bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 703: Suppression of neurotensin receptor type 1 expression and function by apigenin in human colorectal cancers involves protein kinase CK2/JNK pathway
Authors: Wang Xiaofu , Gulhati Pat , Rychahou Piotr G. , Silva Scott R. , Evers B. M.
Published: February 2011

Apigenin, a nonmutagenic chemopreventive agent found naturally in fruits and green vegetables, is an inhibitor of protein kinase CK2 (formerly casein kinase II), which is frequently upregulated in human cancers. Neurotensin (NT), a gut peptide, stimulates growth of colorectal cancers (CRCs) through its high affinity receptor (NTR1). In this study, we found that treatment with apigenin suppressed NTR1 expression in CRC cells HCT116, SW480 and SW620. Additionally, treatment with emodin, another natural inhibitor of CK2, and TBB (4,5,6,7-tetrabromo-1H-benzotriazole), a selective chemical inhibitor of CK2, suppressed NTR1 expression in these CRC cells, indicating that CK2 plays a role in NTR1 regulation. Moreover, apigenin significantly decreased phosphorylation of JNK1/2, whereas TBB decreased phosphorylation of JNK1 and emodin decreased phosphorylation of JNK2 in HCT116 cells; all three compounds decreased phosphorylation of JNK1 in SW480 cells. Treatment with the selective JNK1/2 inhibitor, SP600125, suppressed NTR1 expression in all CRC cell lines examined. Furthermore, apigenin significantly inhibited CRC cell proliferation and prevented NT-stimulated expression of IL-8, c-myc and Mcl-1, all which contribute to CRC proliferation or metastasis. We conclude that apigenin suppresses endogenous NTR1 expression and function in multiple CRC cell lines; this effect may involve CK2/JNK signaling. The downregulation of NTR1 in CRCs may represent an important mechanism for the anti-cancer effects of apigenin.

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 703.
Abstract 713: Active hedgehog pathway in human primary gastric tumor models
Authors: Yu Shijun , Wu Chao , Song Xiaoming , Chen Taiping , Wery Jean-Pierre , Chen Yiyou
Published: February 2011

The hedgehog (Hh) signaling pathway is known to be essential for multiple aspects of embryonic development, and activation of the Hh pathway leads to the development of several human malignancies such as basal cell carcinoma and medulloblastoma. Recent data have implicated a much broader role of the Hh pathway in other human cancer as well as the maintenance of cancer stem cells. Loss-function mutation of Ptc and gain of gunction mutation of Smo in human malignancies make the components in Hh pathway attractive therapeutic targets. However, this pathway is readily deactivated once human tumor cells are propagated in cell culture, a prerequisite of most preclinical human cancer models. In order to identify useful models for the evaluation of novel therapeutics targeting the Hh pathway, we profiled the expression of Ptc, Smo, Gli in a cohort of twenty established human primary gastric tumor models by TaqMan real-time quantitative PCR reaction and immunohistochemistry (IHC). Seven of the twenty models displayed high expression of either Gli-1 or Gli-2. Eight models were found to have high expression level of Shh. And three models were found to have high level of Ptc. The Gli protein expression level is also examined with IHC. High levels of Gli and Shh in the selected models will be very useful to evaluate anticancer drugs against Hh signaling pathway for their drug activity and pharmacodynamic responses. These models, together with the associated clinical and pathological information, provide a unique platform to evaluate the in vivo activities of pharmaceutical agents targeting the Hh pathway.

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 713.
Abstract 734: Development of small molecule inhibitors of the phosphatase Shp2 by fragment screening
Authors: Wu Xin , Scott Latanya , Chen Liwei , Lawrence Harshani R. , Luo Yunting , Sebti Said M. , Wu Jerry , Lawrence Nicholas J.
Published: February 2011

Protein tyrosine phosphorylation, which is controlled by tyrosine kinase (PTK) and tyrosine phosphatase (PTP), regulates numerous cellular processes, including proliferation, survival, differentiation, migration and apoptosis. Accumulating evidence has shown that defective function of PTPs leads to aberrant protein phosphorylation, which is associated with many humane diseases, including cancer. Src homology 2 phosphatase-2 (Shp2) is a cytoplasmic, nonreceptor protein tyrosine phophatase. It is the first proto-oncogene identified in the PTP superfamily. The structure of Shp2 consists of two SH2 (N-SH2 and C-SH2) domains, a single PTP region and a C-terminal hydrophilic tail. In the basal state, Shp2 displays a low catalytic activity due to close interactions between the N-SH2 and PTP domains that keep the phosphatase in an autoinhibited closed conformation. Upon growth factor or cytokine stimulation, the SH2 domains of Shp2 binds to tyrosine phosphorylated docking proteins such as Gab1 and Gab2, which activates Src, Ras, and the Erk1/2 (Erk) mitogen-activated protein (MAP) kinase pathway. Shp2 gain-of-function mutations are found in leukemias and solid tumors and are linked to Noonan syndrome. Although Shp2 is involved in pathogenesis of human cancers, it is not clear how Shp2 mediates tumorigenesis. To aid chemical biology studies and ultimately experimental therapy, we have been actively engaged in the search potent and selective Shp2 inhibitors. We will describe the results of a fragment-based screen as a method for identifying Shp2 inhibitors. The fragment libraries were both purchased and constructed in-house with a bias towards compounds that would potentially function as phosphotyrosine mimics. This has revealed compounds with moderate to low activity (IC50 200-500 µM) that have served as the starting pints for fragment-to-lead development. The emerging structure-activity relationships will be discussed as well as synthesis, modeling and X-ray studies.

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 734.
Abstract 772: Effects of natural products on proliferation of human breast cancer cells induced by estrogen or PhIP, a heterocyclic amine compound derived from cooked meat
Authors: Lee Choong Jae , Lee Mi Nam , Lee Hyun Jae , Lee Su Yel , Seok Jeong Ho , Jordan Mary Ann , Wilson Leslie
Published: February 2011

According to the traditional Asian medicine, herbs containing daidzein, hesperidin, oleanolic acid and bacalein were used as anti-inflammatory and anti-tumor folk medicines. On the basis of this information, in this study, we investigated whether natural products including daidzein, hesperidin, oleanolic acid and bacalein affect proliferation of MCF-7 human breast cancer cells stimulated by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) or estradiol. The results were as follows : (1) Both estradiol and PhIP significantly induced proliferation of MCF-7 cells at the concentrations of 10nM and 100nM, respectively; (2) Oleanolic acid and baicalein inhibited proliferation of PhIP-induced proliferation of MCF-7 cells, dose-dependently; (3) Daidzein and hesperidin also inhibited proliferation of estradiol-induced proliferation of MCF-7 cells, dose-dependently. We suggest that these four natural compounds can be novel drug candidates for preventing breast cancer provoked by dietary estrogenic compounds found in cooked meat such as PhIP. Also, effects of these four natural compounds on MAPK-ERK pathway should be investigated for elucidation of action mechanism through future study.

(Key words: Natural products, MCF-7, PhIP, Estradiol)

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 772.
Abstract 777: Rosehip (Rosa canina) extracts prevent Akt-mediated cell proliferation in glioblastoma cells
Authors: McNair Patrice , Goktepe Ipek , Martin Patrick M.
Published: February 2011

Glioblastoma multiforme (GBM) are aggressive malignant tumors that develop in the brain. GBMs demonstrate increased rates of cell proliferation, a lack of apoptosis as well the propensity to migrate to distal sites in the brain. The clinical management of glioblastoma consists of surgical resection followed by radiotherapy and chemotherapy. However, this treatment regimen is not very effective and more effective therapies need to be developed. Activation of several signaling pathways has been associated with the increased proliferative capacity of GBM cells. Activity of the Akt/mTOR pathway is exceptionally high in GBMs and may regulate sensitivity to chemotherapy and radiotherapy. Akt and its downstream effector p70S6 kinase (p70S6K) demonstrate a high amount of activity in GBMs. Inactivation of Akt and p70S6K attenuate GBM cell growth and may inhibit GBM cell proliferation. Therefore, we investigated the antiproliferative capacity of extracts from the Rosehip (Rosa canina) plant. Rosehip extracts have been used as dietary supplements to relieve symptoms associated with diarrhea, gastritis and rheumatoid arthritis. U-1242MG, a human GBM cell line, treated with Rosehip extracts (250 µg/ml) demonstrated a decrease in cell proliferation. The Rosehip extract-mediated decrease in cell proliferation was equal to the decrease of cell proliferation observed when LY294002 (20 µM),a known Akt inhibitor was utilized. Additionally, pretreatment of the U-1242 MG cells with these Rosehip extracts (250 µg/ml) decreased p70S6K phosphorylation, suggesting these extracts prevent GBM cell proliferation by blocking Akt/mTOR signaling mechanisms. Taken together these data suggest that p70S6K positively regulates GBM cell proliferation, and Rosehip extracts may serve as an alternative or supplement to current therapeutic regimens for GBMs.

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 777.
Abstract 797: Kinase activity profiling of tumor tissues of different origin
Authors: Ruijtenbeek Rob , Houkes Liesbeth , Umar Arzu , Oosterwijk-Wakka Jeannette , de Wijn Rik , Thijssen Victor , Martens John , Dingemans Anne-Marie , Oosterwijk Egbert , Hilhorst Riet
Published: February 2011

Introduction:

Many new anti-cancer drugs target kinase activity. Unfortunately, methods to monitor the drug effects at the enzymatic level in patient derived tumor tissue are lacking. Here, a novel molecular profiling method for application in biomarker discovery is presented. This method is based on measuring kinase activities in tumor tissue extracts, and involves assessment of inhibition by a drug of interest. This ex vivo activity-based approach is enabled by dynamic peptide microarrays. These arrays comprise of peptides, which are known substrates for phosphorylation by protein kinases. Here we investigated the applicability of this approach in the classification of multiple tumors of different origin.

Method:

Patient-derived fresh frozen tissues of different tumor types (24 breast cancer (BC), 14 non-small cell lung cancer (NSCLC), 12 renal cell carcinomas (RCC)) were used for extraction of total protein in lysis buffer. Dependent on the tissue source, 6 slices of 10 µm were sufficient for 20-100 microarray analyses. Equal amounts of total protein were analyzed for kinase activity on dynamic PamChip peptide microarrays. These arrays comprised 144 or 256 different peptides. A PamChip96 plate format was used, enabling 96 microarray incubations per run. Protein amounts ranging from 1 − 5 µg were used per microarray analysis. Tumor extracts were analysed in the presence and absence of kinase inhibitor drugs (RCC: sorafenib and sunitinib, NSCLC: gefitinib).

Results:

We show here that from different tumors kinase activity profiles could be generated reproducibly (10-15% CV for selected peptides). Control experiments showed protein concentration and ATP dependency. In the RCC experiments different phosphorylation profiles were obtained when the non-tumor tissue was compared to tumor tissue derived from the same patient, showing higher kinase activities in the latter. In addition, inhibitor dependent modulation of the peptide phosphorylations was observed (sorafenib vs. sunitinib). Furthermore, differential kinase activity profiles were obtained that could be correlated to different patient subgroups (BC) or clinical data (long vs. short term survivors; NSCLC).

Conclusion:

A novel molecular profiling approach was successfully applied for classification of different tumors. This approach is based on detection of kinase activities as well as inhibition of kinase activity in tumor tissues. Application of this method in the discovery of biomarkers for diagnosis, prognosis or prediction of drug response is foreseen.

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 797.
Abstract 838A: Characterization of sphingosine kinase isoenzyme selective inhibitors
Authors: Gao Peng , Zhuang Yan , Smith Charles D.
Published: February 2011

Sphingosine kinases (SphKs) play key roles in cell proliferation, migration and inflammation by catalyzing the formation of sphingosine-1-phosphate (S1P). However, the two isoenzymes, SphK1 and SphK2, play only partially overlapping roles in tumor epithelial cells. Our genetic approach (siRNA) revealed that SphK2 knockdown cells had more effects on decreasing cell proliferation and migration than SphK1 knockdown. A novel non-radioactive HPLC method based on florescence was developed to measure the activities of SphK. It revealed the increased SphK1 activity induced by SphK2 knockdown could not rescue the cells from apoptosis. In order to confirm the results from the genetic approach, we developed pharmacological approaches that used SphK isoenzymes selective inhibitors to dissect the functions of SphK isoenzymes. After the structure optimization of the lead compounds identified by high throughput screening, two compounds were identified as SphK inhibitors: 3-(4-Chlorophenyl)adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide hydrochloride salt - termed ABC294640 and 3-(4-Chlorophenyl)adamantane-1-carboxylic acid [2-(3,4-dihydroxyphenyl)ethyl]amide - termed ABC294735. The inhibition specificities of these compounds were characterized. ABC294640 is a SphK2 selective inhibitor (IC50 60μM), while ABC294735 (IC50SphK1 6μM, IC50SphK2 10μM) and SKI-II (IC50SphK1 2μM, IC50SphK2 1μM) are dual inhibitors in the presence of 10μM sphingosine as substrate. Lineweaver-Burk plots using the data from recombinant SphK1/2 active enzymes and kinase assay kit revealed ABC294640, ABC294735 and SKI-II were SphK competitive inhibitors. A possibly SphK1-selective inhibitor has also been identified by high-throughput screening and is currently being characterized.

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 838A.
Abstract 842: The detection of circulating tumor cells is a negative prognostic factor in colorectal cancer
Authors: Srovnal Josef , Vyslouzil Kamil , Jancik Sylwia , Drabek Jiri , Radova Lenka , Duda Miloslav , Skalicky Pavel , Klementa Ivo , Stary Lubomir , Cwiertka Karel , Straznicka Jana , Sramek Vlastimil , Melichar Bohuslav , Hajduch Marian
Published: February 2011

Purpose: We tested the hypothesis that the presence of circulating tumor cells (CTCs) is a negative prognostic factor in patients with stage I-III colorectal cancer (CRC).

Patients and methods: This was a prospective study to test for the presence of CTCs in peripheral blood and bone marrow in 182 colorectal cancer patients at the time of surgery and one month after surgery using real-time RT-PCR for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20).

Results: Overall, 24 of 147 (16.3%) stage I-III CRC patients developed recurrence/metastasis postoperatively in a mean follow-up period of 22.9 months. There was no correlation between CTCs and conventional clinical pathological features. In total, 51.7% of patients were CTC positive detected in peripheral blood and/or bone marrow at the time of surgery using CEA and/or CK20 and 47% of patients were CTC positive one month after surgery. At surgery, CTC positive patients measured as CEA mRNA copy number in peripheral blood showed significantly poorer disease-free survival (DFS) (p=0.05). One month after surgery, both increased above threshold CEA and/or CK20 mRNA levels in bone marrow and CK20 mRNA level in blood correlated with shorter DFS (p=0.005, resp. p=0.0035). In addition, systemic increase in CEA gene expression, even if the values remained below cut-off threshold also correlated with poorer DFS (p=0.005).

Conclusion: Detection of CTCs at surgery and/or one month after surgery is an independent negative prognostic factor for relapsing-free survival in stage I-III colorectal cancer.

Acknowledgments of research support: This study was supported by grants MSM 151100001, IGA MZCR NR/7804-5 and IGA MZCR NR/9076.

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 842.
Abstract 844: Tumor cell detection in autologous stem cell harvests in patients with high risk neuroblastoma
Authors: Stutterheim Janine , Vree Florentien M. , Zappeij-Kannegieter Lily , Caron Huib N. , van der Schoot C. Ellen , Tytgat Godelieve A.M.
Published: February 2011

Introduction

The presence of minimal residual disease (MRD) detected by real-time quantitative (RQ)-PCR in autologous stem cell harvests (ASCH) in children with high risk neuroblastoma (NBL) seems to be associated with an unfavourable outcome. However, to date only small studies have been performed, which suffered from lack of specificity of the assay due to background amplification in normal bone marrow (BM) and peripheral blood stem cells (PBSC). We previously developed a new panel of specific neuroblastoma RQ-PCR markers for MRD testing. The goal of this study was to determine the incidence of harvest contamination using this panel of markers and to investigate whether reinfusion of contaminated harvests was associated with poor outcome.

Methods

In this single center study, RQ-PCR was performed with six NBL-specific markers: homeobox2b (PHOX2B), tyrosine hydroxylase (TH), dopamine decarbohydroxylase (DDC), growth associated protein 43 (GAP43), cholinergic receptor3 (CHRNA3), and dopamine beta-hydroxylase (DBH) on 40 BM and 38 PBSC harvests of 70 high risk patients. The prognostic impact of MRD in reinfused autologous harvests (n=50) was assessed using Kaplan-Meier plots and log-rank tests.

Results

NBL mRNA was detected in 42% (18/40) of BM harvests and in 13% (5/38) of PBSC harvests of which in total 50 harvests were reinfused. In reinfused patients, 30% (15/50) received a MRD positive harvest, which was associated with poor outcome (5-y-OS 20±11.8 versus 62.3%±8.8;p=0.02). This association was more pronounced in patients reinfused with BM harvests than in patients reinfused with PBSC harvests, since more BM harvests were MRD positive. Remarkably, overall there was no difference in survival between patients reinfused with PBSC or BM harvest (p=0.7).

Conclusion

The presence of NBL mRNA in stem cell harvests, as reliably measured by a panel of NBL specific-PCR targets, is significantly associated with an unfavourable outcome. This could either mean that the amount of tumor cells reinfused in the graft influences relapse rate or that the stem cell graft reflects remission status.

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 844.
Abstract 856: Blood transfusions and the subsequent risk of hematologic malignancies
Authors: Chang Cindy M. , Quinlen Scott , Warren Joan , Engels Eric
Published: February 2011

Background: Blood transfusions are associated with viral transmission and immunomodulation, perhaps increasing subsequent risk of hematologic malignancies (HMs). Prior studies of transfusion recipients have lacked details on specific HM subtypes. Methods: We evaluated HM risk following blood transfusion in a U.S. population-based case-control study using cancer registry data (77,488 HM cases, 154,509 controls). Transfusions were identified using linked Medicare hospitalization claims. We used polytomous logistic regression to calculate odds ratios (ORs) for associations between transfusion and HM subtypes according to features suggestive of a causal relationship. Results: A history of transfusion was present in 7.9% of HM cases vs. 5.9% of controls. Associations were present for almost all HM subtypes but mostly appeared non-specific and suggested reverse causality: ORs were elevated only during the shortest latency periods; ORs for unspecified anemia and gastrointestinal bleeding, which may be related to undiagnosed HM, were stronger than for surgeries, which are unlikely to be related to HM; and/or there was no dose-response. In contrast, risk for lymphoplasmacytic lymphoma (1,397 cases) was elevated overall (OR 1.59, 95% CI 1.32-1.92), at long latency (OR 1.56 at 10+ years following transfusion), following transfusions for surgeries (ORs 1.22-1.47), and in a strong dose-response relationship with number of transfusion-related hospitalizations (OR=1.53 with 1 hospitalization; OR=1.80 with 2+ hospitalizations, p-trend<0.0001). Risk for marginal zone lymphoma (1,915 cases) was also elevated overall (OR 1.22, 95% CI 1.03-1.45) and at 10+ years following transfusion (OR 1.80). Discussion: Patterns of elevated risk for lymphoplasmacytic and marginal zone lymphomas suggest an etiologic role for transfusion. Both lymphoplasmacytic and marginal zone NHLs have previously been linked to infection with hepatitis C virus (HCV), a blood-borne virus, but HCV infection is too uncommon to explain the association that we observed. Other immunomodulatory effects of transfusion, including pro-inflammatory effects, may be responsible. Strengths of our study include the large number of subjects, population-based sampling of cases and controls, and detailed information on HM subtypes. The large number of cases with each HM subtype allowed us to assess subtype-specific associations with blood transfusions, particularly in terms of latency periods, medical diagnoses and procedures, and dose-response.

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 856.
Abstract 878: Comorbidities in African American and Hispanic/Latina Breast Cancer Patients are associated with IGF-1 and IGFBP3-3 Gene Polymorphisms
Authors: Sarkissyan Marianna , Mishra Dhruva , Wu Yanyuan , Shang Xiying , Sarkissyan Suren , Vadgama Jaydutt V.
Published: February 2011

Increase in comorbidities such as diabetes and hypertension in cancer patients lead to poor disease free survival and overall survival. It is probable that risk factors associated with these comorbidities and cancer itself could be linked to alterations in gene polymorphisms associated with hormones and/or growth factors. In this study, we have investigated if (1) comorbidities were associated with our African American and Hispanic breast cancer subjects; and (2) if there was any association between Insulin-Like Growth Factor 1 (IGF-1), and IGF Binding Protein 3 (IGFBP3) gene polymorphisms with breast cancer and comorbidities. We studied 514 subjects (175 African Americans and 339 Hispanic/Latinas), which included 208 cases and 306 controls (no evidence of breast cancer) subjects. DNA was extracted from blood samples and IGF-1 and IGFBP-3 genotyping was performed by PCR-GeneScan and PCR-RFLP methods, respectively. Our results demonstrated that comorbidity is significantly correlated with breast cancer (OR = 2.12; 95% CI = 1.40-3.21; P-value <0.01); especially the comorbidity of hypertension (OR= 2.27; 95% CI = 1.47-3.49; P-value <0.01). Furthermore, there was a significant association between non-19/non-19 IGF-1 (CA)n polymorphisms and breast cancer (OR= 4.80; 95% CI = 1.87, 12.36; P-value <0.01). This study also found a significant association between the non-19/non-19 IGF-1 (CA)n genotype, breast cancer, and comorbidity (OR= 4.65; 95% CI = 1.57, 13.82; P-value <0.01). In summary, our study demonstrated a significant association of IGF-1 polymorphisms and breast cancer with a further link to comorbid diseases.

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 878.
Abstract 88: Targeting Bcl-XL enhances arsenic-induced cell death in ovarian cancer cells
Authors: Tekedereli Ibrahim , Lopez-Berestein Gabriel , Ozpolat Bulent
Published: February 2011

Autophagy is an evolutionary conserved process in which long-lived proteins and damaged organelles are digested under physiological conditions including starvation. Autophagy has also been shown to act as a programmed cell death mechanism (type II PCD) and considered as caspase independent cell death. Several studies showed that autophagy has been triggered by anti-cancer treatments, such as chemo and hormonal therapy and radiotherapy and growth factor deprivation, function either as a protective survival pathway or cellular death mechanism.

Arsenic trioxide (ATO), which is a FDA approved drug and used as a treatment in acute promyelocytic leukemia, has been reported to induce autophagic and/or apoptotic cell death in leukemia, glioblastoma and also ovarian cancer cells, we have previously found that ATO induces autophagy in ovarian cancer cells. Here, we investigated the role of antiapoptotic protein Bcl-Xl, which inhibits autophagy by binding beclin-1, an essential autophagy promoting protein, in arsenic induced apoptosis and determined the effects of ATO/Bcl-XL RNA interference combination therapy in ovarian cancer. We found that ATO induces dose dependant growth inhibition in MTS proliferation assay. ATO treatment (2-4 uM) induced apoptosis in A2780 (40-50 %) and SKOV3 (20-25 %) cells, detected by annexin V staining and flow cytometric (FACS) analysis and by caspase 9 and PARP cleavage (Western blotting). ATO induced marked autophagy in A2780 (60-70 %) and in SKOV3 (15-20 %) as indicated by LC3-II, a marker for autophagy, formation autophagic vacuoles detected by acridine orange staining and FACS and by transmission electron microscopy. ATO induced Bcl-XL protein expression in ovarian cancer cells. We also found expression of high levels of Bcl-XL in all ovarian cancer cell lines including drug (i.e., cisplatin and paclitaxel) resistant cells. Inhibition of Bcl-XL expression by Bcl-XL siRNA induced growth inhibition (40-60 %), apoptosis (40-60 %) and autophagy (50-60% in A2780 and 15-25 % in SKOV3 ovarian cancer cell line). Furthermore, combination of ATO with Bcl-XL siRNA led to 90 % cell death and 70 % apoptosis in both A2780 and SKOV3 cells. Overall, our results suggest that combination of ATO and Bcl-XL induced predominantly apoptosis, although each of them induced autophagy. In conclusion we provided first evidence that inhibition of Bcl-XL induces autophagy in ovarian cancer cells and sensitizes them to ATO that may be a promising treatment regimen for ovarian cancer patients.

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 88.
Abstract 887: Long-term prognostic role of functional limitations among women with breast cancer
Authors: Braithwaite Dejana , Satariano William , Hiatt Robert A. , Slattery Martha , Caan Bette
Published: February 2011

Background: Functional limitations have been associated with poor survival among women with breast cancer within the first year of diagnosis. The long-term prognostic role of these difficulties in the completion of tasks of everyday life remains unknown. Methods: We studied a cohort of 2270 women diagnosed with breast cancer between 1997 and 2000, who provided information on functional limitations of body functions involving endurance, strength, muscular range of motion and small muscle dexterity at enrollment. The median follow up was 8.7 years (range 0-10 years). We investigated the association of functional limitations with survival from all causes, breast cancer and competing (non-breast cancer) causes in delayed entry Cox regression models. All statistical tests were two-sided. Results: Proportionately more patients with limitations were older, less educated and obese (p<.0001 for each) versus those without these difficulties. The age-adjusted hazard ratio for functional limitations as a 13-level variable of 1.08 (95%CI 1.05-1.14) suggests that there was an 8% increase in risk of death with each additional limitation. In multivariate models, functional limitations were associated with a statistically significant risk of death from all causes [hazard ratio (HR)=1.40, 95% confidence interval (CI) 1.03-1.92] and from competing causes (HR=2.60, 95%CI 1.69-3.98) but not breast cancer (HR=.90, 95%CI .64 −1.26). Conclusion: Women with breast cancer and functional limitations present after initial breast cancer treatment have a greater likelihood of dying of competing causes than breast cancer. Intervening to improve physical function among women with breast cancer may lead to improvements in life expectancy.

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 887.
Abstract 898: Glucose metabolism Gene Polymorphisms and Clinical Outcome in Pancreatic Cancer
Authors: Dong Xiaoqun , Tang Hongwei , Hess Kenneth R. , Abbruzzese James L. , Li Donghui
Published: February 2011

Background Altered glucose-metabolism is the most common metabolic hallmark of malignancies. The ‘Warburg effect’ (aerobic glycolysis, a persistently high rate of glucose conversion into lactate even under normoxic condition), is a distinctive metabolic characteristic of malignancies that distinguishes them from normal cells. Glucose-metabolism plays a crucial role in determining the cell fate (survival or death), has become a therapeutic target for cancer treatment. We explored weather glucose-metabolism gene variations correlate with clinical outcome in pancreatic cancer.

Methods We retrospectively genotyped 26 single nucleotide polymorphisms (SNPs) from 5 glucose-metabolism genes (Hexokinase 2,HK2; glucokinase, GCK; glutamine-fructose-6-phosphate transaminase, GFPT1; glucose phosphate isomerase, GPI; O-linked N-acetylglucosamine (GlcNAc) transferase, OGT) in 154 patients with localized disease enrolled in clinical trials of preoperative gemcitabine-based chemoradiation and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma recruited in a case-control study conducted at The University of Texas M. D. Anderson Cancer Center from February 1999 to May 2007, with follow-up to August 2009. Association between genotypes and overall survival (OS) or tumor characteristics was evaluated using multivariable Cox proportional hazard regression or logistic regression models with adjustment of clinical predictors. Findings GCK IVS1+9652C>T and HK2 N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P < 0.001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (Ps ≤ 0.001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (Ps ≤ 0.001). When data was further analyzed by disease stage, GFPT1 IVS14-3094T>C, HK2 N692N and R844K in patients with localized disease, and GCK IVS1+9652C>T in patients with advanced disease were significant independent predictors for OS (Ps ≤ 0.001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with a P value of 0.004 and 0.007. HK2 N692N CC, R844K GG genotype correlated with poorer tumor response to therapy, advanced tumor stage and lower rate of tumor resectability.

Interpretation We demonstrated that glucose-metabolism gene polymorphisms correlated with clinical outcome in pancreatic cancer. If confirmed, the genotype marker may be useful in identifying patients for glucose-metabolism-targeted 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 898.
Abstract 904: Obesity is an independent prognostic variable in colon cancer survivors
Authors: Sinicrope Frank A. , Foster Nathan R. , Sargent Daniel J. , O'Connell Michael J. , Rankin Cathyrn
Published: February 2011

Purpose: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) upon the prognosis of colon cancer survivors and its relationship to gender remains unknown.

Experimental Design: BMI (kg/m2) was categorized in patients with TNM stage II and III colon carcinomas (n= 4,381) enrolled in 7 randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Cox proportional hazards models were used to determine the association of BMI with disease-free (DFS) and overall survival (OS).

Results: Among colon cancer patients, 868 (20%) were obese (BMI >30 kg/m2) of which 606 were class 1 (BMI 30-34 kg/m2) and 262 were class 2,3 (BMI >35 kg/m2). Obese versus normal-weight patients were more likely to be younger (p=0.038), have distal tumors (0.058), show intact DNA mismatch repair (MMR) (p=0.035), and have more lymph node metastases (p=0.017). In a multivariate analysis, BMI was significantly associated with both DFS (p=0.030) and OS (p=0.0017). Men with class 2,3 obesity showed reduced OS compared to normal weight men [HR 1.35 (1.02, 1.79); p=0.039]. Women with class I obesity had reduced OS [HR 1.24 (1.01, 1.53), p=0.045] compared to normal weight women. Overweight status was associated with improved OS in men (p= 0.006) and underweight women had significantly worse OS (p= 0.019). BMI was not predictive of therapeutic benefit.

Conclusions: Obesity is an independent prognostic variable in colon cancer survivors and shows gender-related differences. These data suggest that obesity-related biological factors can influence clinical outcome.

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 904.
Abstract 91: Advanced computational algorithms for deep interrogation of microbial communities using pyrosequencing
Authors: Sun Yijun , Cai Yunpeng , Goodison Steven
Published: February 2011

The microbial community within the human gastrointestinal tract plays an important role in the balance of health and disease in the individual host. The advent of molecular techniques now facilitates the deep interrogation of the components of the gut microbiota, but the immense amount of data obtained requires the parallel development of advanced computational algorithms in order to maximize information extraction. In this study, we applied a novel computational strategy to analyze a microbial 16S rRNA sequence dataset consisting of more than one million sequences obtained from the fecal material of 154 individuals of known weight status. A large-scale taxonomy independent analysis revealed that collectively the human gut harbors more than 150,000 microbial species, at least one order magnitude larger than previously estimated. Furthermore, discriminant and topology analyses showed that despite the fact that each individual has diverse gut microbial compositions, there exist distinct microbial signatures associated with obese and lean physiological states. The analytic methods we developed for this study have never been used before in the interrogation of microbial communities. The combination of deep sequencing techniques with the computational approach described here will facilitate our understanding of the role the gut microbiota plays in health and disease and may lead to novel interventional strategies to prevent or ameliorate diseases of the gastrointestinal tract.

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 91.
Abstract 92: dbCPCO: The database of genetic predictive and prognostic factors in colorectal cancer
Authors: Savas Sevtap , Younghusband Ban
Published: February 2011

Introduction: Colorectal cancer is the third most common cancer in the North America with a 5-year survival rate of ∼65%. A portion of the inter-patient variability in disease outcome in colorectal cancer patients is attributed to inherited and somatic genetic factors. Identification of these genetic factors helps implementing personalized medicare to improve the chances of cure in patients. While numerous research articles have investigated the genetic basis of clinical outcome in colorectal cancer, there has not been a central resource, such as a public database, that compiles these findings in a systematic, comprehensive and concise way.

Here we describe the dbCPCO, a database of genetic factors investigated in relation to clinicopathological characteristics and clinical outcome (i.e. treatment response and toxicity, prognosis and survival) in colorectal cancer.

Methods: Literature reports were retrieved from PUBMED. The data that met the inclusion criteria were compiled in a relational database and posted in a dedicated website.

Results: The genetic factors included the inherited genetic polymorphisms, somatic and germline mutations in both nuclear and mitochondrial DNA. As of November 2009, the dbCPCO website posts 610 scientific findings on >300 polymorphisms, somatic and germline mutations from 146 genes tested for correlation with clinicopathological and/or clinical outcome in colorectal cancer.

Conclusion: The dbCPCO is a unique and comprehensive database that compiles literature findings on the genetic basis of disease phenotype and clinical outcome in colorectal cancer and will be instrumental in expediting personalized medicine and further research in this disease. The dbCPCO is updated periodically and is freely available for the scientific and medical community at http://www.med.mun.ca/cpco/Default.aspx.

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 92.
Abstract 922: Association of the hSRBC gene polymorphism with endometrial cancer
Authors: Tong Seo-yun , Lee Jong-Min , Lee Seon-Kyung , Han Hyeyeon , Kang Min-Ju , Chi Sung-Gil
Published: February 2011

Background: hSRBC is a putative tumor suppressor located at 11p15.4, at which frequent genomic loss has been observed in several human malignancies. We previously reported that hSRBC expression is frequently downregulated in many types of human cancers due to aberrant promoter CpG sites hypermethylation, and hSRBC activation induces cell cycle arrest and apoptosis by enhancing the protein stability of p53. Interestingly, our recent studies suggest that hSRBC might be a novel transcription target of TNFα, which plays a crucial role in inflammation and tumorigenesis. We explored the possible association of an intreaexonic SNP (T509C), which results in a Leu to Pro substitution, with risk for endometrial cancer development. Methods: TNFα regulation of hSRBC expression was examined using semi-quantitative RT-PCR and immunoblot assays. Endometrial tissues from 147 cancer patients and 191 healthy individuals were included for test for SNP T509C by restriction endonuclease PvuII-based genotyping. Allele frequencies in cancer specimens were compared with those in healthy controls. Results: Allelic frequencies of T and C at the T509C position was 30.27% and 69.73% in healthy control and 37.17% and 62.83% in cancer specimens, respectively. Allelic frequency at T509C in cancer specimens showed no significant difference compared to controls. However, genotype frequencies of TT, CT, and CC in healthy controls were 16.75%, 40.84%, and 42.412%, respectively, while cancer specimens displayed 14.97%, 30.61%, and 54.42%. The CC genotype frequency in cancer specimens was significantly higher (p < 0.05) compared with that in healthy controls. Conclusion: Although the number of specimens used in this study is not enough, this study raises the possibility that the T509C SNP of hSRBC, a putative novel transcription target of TNFα and proapoptotic tumor suppressor, might be associated with endometrial cancer development. Further genotype screening of several other SNPs within hSRBC in cancer patients would provide valuable diagnostic and prognostic information for human cancers.

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 922.
Abstract 935: Genetic variants in chromosome 6p21.3 and risk of non-Hodgkin lymphoma
Authors: Wang Sophia S. , Menashe Idan , Cerhan James R. , Rothman Nathaniel , Severson Richard K. , Davis Scott , Chanock Stephen J. , Bernstein Leslie , Hartge Patricia , Morton Lindsay
Published: February 2011

Background. Non-Hodgkin lymphoma (NHL) case-control studies consistently demonstrate the G-308A promoter polymorphism in the tumor necrosis factor gene on chromosome 6p21.3 to be associated with increased risk of the NHL subtype, diffuse large B-cell lymphoma (DLBCL). Initial results from a genome-wide association study have implicated a polymorphism located on 6p21.33 with increased risk of the follicular lymphoma subtype. In the present analysis, we evaluated 488 candidate gene regions (defined as 20kb 5’, 10kb 3’) and their relation to risk for NHL and the DLBCL and follicular lymphoma subtypes with a particular focus on genes within the 6p21 chromosomal region.

Methods. We genotyped 6679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S.-based case-control study. Genotyping was conducted on a custom-designed Illumina Infinium assay at the NCI Core Genotyping Facility. We obtained a gene region-level summary of association by computing the minimum p-value (“minP test”). We used logistic regression to evaluate the association between single nucleotide polymorphism (SNP) genotypes and haplotypes with NHL (adjusted for sex, race and age). For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression. We evaluated tests for trend under the co-dominant model used a three-level ordinal variable for each SNP.

Results. We identified 34 gene regions significantly associated with all NHL (p <0.05). The three most significant gene regions were all found on chromosome 6p21.3 (RING1/RXRB; AIF1/BAT2; BAT4, p=0.001). Within those gene regions, the most significant SNPs (p<0.0002) were rs2855429 and rs213213 (RING1/RXRB), rs2857597 and rs3130071 (AIF1/BAT2), and rs3115667 (BAT4). All five SNPs were statistically significantly associated with both DLBCL and follicular lymphoma. Additional gene regions on 6p21.3 associated with NHL include MSH5 (p=0.009), FAM46A (p=0.01) and TNXB/CREBL1 (p=0.04). Stratification by age and gender did not alter our results; consistent results were observed in analyses restricted to non-Hispanic Caucasians. Haplotype analyses yielded the same regions and SNPs of significance. Detailed analysis of the 6p21.3 region will be presented.

Conclusions. Our results further implicate gene variants within the 6p21.3 chromosomal region in NHL etiology. Full characterization of the 6p21.3 region and identification of functional variants within this region are warranted for understanding lymphomagenesis.

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 935.