is required to improve CRCLM patient outcomes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3707. doi:1538-7445.AM2012-3707
Abstract 3711: Discovery of new therapeutic strategies for rare cancers with defined genetic lesions
Authors: Kerr Lauren T. , Young Sophie , Williams Elizabeth D. , Thomas David , Johns Terrance G.
Published: August 2012

Rare cancers are defined as those with an incidence of less than 0.05% in a given population, yet collectively make up ∼20% of all cancers. A proportion of these are characterized by a primary, driving genetic lesion which disrupts normal cell regulation, resulting in malignancy. Patients of rare cancer could potentially benefit from clinically approved targeted therapies developed for other cancers; however their rarity makes recruitment for clinical trials extremely difficult. Cell lines derived from these patients often maintain the genetic lesions present in the parent tumor, and therefore can serve as a platform to evaluate the efficacy of novel therapeutic strategies. Here we describe in vitro strategies for identifying novel treatment regimens for the rare, simple karyotype cancer Myxoid Liposarcoma (MLS). MLS is characterized by a single genetic event, the chromosomal translocation t(12;16)(q13;p11), which occurs in >95% of cases. The gene product of this translocation is the constitutively active fusion protein FUS-CHOP, which alters the expression of transcription factors responsible for regulating adipocytic differentiation. This drives the cells into a perpetual state of proliferation in the absence of differentiation, thus leading to malignancy. This study uses the cell lines MLS 402 and MLS 1765, which are derived from MLS patients, and express FUS-CHOP. Cells were screened with a panel of anti-cancer treatments, including antibodies, small molecule inhibitors and chemotherapies. Axitinib was identified as an efficacious treatment both alone and in combination with other therapies. Axitinib caused cell cycle arrest and induced apoptosis as verified by Annexin V flow cytometry assay. This multi-kinase inhibitor targets the membrane-bound receptors c-Kit, PDGFRα/β and VEGFR1/2/3. Western blot and bioplex assays were utilised to determine the downstream target molecules inhibited by axitinib treatment. Axitinib significantly reduced signalling activity through the AKT/mTOR and MEK/ERK1/2 pathways. Axitinib also displayed additive and synergistic anti-tumor activity with other targeted therapies. The establishment of cell lines that retain the key genetic mutation found in rare cancers is a useful approach for identifying novel therapeutic options.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3711. doi:1538-7445.AM2012-3711
Abstract 3715: EP-100 syndergizes with paclitaxel in ovarian, breast and prostate cancer cell lines
Authors: Leuschner Carola , Giardina Cody , Alila Hector W.
Published: August 2012

EP-100 is a targeted anti-cancer drug comprised of Luteinizing Hormone Releasing Hormone (LHRH) fused to a lytic peptide. EP-100 is currently being investigated in human clinical trials. EP-100 seeks and destroys LHRH receptor positive cancer cells via a novel mechanism of action involving direct membrane disruption. Studies were conducted to determine the cytotoxic effects of combining EP-100 with paclitaxel using multi-drug resistant LHRH receptor positive ovarian (OVCAR-3), breast (MDA-MB-231), uterine sarcoma (MES-SA-Dx5), prostate (PC-3) and LHRH receptor negative ovarian (SKOV-3) cancer cells. Cells were cultured in the presence of EP-100 (0.005 nM-50µM, N=8) or paclitaxel (0.0025-500 nM, N=8) alone or in combination for 48 to 72 hours in non-constant and constant ratio formats (N=6). Cell viability was measured by luminometric assays. Data for IC50 values were obtained using the GraphPad Prism and GraphPad Software for the Hill Equation. The synergistic effects of EP-100 and paclitaxel were expressed as Combination Index (CI) using the CompuSyn Software analysis program. EP-100 alone killed LHRH receptor positive OVCAR-3, MDA-MB-231, MES-SA-Dx5 and PC-3 cells at low micromolar concentrations after 48 to 72 h incubation(IC50 values 2.189 ± 0.027 µM, 2.092 ± 0.114 µM, 1.419 ± 0.133 µM and 1.9 ± 0.071 µM respectively). As expected, SKOV-3 cells did not respond well to EP-100 (IC50= 10.3 ±0.36 µM) because they lack LHRH receptors on their surfaces. OVCAR-3, MDA-MB-231, MES-SA-Dx5 and SKOV-3 cells were resistant to paclitaxel (IC50 values = 13.6 ± 0.7 nM 86.2 ± 5.9 nM, 94.1 ± 0.3 nM and 48.52 ± 4.5 nM, for OVCAR-3, MDA-MB-231, MES-SA-Dx5 and SKOV-3, respectively) and PC-3 cells were very sensitive to paclitaxel with IC50 of 5.2 ± 1.1 nM. The combination of EP-100 at 50 nM and paclitaxel at 500 nM resulted in 3620 and 6720- fold increased sensitivity when compared to paclitaxel alone. The median CI values were 0.18, 0.05, 0.25, and 0.6 for for MES-SA-Dx5, OVCAR-3, MDA-MB-231 and PC-3, respectively indicating synergistic responses in the cell lines. No synergy was observed in the LHRH receptor negative SKOV-3 cell line (CI=8.4). These results indicate that a combination of EP-100 and paclitaxel results synergistic responses in LHRH-receptor positive and multi-drug resistant cancer cells.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3715. doi:1538-7445.AM2012-3715
Abstract 3721: Combination of temozolomide and O6- benzylguanine inhibits breast cancer growth
Authors: Jeudy Sheila , Srivenugopal Kalkunte S. , Konduri Santhi D.
Published: August 2012

O6 methylguanine DNA methyltransferease (MGMT) is over expressed in breast cancer cells. A number of cytotoxic agents utilized in the treatment of cancer directly or indirectly damage DNA, thus initiating a cascade of events which finalizes in cell death. MGMT has received significant focus for its role in the repair of DNA damage caused by a number of chemotherapeutics including alkylating agents, chlorethylating and methylating agents. In the present study, we tested the administration of the MGMT inhibitor [O6-benzylguanine (BG)] at non-toxic doses in combination with MGMT alkylator (temozolomide) on breast cancer cells in cell culture and xenograft models. Here, we report that temozolomide in combination with BG effectively inhibits breast cancer cell growth in vitro and in vivo. Here, we also report that BG either alone or in combination with temozolomide inhibits gene expressions which are involved in breast tumorigenesis and cell division process (CDC20, TOP2A, AURKB, BIRC5) and induces the expression of p21cip1 cell cycle inhibitor. The combination also enhanced PARP cleavage, indicative of apoptosis. In breast cancer xenograft models, BG alone or in combination with temozolomide caused marked delay in tumor growth. These findings suggest that MGMT inhibition may provide a novel and effective approach for breast cancer growth inhibition. Furthermore, the combination of MGMT inhibitors and MGMT alkylators can provide alternative therapeutic approaches to treat breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3721. doi:1538-7445.AM2012-3721
Abstract 3734: Paclitaxel disrupts polarized entry of membrane permeable C6 ceramide into ovarian cancer cells resulting in synchronous induction of cell death
Authors: Best Charles , Calianese David , Szulak Kevin , Brum Gabriella , Higgins Katelyn , Carbone Thomas , McCauley Michael , Di Wen , Wanebo Harold , Wan Yinsheng
Published: August 2012

Exogenous cell permeable C6 ceramide is demonstrated to act synergistically with chemotherapeutic drugs: paclitaxel, cisplatin, doxorubicin and histone deacetylase inhibitor trichostatin A (TSA) to induce cell death in a variety of cancer cells. We previously showed that C6 ceramide and paclitaxel act synergistically to induce ovarian cancer cell death via modulation of PI3/AKT cell survival pathway. This current study is focused on the process of C6 ceramide into the cell and its behavior during apoptosis. We investigated the entry pattern of C6 ceramide into ovarian cancer cells using fluorescent short chain C6-NBD sphingomyelin (or C6-NBD). As imaged with confocal microscopy, we observed that C6-NBD enters cells in a polarized pattern, characterized by strong signals at one cellular end, a probable mitosis initiation site. Pretreatment of the cells with filipin, an inhibitor of the raft/caveolae endocytosis pathway, decreases C6-NBD entry into cells. Pretreatment of water channel inhibitor CuSO4 also reduces entry of C6-NBD. Interestingly, pretreatment of cells with paclitaxel disrupts the polarized entry of C6-NBD into the cells, resulting in even distribution of C6-NBD in the cytoplasm. Further studies show that pretreatment of the cells with paclitaxel destabilizes cytoskeletal proteins, releasing increased number of short fragments of tubulins. The data suggests that C6 ceramide enters the cells preferably through a predetermined initial site of mitosis. In addition to diffusion, short chain C6 ceramide enters cells also via water channels and caveolae-mediated endocytosis. Paclitaxel disrupts cytoskeletons and induces an even distribution of C6 ceramide in the cytoplasm resulting in synergistic ovarian cancer cell death.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3734. doi:1538-7445.AM2012-3734