bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1729: Cytoplasmic expression of survivin is an independent predictor of poor prognosis in patients with salivary gland cancer
Authors: Klussmann Jens P. , Stenner Markus , Weinell Antje , Ponert Tobias , Hardt Aline , Hahn Moritz , Preuss Simon , Speel Ernst J.
Published: February 2011

Background: The expression of the inhibitor of apoptosis protein survivin is shown to be a significant prognostic indicator in various human cancers. Its role in cancer of the major salivary glands remains unclear.

Methods: We analysed the survivin expression in 171 patients with malignant parotid gland cancer (12 different histological subtypes) by means of immunohistochemistry. The experimental findings were correlated with clinicopathological and survival parameters. The mean follow-up time was 42 months.

Results: There was no significant correlation of cytoplasmic survivin expression levels with the patients’ clinicopathological characteristics. A strong cytoplasmic expression of survivin was found in 25% of the examined tumors. High cytoplasmic survivin expression was an independent prognostic indicator for a significant poorer 5-year disease-free survival rate (31% versus 67%, p<0.0005) and overall survival (45% versus 62%, p=0.048). In the multivariate analysis survivn expression and distant metastasis were significant predictors for patient outcome (p=0.001, p<0.0005).

Conclusions: The correlation between cytoplasmic survivin expression and survival probabilities of salivary gland malignancies might make this an effective tool in patient follow-up, prognosis and targeted therapy in future.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1729.
Abstract 174: Characterization of methylation-controlled DnaJD1 in Hep3B hepatoma cell line
Authors: Lai Yi-Wen , Tsai Meng-Feng , Chen Chuan-Mu
Published: February 2011

The development of hepatocllular carcinoma (HCC) is a multistep process with accumulation of genetic and epigenetic alternations in regulatory genes, leading to activation of oncogenes and inactivation of tumor suppressor genes. For genome-wide DNA methylation study, we used homemade MCGI (mouse CpG islands) microarray to identify many genes that were hypermethylation in the liver tumor tissues of HBx-overexpressd transgenic mice. These selected hypermethylation genes were also confirmed in human hepatocellular carcinoma cell (HCC) lines. In this study, we focused on a methylation-controlled DNAJ family (MCJ) gene, DnaJD1. It has been observed highly frequent DnaJD1 gene methylation and silencing in ovarian cancer, and associated with increased resistance to chemotherapeutic. The DnaJD1 was found hypermethylation in the promoter region and followed reduced mRNA expression in Hep3B hepatoma cells, which contain HBV genome. After treated by 5-aza-2’-deoxycytidine (DAC) in Hep3B cells, the methylation level of DnaJD1 could be reduced and mRNA re-expressed. We over-expressed DnaJD1 in Hep3B cells to study the physiologic effects of DnaJD1 in cell proliferation, cell migration, and invasion ability in vitro. The tumorgenesis in xenotransplanted nude mice were also examined. Data suggested that DnaJD1 re-expressed in Hep3B cells that could affect the cell morphology and lost cell contact insensitive. In these results, we concluded that DnaJD1 could be the one of main role of HCC progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 174.
Abstract 1740: Over-expression of gelsolin protein in human cervical carcinoma associate with cell migration in vitro and recurrence-free survival in vivo
Authors: Wu Tzu-I , Liao Chia-Jung , Chang Ting-Chang , Lin Kwang Huei
Published: February 2011

Introduction:

The global yearly incidence and mortality of cervical cancer are 471,000 annual new cases and 233,000 deaths. Almost 80% cases occur in less developed countries, where it accounts for 15% of cancer in women. Cervical carcinoma ranks as the leading malignancy of genital tract malignancy in the developing countries. The recurrence indicate poor prognosis while the clinicopathological risk factors exist. In order to identify the potential molecular biomarker, proteomic analysis was performed and gesolin protein was selected.

Materials and Methods:

The plasma from normal healthy and cervical cancer, and tissue of cervical cancer plus adjacent normal tissue were collected for Western blotting assay, enzyme-linked immunosorbent assay (ELISA) or immunohistochemical stain (IHC). One hundred and twenty four patients with cervical cancers underwent surgical management were enrolled to evaluate IHC Histoscore of gesolin according to the multiply of immunoreactivity and involved percentage. The Transwell assay was conducted for cell migration analysis in HeLa cell line. The statistical analysis include independent t tests, Kaplan-Meier method using the log-rank test and the Cox proportional hazard model Receiver operating characteristics (ROC) curve analysis was used to determine cut-off points of the predictive parameters in univariate analysis.

Results:

The Western blot and ELISA assay both demonstrated the overexpression of plasma gelsolin in cases with cervical cancer rather than normal population, and with staged III/IV rather than stage I/II cases, In addition, gelsolin protein level also increased in conditional medium of cultured HeLa cell. Thus in vitro cell migration assay revealed decreased cell numbers while adding the gelsolin neutralizing antibody or small interference RNA compared with adding mock, non-specific antibody or Luciferase-shRNA. The other clinical parameters including stage, tumor size and lymph node status also put into consideration. The best cut-off point of gesolin Histosore to clarify the recurrence by ROC curve analysis is 115. The gelsolin Histosore (≤ 115 vs > 115, P= 0.018) and lymph node metastasis (no vs yes, P<0.001) play important prognostic role in recurrence by multivariate analysis.

Conclusion:

Overexpression of plasma and cytoplasmic gelsolin protein in cervical cancer promote cell migration by binding to actin cytoskeleton for rearrangement and cell motility. Among the clinicopathological parameters, the gelsolin overexpression and lymph node metastasis disclosed the recurrence-free survival impact by multivariate analysis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1740.
Abstract 1741: Quantitative Real-Time PCR analysis of SPARCL1 and SPARC expression in colorectal cancer tissues
Authors: Georges Rania , Adwan Hassan , Schimanski Carl C. , Berger Martin R.
Published: February 2011

The SPARC family of proteins comprises 10 members, which share structural similarities in one or more protein domains. SPARC-like protein 1 (SPARCL1; also known as hevin) and SPARC are two important family members, which have been found to be involved in various tumors.

The relationship between these two molecules and colorectal cancer and its liver metastasis has not yet been fully studied and understood.

cDNA microarray was used to analyze the expression profiles of 22523 genes in CC531 rat colon adenocarcinoma cells. Briefly, 2 × 106 CC531 were injected into the portal vein of male Wag/Rij rats to grow in the liver. The tumor cells were then re-isolated from rat livers at different time points (after 3, 6, 9, 14 and 21 days). SPARCL 1 and SPARC were among the genes, which were up-regulated in the re-isolated metastatic cells as compared to control CC531 cells grown in vitro, especially on days 3 (two- and nine-fold for SPARCL1 and SPARC) and 6 (four- and eleven-fold for SPARCL1 and SPARC) following tumor implantation.

These results motivated us to analyze the expression of these two genes in 65 colorectal cancer tissues taken from patients in different UICC tumor stages (I, n=11; II, n=23; III, n=17; IV, n=14). A mixture of 10 mucosa samples was taken for comparison as normal control.

Quantitative real time-PCR results showed that SPARCL1 mRNA was significantly down-regulated in 44 samples (68%) with these levels being on average fourfold lower (0.24 ± 0.21) than those in normal mucosa. Normal levels were found in 18 samples (28%), and up-regulated levels were detected in only 3 samples (4%) with these levels being on average threefold higher than those in normal mucosa (3.0 ± 1.1). No correlation between this down- or up-regulation and tumor stage could be found.

In contrast to the results for SPARCL1, SPARC showed an almost consistent up-regulation in 60 of the tumor samples (92%). The average level of SPARC up-regulation was higher than that of SPARCL1 (6.5 fold higher than in normal mucosa). It is worth noting here that in those 21 samples, in which SPARCL1 mRNA was not down-regulated, SPARC expression was on average twofold higher (13fold higher than in normal mucosa) than the average expression level of all samples.

These results suggest a relationship between the two family members, but it is still not clear, whether they have opposing or complementary functions in the context of tumor initiation and progression. More studies should be performed to uncover the possible role of these proteins in the course of colorectal cancer and its liver metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1741.
Abstract 1745: Foxp3 expression and prognosis in early stage non-small cell lung cancer
Authors: Tao Hiroyuki
Published: February 2011

Foxp3 is a transcription factor that specifically characterizes regulatory T cells (Tregs). Increased number of tumor-infiltrating Tregs has been reported to be related to poor prognosis. Recently, it has been demonstrated that cancer cells also can express foxp3 and its expression level correlates with unfavorable prognosis in several types of malignant tumors. In non-small cell lung cancer (NSCLC), prognostic impact of foxp3 expressing cancer cells is not yet determined. We examined foxp3 expression in resected NSCLC and investigated its association with recurrence.

Methods: Foxp3 expressing cancer cells were detected by immunohistochemical staining from surgically removed specimens of the 59 patients with NSCLC that were pathologically diagnosed with Stage Ia or Ib. Prognostic value of foxp3 was evaluated by Kaplan-Meier analysis and log-rank test.

Results: Male/female: 41/19, p-stage Ia/Ib: 39/20, squamous(sq)/adeno(ad)/adenosquamous(adsq)/large and LCNEC: 16/36/3/4. Foxp3 positive cancer cells were observed in 17 of 59 patients (28.8%, male/female: 9/8, p-stage Ia/Ib: 10/7, sq/ad/adsq/large and LCNEC: 2/12/1/2). Of the 59 patients examined, recurrent tumors were seen in 12 within two years. Of the 12 patients who experienced recurrence, foxp3 expression in cancer cells were detected in 4 (33.3%). Of the 47 patients without relapse within five years, foxp3 positive tumor cells were observed in 13 (27.7%). Kaplan-Meier analysis and log-rank test showed no significant difference between the presence or absence of the foxp3 positive cancer cells both in overall and relapse free survival.

Conclusions: In our study, foxp3 expressing tumor cells were seen in 28.8% of the patients with node-negative NSCLC. Prognositic value of foxp3 positive cancer cells in p-Stage I NSCLC was not determined.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1745.
Abstract 1746: Expression of the translation regulatory protein RBM3 is associated with a favourable prognosis in epithelial ovarian cancer
Authors: Åsa Ehlén , Brennan Donal J , Alvarado-Kristensson María , Nodin Björn , O'Connor Darran J , Uhlén Mathias , Pontén Fredrik , Jirström Karin
Published: February 2011

Background: RNA binding proteins are important regulators of gene expression involved in various post-transcriptional processes like mRNA stability and translation. We have recently demonstrated that high expression of RBM3 is associated with a favourable prognosis in breast cancer.

Aims and Methods: The aim of the present investigation was to examine the prognostic value of RBM3 in epithelial ovarian cancer (EOC). For this purpose, protein expression of RBM3 was examined by immunohistochemistry in tumour samples from 154 prospectively collected EOC cases (Cohort I). In addition, RBM3 gene expression was examined in an independent cohort with 282 EOC cases (Cohort II).

Results: No significant correlation was seen between RBM3 protein expression and any established prognostic clinicopathological parameters. However, survival analysis revealed a significant association between RBM3 nuclear expression and prolonged survival (HR=0.633, 95% CI=0.421-0.952, p=0.028) in cohort I. This association did not remain significant in multivariate analysis. In line with the IHC data, high RBM3 mRNA levels were associated with prolonged survival in Cohort II in both univariate (HR=0.671, 95% CI=0.504-0.894, p=0.006) and multivariate (HR=0.751, 95% CI=0.562-1.004, p=0.053) analysis.

Conclusion: In accordance with our previously studies of breast and colon cancer, high nuclear expression of RBM3 was associated with improved survival in patients with ovarian cancer. Further investigations are needed in order to understand the role of RBM3 in tumour progression and to confirm the utility of RBM3 as a prognostic biomarker in various cancer forms. We are currently investigating the role of RBM3 in cisplatin response in ovarian cancer cell lines.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1746.
Abstract 1747: Helicobacter pylori-positive diffuse large b-cell lymphoma: a distinct clinicopathologic entity
Authors: Kuo Sung-Hsin , Lin Chung-Wu , Chen Li-Tzong , Hsu Ping-Ning , Hsu Chiun , Wu Ming-Shiang , Yeh Kun-Huei , Tzeng Yi-Shin , Yeh Pei -Yen , Wang Hsiu-Po , Cheng Ann-Lii
Published: February 2011

Background

We previously reported that H. pylori-positive gastric DLBCL, with or without evidence of MALT origin, may respond to H. pylori eradication therapy. In this study, we further investigated the clinicopathologic features of H. pylori-positive DLBCL without histologic evidence of MALT origin.

Methods

We reviewed consecutive cases of gastric DLBCL without histologic evidence of MALT origin. H. pylori infection was documented by histologic examination, a urease test or bacterial culture. H. pylori-positive cases were further examined for CagA protein expression.

Results

A group of 45 patients positive for H. pylori were not histomorphologically different from a group of 48 patients negative for H. pylori. However, patients with H. pylori infection had a better International Prognostic Index score (0-1, 70% vs 30%, P = ·001), a lower clinical stage (I-IIE1, 73% vs 33%, P < [[Unable to Display Character: ∙]]001), a better tumor response to chemotherapy (complete response, 80% vs 50%, P = .01), and significantly better 5-year event-free survival (EFS) (71% vs 24%, P < [[Unable to Display Character: ∙]]001) and overall survival (OS) (73% vs 30%, P < [[Unable to Display Character: ∙]]001). CagA expression, as defined by more than 5% of tumor cells with CagA staining, was identified in 23 (68%) of 34 H. pylori-positive tumors. Compared with the 11 H. pylori-positive but CagA-negative cases, the 23 H. pylori-positive, CagA-positive cases were associated with significantly better 5-year EFS (73% vs 15%, P = [[Unable to Display Character: ∙]]002) and OS (91% vs 27%, P = [[Unable to Display Character: ∙]]001).

Conclusion

H. pylori-positive gastric DLBCL, particularly with CagA expression in tumor cells, appears to be a distinct tumor entity, sharing some key clinicopathologic features with H. pylori-associated gastric MALT lymphoma.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1747.
Abstract 175: Lack of rDNA promoter hypomethylation in clinical prostate cancer specimens and cell lines
Authors: Uemura Motohide , Zheng Qizhi , Nelson William G. , Yegnasubramanian Srinivasan , De Marzo Angelo M.
Published: February 2011

INTRODUCTION

Alterations in the structure of nucleoli are hallmarks of prostate cancer cells. However, the molecular mechanisms that result in enlarged nucleoli in prostate cancer are unclear. The nucleolus is formed around tandem repeats (n=∼400) of the ribosomal RNA genes (18S, 5.8S and 28S) each of which contains an upstream promoter region. Only a limited number of repeat units are activated at any one time, and the inactive silent repeat units are characterized by dense methylation of the CpG island of the upstream promoter. While a previous study in liver cancer indicated that tumor cells contained hypomethylated CpG islands in the rDNA promoter, there are no prior studies in prostate cancer. Since MYC is overexpressed in most human PIN and prostate cancers, can affect nucleolar structure and activates rRNA transcription, we also addressed whether MYC levels affect rDNA promoter methylation.

METHODS

Genomic DNA was extracted from clinical samples of ten fresh frozen matched pairs of tumor and normal tissues obtained from radical prostatectomies, as well as, from 7 prostate cancer cell lines. Isolated DNA was subjected to sodium bisulfite sequencing of a region of the rDNA promoter, as well as, real-time methylation specific PCR. The functional role of MYC was explored by siRNA mediated knockdown in cell lines.

RESULTS

Most prostate cancer cell lines showed two roughly equal populations of the rDNA promoter region repeat units consisting of those that were densely methylated and those that were largely unmethylated. All clinical specimens were similar to the cell lines showing 2 populations with no changes in cancer compared to normal. After MYC knockdown in PC3 cells, there was an unexpected marked reduction in methylation of the rDNA promoter, despite decreased rRNA transcription. Chromatin immunoprecipitation (ChIP) followed by bisulfite sequencing revealed that MYC was bound nearly exclusively to the fully unmethylated promoters.

CONCLUSIONS

Clinical prostate cancer specimens, as well as most prostate cancer cell lines, do not show rDNA promoter hypomethylation. Thus, hypomethylation of the rDNA promoter does not explain why tumor nucleoli are enlarged. While MYC can activate transcription from unmethylated rDNA promoters, we show for the first time that it is unexpectedly required to maintain proper rDNA promoter methylation levels in the inactive repeat units.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 175.
Abstract 1751: The influence of sex on prognostic markers for non-small cell lung cancer
Authors: Paul Boutros C.
Published: February 2011

There are significant differences between the sexes in the incidence, presentation, and response to therapy of non-small cell lung cancer (NSCLC). This study evaluated the effects of these differences on mRNA-based prognostic markers.

Several prognostic markers have been developed over the past decade by various groups, generally from microarray datasets. These markers look at the mRNA levels of specific genes and use these to determine whether a patient is likely to good or poor outcome. If such markers were successful at complementing traditional staging criteria (i.e. molecular sub-staging) then patients predicted to have poor outcome could receive additional or more intensive therapies. Surprisingly, to date, the effect of sex on such markers has not been evaluated, despite major differences in disease between males and females.

To evaluate this issue, I compiled the data from nine transcriptomic studies of primary NSCLC. These studies were integrated using a novel normalization approach and then subject to meta-analysis. For each gene present in the analysis (16,391 in total), the univariate prognostic capacity was calculated separately for men and women using median dichotomization and Cox proportional hazards modeling. Of the top 100 genes in each sex, only 12 were overlapping. Novel sex-specific prognostic signatures were then derived, and shown to out-perform sex-independent signatures by a statistically significant (p < 0.01) margin.

In summary, sex plays a major role in NSCLC etiology and response to therapy. I have demonstrate here that it also greatly effects the efficacy of transcriptomic prognostic markers.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1751.
Abstract 1752: Prognostic significance of Aquaporin(AQP) expression in gastric and colorectal cancer
Authors: Osawa Soshi , Shimada Yutaka , Sekine Shinichi , Shigeaki Sawada , Kashima Shiro , Fukuoka Jyunya , Okumura Tomoyuki , Tsukada Kazuhiro
Published: February 2011

Introduction :

Aquaporins (AQPs) are a membrane proteins involved in water transport and have been found to be expressed in several cancers. We have already reported that AQP 5 expression is associated with differentiation for gastric cancer (J Physiol Science 2009). However, the role of AQP family expression has not been well evaluated yet. In this study, we examined the expression of AQP 1, 4, 5 and 8 in gastric cancer and colorectal cancer, and compared them with the clinico-pathological characteristics of the patients.

Method :

The expression of AQP1, 4, 5, and 8 was comprehensively examined by tissue microarray (TMA1150) that has been established in our hospital. The specimens of gastric cancer and colorectal cancer were obtained from the patients who receive an operation between 1993 to 2004. Clinico-pathological data were obtained from the patients’ medical records. After careful examination of two independent pathologists, the results were scored according to the intensity and the distribution. Finally, AQP expressions were compared to the clinical pathologic finding of the patients.

Result :

In stomach cancer, positivity of AQP1, 4, 5, and 8 expressions were 40.7% (22/54), 43.2% (19/44), 97.6% (41/42) and 18.2% (8/44) respectively. AQP4 positive patients have a significant better prognosis than that of negative patients (p=0.004) and low expression of AQP4 tended to relate to poorly differentiated adenocarcinoma (p=0.07). However there was no significant difference between the prognosis, histological type, disease stage (TNM classification) and AQP1, 5, and 8 expressions.

With regard to colorectal cancer, positivity of AQP1, 4, 5, and 8 expressions were 27.4% (20/73), 45.9% (34/74), 98.4% (61/62), and 76.4% (55/72) respectively. AQP4 positive patients tended to have a favorable prognosis (p=0.12), on the other hand AQP1 positive group tended to have a worse prognosis (p=0.06). There was the other relationship between low expression of AQP4 and N factor (p=0.04).

Conclusion :

AQP 1 and 4 expression have some roles in the progression of gastric cancer and colorectal cancer, however the role of AQP 5 and 8 are still unknown. Our findings suggested that AQP 1 and 4 may be a molecular target of gastric cancer and colorectal cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1752.
Abstract 1753: High expression of the microtubule destabilizing protein stathmin is prognostic for worse outcome in breast cancer
Authors: Baquero Maria , Hanna Jason , Agarwal Seema , Killiam Elizabeth , Camp Robert L. , Rimm David L.
Published: February 2011

INTRODUCTION: Taxanes are microtubule targeting agents (MTAs) and potent cytotoxic molecules recognized as highly effective chemotherapeutic agents. In large randomized clinical trials, taxane-based chemotherapies provided benefits in overall and disease-free survival, but they are accompanied by significant adverse effects. Thus the clinical utility of taxane therapy would be enhanced if there were companion diagnostic tests so that only the taxane-sensitive patients (about half of breast cancers) could be treated with this drug. Accumulating evidence indicates that microtubule associated proteins (MAPs) may be responsible for tumor cell resistance to taxanes. Here we use a large retrospective cohort to measure expression levels of stathmin, a microtubule destabilizing protein, and to determine prognostic value, as a first step toward development of a companion diagnostic.

METHODS: Stathmin expression was measured in a large retrospective breast cancer cohort (n= 645) with 20 year follow-up using tissue microarray technology (TMA) in two-fold redundancy and quantitative immunofluorescence (AQUA). Patient stathmin expression levels were correlated with clinical, pathological, and disease free survival variables.

RESULTS: Stathmin expression exhibited nonparametric distribution with high correlation (R= 0.70) between redundant TMA cores. Prognostic evaluation of the cohort using univariate analysis indicated an inverse correlation between high stathmin expression and overall survival (HR = 1.30, 95% confidence interval [CI] = 1.02-1.65; p< 0.028). Kaplan Meier survival analysis showed 10-year survival of 54% for patients with high stathmin expression versus a 65% survival rate for low expressers (log rank, P<.0058). Multivariate analysis indicated that high stathmin expression, nodal status, HER2 expression, and tumor size are independent predictors of survival.

CONCLUSIONS: Stathmin expression in breast tumor tissue functions as a prognostic factor where high expression is associated with worse outcome. Since stathmin expression is useful in predicting survival, it may serve as marker to accurately select patients for current taxane-based or other anti-microtubule therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1753.
Abstract 1756: Automated digital analysis of interleukin-6 (IL-6) expression in a prostate cancer (PCa) matched case-control outcome based tissue microarray (TMA) design set
Authors: Shah Jarna , Macias Virgilia , del Mundo-Galicia Marisa , Xue Mark , Kajdacsy-Balla Andre A.
Published: February 2011

IL-6 is a multifunctional cytokine that has been involved in modulation of growth and differentiation in several malignant tumors. Studies have shown its role as an important autocrine growth factor for androgen-dependent human prostate cancer in vivo. Serum IL-6 has also been associated with poor prognosis in prostate cancer. We performed a digital analysis of IL-6 immunoreactivity in prostate cancer epithelial cells to determine differences in IL-6 expression between recurrence and non-recurrence groups in a PCa nested case-control cohort.

We analyzed an outcome-based TMA obtained from the Cooperative Prostate Cancer Tissue Resource (CPCTR) containing quadruplicate cores (0.6mm core diameter) from 200 pairs of PCa tumor samples (n=400). Cases with PSA recurrence were matched 1:1 with cases without recurrence by race, age, year of surgery, Gleason grade, and pathological stage. All cases had at least five-years follow up. TMA slides were incubated with rabbit polyclonal IL-6 antibody (Abcam) in a 1:600 dilution. Expression levels of IL-6 were assessed by Colocalization Algorithm (ScanScope®, Aperio Corp). Differences in IL-6 intensity between case-control pairs were calculated by Wilcoxon signed rank paired test.

Automated data was available for analysis in 149 pairs (n=298). The Wilcoxon signed rank test showed no statistically significant differences in IL-6 intensity between the two groups (p = 0.7).

To the best of our knowledge, this is the first study to examine the expression of IL-6 in a large PCa TMA set. Our results revealed IL-6 expression in cancer tissue; however, after statistical analysis, no significant differences were obtained to indicate that IL-6 may be considered as prognostic marker of prostate cancer with biochemical recurrence if cases were first matched by race, age, date of prostatectomy, Gleason score, and stage. In our study we excluded stromal and inflammatory cells IL-6 expression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1756.
Abstract 1767: Gene expression signatures as predictors of chemotherapeutic response in breast cancer
Authors: Fournier Marcia V. , Martin Katherine J.
Published: February 2011

The purpose of this study is to evaluate a novel 22-gene signature as a predictor of response to chemotherapy in breast cancer. The extent of residual viable tumor following chemotherapy is the most important predictor of long-term outcome in breast cancer. It is essential to identify patients who will not respond to chemotherapy to avoid ineffective therapies as well as unnecessary side effects. The rate of complete pathologic response to chemotherapy is relatively low, ranging from 3% to 27% of patients. Much work has been performed to predict chemotherapy responsiveness, but, as of yet, no test is effective and widely used in the clinic. Gene expression signatures are a multifaceted approach to characterizing disease states. They offer the potential to tailor a chemotherapy regimen to an individual patient. Here we compare the ability of multiple gene signatures, including the 70-gene prognostic signature (MammaPrint) and the 22-gene signature among others, to accurately predict response to multiple different regimens of primary chemotherapy in breast cancer. Predictive ability is compared in independent microarray datasets totaling approximately 157 breast cancer patients treated with primary chemotherapy. Sensitivity, specificity, and overall accuracy were evaluated by receiver operating characteristics (ROC) graphs, a technique for visualizing, organizing, and selecting classifiers based on their performance. Results show that the 22-gene signature accurately predicts response to multiple primary chemotherapies (p<0.05). Importantly, the 22-gene signature outperformed other signatures with highly significant p-values in all datasets tested. This signature potentially represents a clinically useful method to select a personalized chemotherapy regimen for breast cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1767.
Abstract 1768: Comprehensive mass spectrometry based metabolomic profiling of blood plasma reveals potent discriminatory classifiers of pancreatic cancer
Authors: Urayama Shiro , Zou Wei , Tolstikov Vladimir
Published: February 2011

Background: Poor outcome of pancreatic cancer (PDAC) necessitates development of early diagnostic method to reduce mortality. In current study, metabolic profiling of plasma samples from selected cancer patients and noncancerous controls was performed to seek novel metabolic biomarkers of PDAC. Comprehensive mass spectrometry based analytical platform were applied for detection of compounds in the plasma from early stage PDAC patients.

Methods: Plasma available from the patients involved in the IRB-approved UC Davis Pancreas Registry was utilized. Five histologically proven cases of early stage pancreatic cancer without clinical evidence of distant metastasis [AJCC TNM stages: IB (2) and IIB (3)] and 5 noncancerous cases [3 chronic pancreatitis, 2 normal-based on clinical and follow-up evidences] were chosen from the Registry. Combination mass spectrometry (MS) methods, GC-TOF-, HILIC-LC-ESI-, and RP-LC-ESI-MS were applied for the plasma analysis. Data values obtained were evaluated for principle component analysis (PCA). Further feature selection and ANOVA were conducted after the PCA. Statistical significance was defined as p-value less than 0.05. Feature components with statistically significant classifiers of the PDAC were analyzed further with LTQ-Orbitrap MS for accurate mass measurement. Mass spectra of potential biomarkers thus obtained were spectrally corrected and unique elemental formula was searched against CAS database using the strategy of Explore Substances-Chemical Structure for known compounds. Mass Frontier 5.0 was used for MS/MS fragmentation modeling analysis; with parent compounds that had the best match of MS/MS fragmentation pattern were considered as the molecular structure of the potential biomarkers.

Results: The candidate biomarkers included amino acids (N-methylalanine, lysine, glutamine, phenylalanine), fatty acids (arachidonic acid), lipids (lysoPC (18:2), PC (34:2), PE (26:0)), and bile acids (tauroursodeoxycholic and taurocholic acids, deoxycholylglycine, cholylglycine).

Conclusion: We have demonstrated that combination of the comprehensive mass spectrometry based metabolic profiling techniques, data mining, and data analysis successfully find potent classifiers for pancreatic cancer in plasma. These metabolites upon validation, selectivity study, and broader cohort study could become clinical biomarkers for early diagnosis of pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1768.
Abstract 178: RASSF10 is frequently methylated in epithelial cancers
Authors: Hill Victoria , Krex Dietmar , Bieche Ivan , Minna John , Morton Dion , Yao Msahiro , Maher Eammon R. , Latif Farida
Published: February 2011

The classical Ras-association domain family (RASSF1-6) are a group of Ras effector molecules that contain a C-terminal Ras-association (RA) domain of the RalGDS/AF-6 variety and a protein interaction domain known as the Sav/RASSF/Hippo (SARAH) domain. Several members of the classical RASSF family are involved in tumorigenesis since epigenetic inactivation of many isoforms is a frequent event across many tumor types and their functions are consistent with roles as tumor suppressor proteins. Recently several additional RA-domain containing family members have been identified and designated N-terminal RASSF proteins (RASSF7-10). These comprise RASSF7 (also known as HRC1 located 11p15.5), RASSF8 (also known as HOJ-1 or C12ORF2 located 12p12.1), RASSF9 (also known as P-CIP1 or PAMCI located 12q21.31) and RASSF10 (located 11p15.2). These proteins are divergent and structurally distinct from RASSF1-6, containing an RA domain within their extreme N-termini and lacking the SARAH protein interaction domain. Little is known about the N-terminal RASSF7-10 proteins although they represent an evolutionarily conserved group of proteins with orthologues of all four in the lower vertebrate Xenopus laevis and a RASSF7/8 homologue in Drosophila melanogaster distinct from the RASSF1-6 Drosophila homologue.

We have recently characterized the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 5’ CpG island in acute lymphoblastic leukemia. In this report we analysed the methylation status of the CpG island in a range of common epithelial cancers. RASSF10 was frequently methylated in grade II-IV gliomas (grade II, 50%; grade III, 80%, grade IV 57%) but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. In other common epithelial cancers RASSF10 was also methylated but at a lesser frequency compared to grade II-IV gliomas. RASSF10 was methylated in 25% breast tumors, 31% of colorectal cancers, 20% lung tumors and 28% of renal cell carcinomas. RASSF10 was unmethylated in DNA from corresponding normal tissues or control tissue samples.

This work demonstrates that RASSF10 is a frequent target of epigenetic inactivation in a range of epithelial cancers as well as haematological cancers. We are now undertaking biological characterization of this novel protein.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 178.
Abstract 1783: Activated c-MET; a prognostic factor and potential therapeutic target for malignant peripheral nerve sheath tumors (MPNST)
Authors: Torres Keila E. , Ghadimi Markus , Wang Suizhao , Liu Jun , Lazar Alexander , Pollock Raphael E. , Lev Dina
Published: February 2011

There is a crucial need for sensitive prognosticators and novel therapeutic approaches for better management of MPNST. These tumors harbor a dismal prognosis due to their chemoresistant nature and enhanced metastatic propensity. A large body of evidence suggests a role for the tyrosine kinase receptor c-Met in cancer and its utility as a target for cancer therapy is currently being investigated. Here we aimed to evaluate the role of the c-Met signaling pathway in human MPNST. Expression level of c-Met, its ligand HGF and phosphorylated c-Met was determined immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign neurofibromas (n = 31). All three markers were found to be over-expressed in MPNST as compared to their pre-malignant precursors (neurofibroma; p<0.05). Furthermore, univariable and multivariable analyses identified a statistically significant correlation between activated-c-Met expression and poor patient outcome (HR=2.32, p=0.012 and HR=1.48, p<0.001, respectively). Human MPNST cell lines expressed c-Met, HGF, and activated c-Met to varying levels. An activating c-Met mutation (Exon 2: N375S) was identified in one cell line (T265); all cells evaluated (n=3) harbored c-Met and HGF amplification based on aCGH. c-Met activation resulted in significantly increased MPNST cell motility and invasion. Furthermore, c-Met activation enhanced the pro-angiogenic effects of MPNST. c-Met blockade (via siRNA or a small molecule inhibitor) abrogated the HGF-induced downstream signaling and MPNST cell migration/invasion. Dual blockade of c-Met and VEGFR significantly abrogated MPNST local and metastatic growth in vivo. In conclusion, Human MPNST tumors and cell lines express the c-Met receptor which, upon activation, results in increased MPNST migration, invasion, and angiogenesis. Inhibition of c-Met-mediated signaling could impair MPNST metastatic capacity, and therefore merits further consideration as a potential MPNST therapeutic target.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1783.
Abstract 1788: Preclinical development of a selective, potent small molecule ALK inhibitor
Authors: Lovly Christine M. , de Stanchina Elisa , Liang Chris , Pao William
Published: February 2011

A chromosomal inversion [inv (2)(p21p23)] resulting in the expression of an oncogenic kinase fusion protein known as EML4-ALK [echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase] has been implicated in the pathogenesis of a subset of lung adenocarcinomas. An agent (PF-02341066), originally described as a MET tyrosine kinase inhibitor (TKI) but with “off-target” ALK activity, has demonstrated significant activity in ALK-fusion positive lung cancer patients and is currently in phase II/III clinical trials. In this study, we describe the development and characterization of a novel and highly selective ALK TKI. X-276 (racemic mixture) is an orally bioavailable ATP mimetic that has high selectivity for ALK as assessed by Ambit assays (binding constant 2nM). Treatment of H3122 lung adenocarcinoma cells, which harbor the EML4-ALK E13;A20 fusion product, resulted in potent inhibition of cell growth with an IC50 of 10nM, approximately 10 fold less than the IC50 of H3122 cells treated with a racemic mixture of PF-02341066. Immunoblot analysis confirmed that X-276 inhibited ALK phosphorylation in H3122 cells. Importantly, the IC50 of X-276 in H1993 lung cancer cells, known to be MET-dependent, was >100 fold higher. In addition, the selectivity index of H3122 cells vs. hepatocyte HepG2 cells was >135. Finally, compared to vehicle controls, X-276 delayed the growth of H3122 xenografts in established nude mice by >60%. Collectively, these data show that TKIs can be developed with greater specificity against ALK. Such compounds may lead to the development of ‘second-generation’ ALK TKIs with more potency against ALK-mutant cancers. Future studies will focus on determining the mechanism of acquired resistance to ALK TKIs using these more potent ALK inhibitors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1788.
Abstract 1793: Platelet-derived growth factor receptor alpha blockade significantly enhances sensitization to docetaxel in ovarian carcinoma
Authors: Matsuo Koji , Stone Rebecca L. , Shahzad Mian , Carroll Amy R. , Han Hee-Dong , Lee Sun-Joo , Nishimura Masato , Mora Edna , Lu Chunhua , Loizos Nick , Sood Anil K.
Published: February 2011

Objective: Platelet-derived growth factor receptor alpha (PDGFRα) is a member of class III receptor tyrosine kinase and is associated with cell survival. Here, we examined whether PDGFRα blockade enhances the anti-tumor activity of taxanes in ovarian carcinoma.

Methods: PDGFRα expression was evaluated with RT-PCR and Western blot in multiple ovarian cancer cell lines. Human-specific monoclonal antibody to PDGFRα (IMC-3G3, ImClone Systems, NJ, USA) was used for in-vitro (cell viability assay, apoptosis assay) and in-vivo experiments with or without docetaxel.

Results: All eleven tested ovarian cancer cell lines had variable expression of PDGFRα. OVCA433 cell line had the highest level of expression of PDGFRα. IMC-3G3 blocked PDGFRα phosphorylation in response to PDGF-AA stimulation. IMC-3G3 alone had no affect on cell viability in all tested cell lines. However, IMC-3G3 significantly enhanced sensitization to docetaxel: IC50 reduction rate, SKOV3-ip1, 25.5%; HeyA8-parental, 31.7%; OVCA433, 35.3%; and HeyA8-MDR, 44.2% (all, p<0.05). While treatment with IMC-3G3 alone did not increase apoptosis, concurrent use with docetaxel significantly enhanced docetaxel-mediated apoptosis (mean percentage of total apoptotic cells in SKOV3-ip1, untreated vs IMC-3G3 alone vs docetaxel alone vs docetaxel with IMC-3G3, 7.3% vs 7.1% vs 15.4% vs 22.2%, p<0.001). In the in-vivo experiment with SKOV3-ip1 bearing mice, administration of IMC-3G3 monotherapy had no significant anti-tumor effects compared to the control group (mean tumor weight, 2.5 ± 0.32 vs 2.9 ± 0.51 grams, p>0.05). Concurrent use of IMC-3G3 with docetaxel significantly reduced tumor weight compared to docetaxel alone (mean tumor weight, 0.22 ± 0.07 vs 0.63 ± 0.14 grams, tumor reduction rate 65.1%, p<0.05).

Conclusion: IMC-3G3 significantly enhances the anti-tumor effects of docetaxel. Therefore, targeting PDGFRα may be an attractive approach for increasing the cytotoxic effects of chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1793.
Abstract 1798: TORC1/2 inhibitors have more potent anti-leukemic efficacy and are less immunosuppressive than rapamycin
Authors: Fruman David A. , Janes Matthew R. , Limon Jose J. , So Lomon , Chen Jing , Martin Michael B. , Ren Pingda , Liu Yi , Rommel Christian
Published: February 2011

The purpose of this study was to evaluate the anti-leukemic and immunosuppressive properties of novel, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). The mTOR inhibitors currently in clinical use, exemplified by rapamycin and related analogs (“rapalogs”), have achieved some success as anticancer therapies. However, these agents also suppress proliferation of both B and T lymphocytes. In addition, rapalogs have a mechanistic limitation: not only are they allosteric inhibitors that selectively bind to mTOR complex-1 (TORC1) and not to mTOR complex-2 (TORC2), but they do not fully inhibit TORC1. In contrast, novel ATP-competitive active-site inhibitors of the mTOR kinase overcome these limitations, displaying full inhibitory activity of both TORC1 and TORC2. We compared rapamycin with active-site TORC1/2 inhibitors in models of Philadelphia chromosome-positive pre-B acute lymphoblastic leukemia (Ph+ B-ALL). We find that PP242 and INK128, active-site TORC1/2 inhibitors, but not rapamycin cause death of murine and primary human leukemia cells. These compounds are also more potent than rapamycin in growth assays of solid tumor cell lines. Biochemical assays confirm that PP242 and INK128 inhibit rapamycin-resistant outputs of both TORC1 and TORC2. In vivo, oral administration of PP242 or INK128 delays leukemia onset and augments the effects of tyrosine kinase inhibitors. Surprisingly, active-site TORC1/2 inhibitors have much weaker effects on proliferation and function of normal B and T cells than rapamycin. Selective TORC1/2 inhibitors are also less immunosuppressive than PI-103, a panPI3K-mTORC1/2 inhibitor. These findings establish that transformed lymphocytes are selectively sensitive to TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1798.