bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 240: Transcriptional knockdown of urokinase-type plasminogen activator receptor (uPAR) induces apoptosis in glioblastoma xenograft cells via activation of p53
Authors: Chetty Chandramu , Ponnala Shivani , Veeravalli Krishna Kumar , Gujrati Meena , Dinh Dzung H. , Rao Jasti S.
Published: August 2012

Elevated levels of urokinase plasminogen activator receptor (uPAR), a glycoprotein tethered to the cell membrane with a glycosylphosphotidylinositol (GPI) anchor, is associated with tumor malignancy in a variety of cancers including glioblastoma (GBM). In this study, we show that inhibition of uPAR via RNA interference (puPAR-Si) induced p53-mediated massive cell death in human GBM xenograft cell lines, 4910 and 5310. Induction of Fas expression and cleavage of caspases-8, -9 and -3 and PARP (poly (ADP-ribose) polymerase) revealed induction of the extrinsic apoptotic pathway. Inhibition of Fas death receptor blocked puPAR-Si-induced apoptosis. Further, uPAR inhibition induced the expression of tumor suppressor p53 and its downstream target gene p21. Transcriptional knockdown of p53 rescued cells from apoptosis, thereby indicating that p53 was critical for induction of apoptosis. Moreover, puPAR-Si treatment inhibited pre-established tumor growth in an intracranial model. Indeed, histological analysis of tumor sections collected from mice that were treated with uPAR siRNA revealed increased immunoreactivity of phosphorylated p53, Fas, active caspase 3 and induction of programmed cell death. These data suggest a novel function of uPAR acting as a survival factor for GBM by downregulating p53; inhibition of uPAR induces a pro-apoptotic signaling pathway via p53. These findings may offer new treatment strategies for GBM.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 240. doi:1538-7445.AM2012-240
Abstract 2403: DNAJB6 suppresses the Wnt/β-catenin pathway
Authors: Mitra Aparna , Menezes Mitchell E. , Honkanen Richard E. , Shevde Lalita A. , Samant Rajeev S.
Published: August 2012

DNAJB6 is an HSP40 family protein which plays an important role in regulating tumorigenicity and metastasis of breast cancer and melanoma. Expression of DNAJB6 is found to be reduced in advanced stages of the disease. Restoration of its expression significantly decreases tumor growth and metastasis in xenograft studies. DNAJB6 expressing cells also show altered morphology, gain in epithelial markers and loss of mesenchymal markers and increased expression of DKK1, a secreted Wnt/β-catenin signaling. Our current studies elaborate the intricate mechanistic details about contributions of DNAJB6 to the negative regulation of the Wnt/β-catenin pathway. We describe the important role of the “J” domain of DNAJB6 in inhibiting Wnt/β-catenin. Deletion of “J” domain renders DNAJB6 incapable of impeding tumor growth and metastasis. Co-immunoprecipitation, mammalian-two-hybrid and FPLC studies show that DNAJB6 can form a multimeric complex with HSPA8 (HSC70), GSK3β and PP2A. DNAJB6 binds HSC70 and dephosphorylates GSK3β by recruiting PP2A. Activated GSK3β in-turn degrades β-catenin protein. Deletion of the J domain does not allow the formation of this multiprotein complex, which inactivates GSK3β and restores β-catenin levels. We further noted that the morphology of the cells grown in three dimensional matrix show distinct difference in WT-DNAJB6 and J-domain deleted expressors. In vivo and in vitro studies done with J domain deleted expressors showed increased malignancy. We also demonstrate the importance of J domain of DNAJB6 in suppressing osteopontin as one of the critical factors contributing to its reduced malignant activity in suppressing invasion and growth of xenografts. In summary, our studies unravel a novel mechanistic role of DNAJB6 in regulating GSK3β, a critical kinase which restricts tumor progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2403. doi:1538-7445.AM2012-2403
Abstract 2464: Novel MMP-3 generated PTHrP peptides promote osteoblast proliferation: Implications for prostate to bone metastases
Authors: Frieling Jeremy S. , Pamen Lizzie Atomi , Lynch Conor C.
Published: August 2012

Up to 90% of patients that succumb to prostate cancer will have evidence of bone metastasis. Prostate to bone metastases generate mixed lesions hallmarked by areas of extensive bone resorption and formation mediated by osteoclasts and osteoblasts respectively. Tumor derived PTHrP has been defined as a major molecule facilitating tumor-osteoblast interaction. Mature PTHrP is comprised of 36 amino-acids and new data from our lab has identified that MMP-3, one of several MMPs we have found highly expressed in the prostate cancer-bone microenvironment, can process PTHrP to yield novel distinct peptides. We posit that MMP-3 generated PTHrP peptides can have distinct biological effects on osteoblasts. Our results to date demonstrate that MMP-3 processes mature PTHrP to yield PTHrP1-16, PTHrP17-26, and PTHrP27-36 amino acid peptides in vitro as determined by N-terminal amino acid sequencing and MALDI-TOF analysis. Next, we determined the biological activity of the MMP-3 generated PTHrP peptides by treating osteoblast cell lines and examining differentiation and proliferation. We found using alizarin red staining that the MMP-3 generated PTHrP peptides did not impact osteoblast differentiation. However, analysis of cell proliferation, using an MTT assay, identified that the PTHrP1-16 peptide stimulated osteoblast proliferation over a 24-hour period. Follow-up studies revealed that the MMP-3 generated PTHrP1-16 fragment significantly enhanced phosphorylation of MAPK 42/44 and CREB, presumably via the PTHrP receptor, PTH1R. In conclusion, our data identify for the first time that PTHrP is an MMP substrate and that MMP-3 generated PTHrP peptide PTHrP1-16, can promote osteoblast proliferation. These findings suggest that MMP-3 expression in the prostate tumor microenvironment can potentially impact osteoblast expansion and may play a role in the generation of osteoblastic lesions that are commonly associated with prostate to bone metastases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2464. doi:1538-7445.AM2012-2464
Abstract 247: Aldose reductase inhibition sensitizes colon cancer cells to TRAIL-induced apoptosis
Authors: Ramana Kota V. , Shoeb Mohammad , Srivastava Satish K.
Published: August 2012

Sensitization of cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), particularly TRAIL-resistant cancer cells, could improve the effectiveness of TRAIL as a potential chemotherapy drug. Therefore, development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL should be an effective strategy to kill the chemotherapy resistance cancer cells. We have recently shown that inhibition of polyol pathway enzyme, aldose reductase (AR) that mediates NF-kB-dependent expression of inflammatory markers, prevents human colon cancer cell growth and metastasis in culture as well in nude mouse models. We now have investigated the role of AR in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. Our results demonstrate that inhibition of AR potentiates TRAIL-induced apoptosis in colon cancer cells (HT-29, HCT-116) by upregulation of both death receptor (DR)-5 and DR4. Specific siRNAs -mediated knockdown of DR5 and DR4 significantly (>85%) reduced the sensitizing effect of AR inhibition by pharmacological agent, fidarestat, on TRAIL-induced apoptosis. AR inhibition also down-regulated TRAIL-induced cell survival proteins such as Bcl-xL, Bcl-2, survivin, XIAP, and cFLIP, and up-regulated the expression of pro-apoptotic proteins such as Bax. Further, AR inhibition also altered the mitochondrial membrane potential leading to cytochrome c release, caspases-3 activation and PARP cleavage. Furthermore, our results indicate that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO3a. Knockdown of FOXO3a significantly (>80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that AR inhibition potentiates TRAIL-induced apoptosis through down-regulation of cell survival proteins and upregulation of death receptors and thus AR inhibitors along with TRAIL could be effective therapy for the treatment of colon cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 247. doi:1538-7445.AM2012-247
Abstract 2483: Inhibition of the polycomb group gene EZH2 suppresses growth and radiosensitizes ATRT cells by promoting senescence and inhibiting the CycinD-E2F1 axis
Authors: Alimova Irina N. , Venkataraman Sujatha , Harris Peter , Marquez Victor E. , Birks Diane , Foreman Nicholas K. , Vibhakar Rajeev
Published: August 2012

Overexpression of the polycomb group gene Enhancer of Zeste 2 (EZH2) occurs in many tumors including prostate cancer, breast cancer and brain tumors such as Glioblastoma multiform and Medulloblastoma. Recent evidence suggests it may also have a role in rhabdoid tumors. Atypical teratoid rhabdoid tumor (ATRT) is a rare high-grade brain tumor with very poor survival that occurs most commonly in children. AT/RT tumors are characterized by deletion of the chromatin associated protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes we chose to investigate the role of EZH2 in AT/RT. Here we show that targeted disruption of EZH2 by RNAi or pharmacologic means strongly impairs ATRT cell growth, induces apoptosis and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity we found the Cyclin D-E2F1 axis to be repressed upon EZH2 depletion in ATRT cells. Taken together our observations provide evidence that EZH2 regulates cell cycle progression by targeting the G1-S transition machinery and may be an important new therapeutic target particularly in combination with radiation in ATRT.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2483. doi:1538-7445.AM2012-2483
Abstract 2498: Differential rapamycin sensitivity distinguishes two distinct populations of tumor cells in murine glioma
Authors: Kaul Aparna , Solga Anne , Lee Da Yong , Gianino Scott M. , Gutmann David H.
Published: August 2012

Solid tumors are complex ecosystems, composed of a heterogeneous ensemble of cells that comprise the tumor mass (neoplastic compartment) and the surrounding stroma (non-neoplastic compartment). Currently, research efforts are aimed at defining the individual contributions of each cell type to tumor development and maintenance. Previous studies using a genetically-engineered mouse model of Neurofibromatosis type 1 (NF1)-associated optic glioma have underscored the critical role of one stromal cell type (microglia) in the growth of these tumors. In the current study, we analyze neoplastic cell heterogeneity and demonstrate that two distinct proliferating populations of neoplastic cells exist in the tumor. These distinct cell types, neuroglial progenitors and differentiated astrocytes, are distinguished by their sensitivity to rapamycin. The molecular basis for this differential sensitivity to rapamycin reflects dramatic differences in mammalian target of rapamycin (mTOR) complex protein expression and basal mTOR activation. We leverage this cell type-specific sensitivity to target neuroglial progenitor cells in the tumor and inhibit optic glioma formation in vivo. Collectively, these findings emphasize the importance of cellular diversity in glioma formation and growth, and highlight the importance of developing novel treatment strategies that co-target multiple cell populations for maximal therapeutic benefit.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2498. doi:1538-7445.AM2012-2498
Abstract 2505: Targeting the p53 response in pediatric B-cell acute lymphoblastic leukemia
Authors: Wolak Kathryn E. , Skol Andrew , Bainer Russell , Onel Kenan
Published: August 2012

B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. Despite a cure rate of approximately 85%, the prevalence of this disease causes B-ALL to be the leading cause of cancer-related death in children. Additionally, the toxic drugs necessary for cures can cause severe side effects in developing children. Thus, there is a tremendous need for innovative therapies to combat B-ALL. The p53 tumor suppressor is a key regulator of apoptosis and is almost always wild-type in pediatric B-ALL, in stark contrast to virtually all other cancers. Alterations in the p53 pathway are associated with drug resistance, underscoring its central role in determining response to chemotherapy. We identified a set of p53-regulated transcriptional targets that comprise an apoptotic gene signature significantly associated with response to therapy and independently prognostic for outcome in pediatric ALL. We hypothesize that cells can be primed for an enhanced apoptotic response to chemotherapy by modulating expression levels of the p53-regulated apoptotic signature genes with small molecules before administering chemotherapy. We conducted a high-throughput screen to identify novel compounds that prime ALL cells for apoptosis to convert a chemotherapy-resistant cell into one that is sensitive. This screen was performed using 83,745 compounds in both the wild-type p53 cell line TK6 and the mutant-p53 line, WTK1. Cells were treated with either compound alone or compound plus daunorubicin, a drug used to treat ALL. Compounds were normalized and scored by using both the B-score and the robust Z-score. “Hits” were defined as compounds that do not significantly alter viability of the cells alone, but significantly increase daunorubicin-induced cell death. As our primary screen takes a functional approach with an endpoint of viability rather than expression of our gene signature, it's possible that compounds we have identified function through alternative mechanisms. As our secondary screen, we interrogate these hits for induction of the signature. Because patient outcome was associated with the gene signature, we hypothesize that the most successful compounds will act by altering the signature from the “bad risk” expression to the “good risk” expression, thereby having the potential to convert a chemoresistant cell into one that is sensitive.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2505. doi:1538-7445.AM2012-2505
Abstract 2516: Immunohistochemical characterization of a novel, highly sensitive monoclonal antibody to folate receptor α
Authors: O'Shannessy Daniel J. , Somers Elizabeth B. , Fu Yao-Shi , Smale Robert , Thiel Robert P. , Nicolaides Nicholas C.
Published: August 2012

Background: Folate receptor ≤ (FRα) has restricted expression in normal tissues but high-level expression in a subset of epithelial-derived tumors, including non-mucinous ovarian carcinomas and non-small cell lung (NSCL) adenocarcinomas. FRα has shown significant potential for targeted cancer therapy and several promising agents are in late-stage clinical development. As such, robust reagents are needed that can be used across diverse diagnostic platforms to identify patients who have FRα-expressing tumors. The immunohistochemical (IHC) characterization of a novel, high-affinity monoclonal antibody (MAb) against FRα is described. Methods: MAbs were generated to modified full-length FRα protein using standard methods. One MAb, 26B3.F2, displayed high affinity and the ability to bind FRα on both fresh/frozen and formalin-fixed, paraffin-embedded tissue sections. An optimized IHC protocol was developed and FRα expression was assessed on commercial tissue microarrays (US Biomax). Data were analyzed using an M-score, a newly introduced, weighted-intensity score that incorporates both the proportion of FRα-positive cells and the staining intensity. A board-certified pathologist scored the level of FRα expression. Results: Normal tissue staining for MAb 26B3.F2 demonstrated a limited distribution on focal epithelial surfaces of pancreas, lung, salivary gland, kidney, hypophysis, thyroid, and breast samples. Staining was mainly located in the lumen. The tissue distribution is consistent with the published literature. Strong staining was observed in 100% of serous ovarian samples and a significant proportion of ovarian endometrioid adenocarcinoma samples. FRα expression, as determined by MAb 26B3.F2 in NSCL cancer samples, demonstrated high discrimination between adenocarcinoma (positive) and squamous cell carcinomas (negative) (P < 0.001). Conclusion: MAb 26B3.F2 is a highly sensitive, robust agent suitable for identifying FRα expression by IHC and other diagnostic platforms. In addition to the expected distribution in normal tissue, MAb 26B3.F2 revealed high-level expression of FRα in ovarian cancer and NSCL adenocarcinoma samples, and the ability to discriminate differential expression between two NSCL cancer subtypes, squamous cell carcinoma and adenocarcinoma. Preliminary evidence therefore suggests that MAb 26B3.F2 IHC will be a useful tool to support further development of FRα-targeted therapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2516. doi:1538-7445.AM2012-2516
Abstract 2517: Potent antitumor activity of AbGn-ADC, a humanized monoclonal antibody conjugated with dolastatin analogue, to gastric and pancreatic cancers expressing AbGn carbohydrate epitope
Authors: Huang Chiu-Chen , Hsieh Yu-Chi , Tsai Yu-Ying , Lee Shu-Hua , Chiang Evelyn , Liu Meng-Ru , Lin Shih-Yao
Published: August 2012

AbGn is a glycotope-specific humanized monoclonal antibody recognizing Lewisa- like carbohydrate expressed in gastric and pancreatic cancer cells. While AbGn binding to normal tissues is restricted to only luminal surface of the epithelium in gastro-intestinal track and secretory glands, about 50% of gastric and pancreatic cancer samples tested express AbGn epitope and can be recognized by AbGn antibody. FACS analysis and confocal microscopic studies demonstrated extensive internalization of AbGn after binding to the cell surface. The internalized AbGn co-localized with lysosomal marker LAMP1, suggesting that AbGn-mediated internalization followed the lysosomal pathway. A novel antibody-drug conjugate (AbGn-ADC) was generated by linking AbGn to a dolastatin analogue, a potent inhibitor of microtubulin polymerization, through a dipeptide-based cleavable linker. This AbGn-ADC was evaluated for antitumor activity in vitro and in mouse xenograft models. AbGn-ADC eliminated cancer cell lines with nanomolar potency in vitro. No cell death could be detected in SW480 cells, a gastric cell line with no AbGn epitope expression, suggesting high selectivity of AbGn-ADC. When used to treat mice with established human gastric (SNU-16) or pancreatic (Panc.02.03B) cancer xenografts, AbGn-ADC significantly reduced the size of the established tumors (p<0.01). No body weight loss or signs of toxicity was observed in AbGn-ADC treated mice. These findings support the potential of further development of AbGn-ADC for treating gastric and pancreatic cancers. Data from pre-clinical AbGn-ADC tolerability study in relevant non-human primate will be presented.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2517. doi:1538-7445.AM2012-2517
Abstract 2611: Role of circadian genes in breast cancer: Analysis of the CECILE study, a population-based case-control study conducted in France
Authors: Truong Therese , Menegaux Florence , Richardson Sylvia , Guénel Pascal
Published: August 2012

Breast cancer risk has been associated with shift work and light exposure at night. It has been suggested that disruption of circadian rhythms induced by these exposure may play a role in tumorigenesis. Circadian rhythms regulate diverse physiologic processes, including regulation of sex hormone levels, and genes controlling the circadian rhythm were found to regulate cell proliferation, cell cycle regulation and apoptosis. However, only few studies have investigated the role of these genes in breast cancer. The purpose of this study was to analyze the association between polymorphisms in circadian genes and breast cancer risk. The CECILE study is a population-based case-control study on environmental and genetic factors. A total of 1135 incident cases and 1167 controls provided DNA samples. We genotyped 570 tagging and functional SNPs from the 22 genes in the circadian rhythm pathway defined by KEGG. Preliminary results based on a SNP by SNP analysis using unconditional logistic regression highlighted 36 SNPs with p-value<0.05 in RORA, CUL1, NPAS2, CRY1, CRY2 and CLOCK genes. Of these, 3 SNPs in RORA were significantly associated with breast cancer after Bonferroni correction for multiple testing (p<0.0001). In ongoing analyses, we use the Multilevel Inference for SNP Association (MISA) method, which is a more powerful method that allows estimating associations at the SNP, gene and pathway level. These analyses will be presented. Our results suggest a role of the circadian gene in breast cancer risk. Further analysis on possible interaction between shift work and genetic variants highlighted in this study in relation to breast cancer risk will be conducted in the CECILE study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2611. doi:1538-7445.AM2012-2611
Abstract 2614: Distinguished features of ERG oncoprotein expression among matched cohorts of African-American and Caucasian-American prostate cancer patients
Authors: Dobi Albert L. , Rosen Philip , Pfister David , Young Denise , Chen Yongmei , Petrovics Gyorgy , McLeod David , Srivastava Shiv , Sesterhenn Isabell
Published: August 2012

Introduction and Objective: The ETS-related gene (ERG) proto-oncogene is frequently overexpressed in prostate cancer (CaP) as a result of a genomic rearrangement that places ERG under the control of the androgen-dependent TMPRSS2 promoter. The initial report of quantitative ERG mRNA expression in micro-dissected prostate tumor cells showed significantly higher ERG expression in CaP of Caucasian-Americans (CA) patients vs. African-American (AA) patients (Petrovics et al, Oncogene, 2005). Recent studies (Magi-Galluzzi et al, Prostate, 2011; Elliott et al, USCAP Mtg., 2011) have also shown higher frequency of ERG rearrangement or ERG oncoprotein expression in CaP of CA patients. We evaluate the frequency and pattern of the ERG oncoprotein expression in prostate tumors of matched CA and AA CaP patients to better understand the biological basis for differences in prostate cancer between the two populations. Methods: Ninety one AA and 91 CA CaP patients were matched for age, Gleason score and pathologic stage. All underwent radical prostatectomy between 1993 and 2010. Whole mount prostate specimens were used for the immunohistochemical detection of the ERG oncoprotein by a highly specific ERG monoclonal antibody (clone 9FY). Individual foci of tumors were reported as either positive or negative. ERG staining data was linked to clinico-pathologic data. Biochemical recurrence was defined as two serum PSA measurements of 0.2 ng/mL or higher at least 8 weeks from surgery. Results: A higher percentage of CA (61.8%) than AA (28.2%) CaP patients had ERG positive index tumors and had at least one focus of tumor positive for ERG. A higher percentage of overall tumor foci were also positive for ERG in CA than AA CaP patients. There was high concordance of ERG positive prostatic intra-epitheilal neoplasia (PIN) and ERG positive CaP in both AA and CA patients. Conclusions: ERG expression is more prevalent among CA than AA CaP patients in matched cohorts. Differences in the pattern of ERG expression in CaP and differing trends in biochemical recurrence between CA and AA patients with ERG (+) index tumors suggest a dominant clonal selection of ERG-positive tumors in CA patients. These differences in ERG expression have the potential to delineate biological distinctions of CaP in the two patient populations. Acknowledgement: This study was supported in part by USU-CPDR and NIH grant CA162383 to SS.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2614. doi:1538-7445.AM2012-2614
Abstract 2617: Cytokine and cytokine receptors of adaptive immune response are differentially associated with breast cancer risk in women of African ancestry and European ancestry
Authors: Quan Lei , Yao Song , Gong Zhihong , Bandera Elisa V. , Hwang Helena , Roberts Michelle , Zirpoli Gary , Ciupak Gregory , Davis Warren , Sucheston Lara , Pawlish Karen , Bovbjerg Dana , Jandorf Lina , Ambrosone Christine B. , Hong Chi-Chen
Published: August 2012

Disparities in breast cancer biology are evident between women of African ancestry (AA) and women of European ancestry (EA), and may be due, in part, to differences in inflammatory pathway genes. Studies on the relationships between cytokines and breast cancer risk have focused on a small number of genes and have not included AA women. In a large case-control study of 1008 AA (n=547 cases) and 763 EA (n=381 cases) women, we systematically tested the association between risk of breast cancer and single-nucleotide polymorphisms (SNPs) in 22 cytokine and cytokine receptor genes involved in adaptive immune response pathways. Logistic regression was used to estimate odds ratios and 95% confidence intervals in a genotypic (co-dominant) model adjusting for major breast cancer risk factors including age, education, body mass index (BMI), family history of breast cancer and proportion of European ancestry. All analyses were stratified on race. SNPs rs17810546 in IL12A (interleukin 12A), rs1041981 in LTA (lymphotoxin alpha), and rs3135932 in IL10RA, were associated with breast cancer risk in AA but not EA women. When stratifying by menopause and ER status, SNPs rs2070874 in IL4, rs1041981 in LTA and rs2430561 in IFNG (interferon gamma) were associated with breast cancer risk in pre-menopausal AA women, and SNPs rs2243248 in IL4 and rs746868 in LTA were associated with ER-negative breast cancer in EA women. Common variants in inflammatory pathway genes may help to define populations at high risk of breast cancer. Notable differences in distributions of SNPs and associations by ancestry may be related to the differential epidemiology of breast cancer in AA and EA women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2617. doi:1538-7445.AM2012-2617
Abstract 2622: SNP markers in the FGF9 and MAP3K1 region associate with testicular germ cell tumor susceptibility
Authors: Koster Roelof , Kanetsky Peter A. , Mitra Nandita , Vardhanabhuti Saran , Ciosek Stephanie L. , Letrero Richard , D'Andrea Kurt , Doody David R. , Chen Chu , Vaughn David J. , Schwartz Stephen M. , Nathanson Katherine L.
Published: August 2012

Testicular germ cell tumors (TGCT) are the most common cancers in young men, and several lines of evidence point to their substantial genetic component. To date, genome-wide association (GWA) studies have uncovered six TGCT susceptibility loci. Together these loci account for 11-16% of TGCT disease risk to first degree relatives, arguing that additional genetic variation contributing to TGCT susceptibility must exist. Recently we and others indentified variation at DMRT1 associated with TGCT risk. DMRT1 is highly conserved across many species and plays a crucial role in male gonadal development and sex determination. Deletions in DMRT1 lead to male to female (XY) sex reversal. Therefore, we undertook a targeted pathway-based analysis of genes influencing XY sex reversal to identify associations with TGCT risk. Through review of the literature, we identified 27 additional genes in which mutations or deletions are associated with XY sex reversal. Using our existing GWA data in 349 cases and 919 controls, ∼570 risk markers in the 28 candidate loci were evaluated for replication based on a significance threshold of p < 2 x 10−5 for at least two SNP markers. Two markers that mapped near to MAP3K1 and FGF9 meet these criteria. We genotyped the most statistically significant SNP markers in the MAP3K1 (rs252906; p = 1.89 x 10Δ5) and FGF9 (rs628137; p = 1.66 x 10Δ5) region in two independent replication sample sets, consisting of 439 cases of TGCT and 960 controls and of 768 cases and 674 controls respectively. In combined analysis, TGCT cases had elevated odds of carriage of the rs252906 major T allele [per-allele odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16, 1.377; P = 5.87 × 10−5] and the rs628137 major G allele (per allele OR = 1.20, 95% CI 1.08, 1.34, P = 5.28 x 10−4 compared with controls. Similarly to KITLG, the susceptibility locus most strongly associated with TGCT risk, FGF9 is associated with proliferation, migration and survival of primordial germ cells, the progenitor cells for human TGCT. MAP3K1 and FGF9 play a crucial role in normal testes development. These finding strengthen the supposition that variation in genes influencing sex determination, and male germ cell development and differentiation play an important role in inherited TGCT susceptibility.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2622. doi:1538-7445.AM2012-2622
Abstract 2623: The role of polymorphisms in DNA repair genes and HPV 16 integration status in cervical dysplasia
Authors: Amirian E. Susan , Marquez-Do Deborah , Adler-Storthz Karen , Follen Michele , Scheurer Michael E.
Published: August 2012

BACKGROUND: Cervical cancer is the second leading cause of death in women worldwide, and yet, little is understood about why some HPV-infected women develop cancerous lesions while others are able to clear the infection with no sequelae. Previous evidence has indicated that HPV integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process has been understudied. The purpose of this study was to examine the association between both HPV 16 viral integration status and single nucleotide polymorphisms (SNPs) in non-homologous end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia, comparing women with no dysplasia to those with low-grade or high-grade squamous intraepithelial lesions. METHODS: A total of 765 women were selected from two large trials designed to evaluate optical technologies for cervical cancer, being conducted at MD Anderson Cancer Center, Lyndon B Johnson General Hospital, and the British Columbia Cancer Agency. Genotyping was conducted using the Illumina Golden Gate platform; individuals with call rates <85% were excluded from the analyses. HPV integration status was determined using an assay described in the literature. Chi-square and Fisher's exact tests were conducted to determine which SNPs were significantly associated with normal cytology, low-grade, or high-grade lesions. Among participants with cervical dysplasia, chi-square tests and polytomous logistic regression models were used to evaluate the effect of each polymorphism on viral integration status. We used an additive genetic model for all tests. P-values were adjusted using the false discovery rate method and FDR-adjusted q values are reported. RESULTS: Women with high-grade lesions were significantly younger than women with low-grade or no lesions. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC5, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV 16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV 16 integration status. CONCLUSION: Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression. This is the first time that host genetic variation has been linked to the viral integration event.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2623. doi:1538-7445.AM2012-2623
Abstract 2624: Evaluation of the association of the ABO blood group SNP rs505922 with breast cancer phenotypes
Authors: Rummel Seth K. , Ellsworth Rachel E. , Shriver Craig D.
Published: August 2012

Purpose: To date, evaluation of the association of the ABO blood group and breast cancer has yielded mixed results. SNP rs505922, located within the first intron of the ABO gene, has been associated with the adenocarcinoma subtype of pancreatic cancer. To determine whether the ABO blood group is associated with risk of breast cancer, rs505922 was genotyped in 629 Caucasian women with invasive breast cancer, representing a variety of clinical and pathological tumor types. Methods: Genomic DNA was isolated from blood clots. TaqMan SNP assay C_2253769_10 was used to determine the genotypes for rs505922. Statistical analysis was performed using chi-square analysis using a P-value <0.05 to define significance. Results: Genotypes were generated for 100% of the 629 patients in this study. Allele and genotype frequencies did not vary significantly for age at diagnosis, tumor stage, size or grade, hormone, HER2 or lymph node status, intrinsic subtype, tumor type or patient outcome. Conclusions: Allele frequencies for rs505922 did not differ between women with breast cancer and published HapMap frequencies. Further stratification into different tumor phenotypes also failed to reveal an association between rs505922 and any tumor characteristics. Together, these data suggest that the minor allele of rs505922 and the resulting non-O blood types, are not associated with increased risk or less favorable tumor characteristics or prognosis in breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2624. doi:1538-7445.AM2012-2624
Abstract 2627: Polymorphisms of retinol transporter genes and risk of head and neck cancer
Authors: Chang Jeffrey S. , Hsiao Jenn-Ren , Wong Tung-Yiu , Tsai Sen-Tien , Ou Chun-Yen , Lo Hung-I , Huang Cheng-Chih , Lee Wei-Ting , Chen Ken-Chung , Huang Jehn-Shyun , Wang Yi-Hui , Weng Ya-Ling , Yang Han-Chien
Published: August 2012

Background: Retinoic acid is important for cell growth, differentiation, and apoptosis, which when dysregulated may predispose the development of cancer. Retinoic acid metabolism can be influenced by ethanol, cigarette smoking, and areca nut, the three major risk factors of head and neck cancer (HNC). A previous genome-wide association study reported an association between serum retinol level and two single nucleotide polymorphisms (SNPs) in two retinol transporter genes (TTR rs1667255 and RBP4 rs10882272) (1). The current study assesses the association between these two SNPs and HNC risk. Methods: 133 incident cases of HNC and 128 sex- and age- matched controls were recruited from the department of otolaryngology and department of stomatology. Data on the use of alcohol, cigarette, and areca nut were ascertained through in-person interview. Genotyping of TTR rs1667255 and RBP4 rs10882272 was performed using the Taqman-based real-time PCR method. Unconditional logistic regression was performed to estimate HNC risk associated with the two SNPs. Results: No association between HNC risk and TTR rs1667255 or RBP4 rs10882272 was observed. However, the two SNPs appeared to modify the relationship between alcohol consumption and HNC risk. There was an increased risk of HNC associated with daily alcohol drinking only among subjects with the “high serum retinol genotypes” (CC for TTR rs1667255: odds ratio (OR) = 4.6, 95 confidence interval (CI): 1.3-16.3; TT for RBP4 rs10882272: OR = 2.3, 95% CI: 1.2-4.4). While daily alcohol drinking was not associated with an increased risk of HNC among subjects with the “low serum retinol genotypes” (AA or AC for TTR rs1667255: OR = 1.4, 95% CI: 0.7-2.9; TC or CC for RBP4: OR = 0.7, 95% CI: 0.1-3.6). Conclusion: The association between alcohol consumption and HNC risk is modified by the polymorphisms of retinol transporter genes. Reference: 1. Mondul AM, Yu K, Wheeler W, et al. Genome-wide association study of circulating retinol levels. Human molecular genetics 2011;20:4724-31.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2627. doi:1538-7445.AM2012-2627
Abstract 2716: Development of tanapox virus for oncolytic therapy
Authors: Seibert Krystal N. , Essani Karim , Bejcek Bruce E.
Published: August 2012

Vaccinia virus has been included in the many viruses that have been used to target cancer cells. However, vaccinia virus has some drawbacks in that it infects both tumor and non-tumor cells (Guo, Z. S. etal. 2005 Cancer Research 65: 9991-9998), and hosts often have a pre-existing immunity to it (Hu, Y. etal. 2001 J. Virol. 75, 10300-10308). Due to these drawbacks with vaccinia virus we are developing a poxvirus family member, tanapox virus (TPV), for use as an oncolytic therapy. TPV does not cross-react with vaccinia virus antibodies, replicates in human cells, and results in a relatively mild infection under normal conditions making it safer to work with (Paulose, M. etal. 1998 Microbial Pathogenesis 25, 33-41). Tumor suppressor protein p53 is mutated in over half of all cancers making it a promising target for virotherapy. In this study we characterized the 142R protein of TPV, demonstrating its potential as a conditionally replicating oncolytic virus. By analyzing the sequence of 142R it was determined that the protein has a serine-threonine kinase domain that is homologous to the vaccinia virus B1R gene that has been shown to phosphorylate p53. Viral tropism towards cancer can be enhanced by engineering the virus to be conditionally replicating (Vähä-Koskela, M. J. V. etal. 2007 Cancer Letters 254, 178-216), such as the adenovirus ONYX-015 in which the E1B gene has been deleted, restricting its replication to cells not containing a wild-type p53. When comparing the sequence of 142R to B1R we showed that 142R had 50% identity to B1R. 142R also has the same nucleotide binding, phosphotransfer and proton transfer, ATP binding and catalytic domain indicator regions as B1R. We then created a plasmid with 142R that was transfected into COS-7 cells, harvested and the protein eluted from a cobalt column. This protein was then used in a protein kinase assay against p53. This indicates that the 142R protein of TPV is capable of interacting with p53 so is a good candidate for creating a conditionally replicating virus.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2716. doi:1538-7445.AM2012-2716
Abstract 2719: MM-141, a novel bispecific antibody co-targeting IGF-1R and ErbB3, blocks ligand-induced signaling and demonstrates antitumor activity
Authors: Baum Jason , Johnson Bryan , Adams Sharlene , Tang Jian , Kohli Neeraj , Rennard Rachel , Sundararajan Pragalath , Xu Lihui , Jiao Yang , Schoeberl Birgit , Nielsen Ulrik , Fitzgerald Jonathan , Lugovskoy Alexey
Published: August 2012

Monoclonal antibodies have significantly advanced our ability to treat cancer, but most patients do not show durable responses to therapy. This, in part, can be explained by the tumor cells responding to two or more growth factors in a redundant fashion. We show that cancer cell lines frequently rely on Insulin-like growth factor 1 (IGF-1) and Heregulin (HRG) signaling to support their survival and proliferation. Using a Network Biology approach, we have designed, constructed and optimized a novel bispecific antibody, MM-141, for co-targeting of ErbB3 and IGF-1R. MM-141 blocks IGF-1, IGF-2, and HRG binding to IGF1R and ErbB3, and causes downregulation of these receptors. MM-141 inhibits phosphorylation of IGF1R and ErbB3 as well as downstream activation of the PI3K/Akt pathway. In our in vitro and in vivo testing, MM-141 displays potency in the presence of single or multiple ligands, over a broad range of receptor profiles. Inhibition of growth by MM-141 has been observed in vitro as well as in vivo in multiple xenograft models including human pancreatic cancer (BxPC-3) and human prostate cancer (DU145). MM-141 does not bind the insulin receptor, thus reducing the risk of metabolic side effects. Our in vivo and in vitro studies reveal that MM-141 has favorable pharmaceutical properties and pharmacokinetic profiles. We are advancing MM-141 into preclinical development. Taken together, these results suggest that MM-141 has the potential to be an effective therapeutic for treatment of patients with solid tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2719. doi:1538-7445.AM2012-2719
Abstract 2801: Dual Targeting Glioblastoma Multiforme (GBM) with a Phosphatidylinositol 3-kinase inhibitor (ZSTK474) and a Proteasome Inhibitor (Velcade)
Authors: Yin Dong , Gaut Daria , Ho Quoc H. , Koeffler H. Phillip
Published: August 2012

Proteasome inhibitor has been proven to be an effective anticancer compound in many tumor models, including Glioblastoma multiforme (GBM). In this study, we found that the proteasome inhibitor Velcade (PS-341/bortezomib) activated the PI3K/Akt pathway although causing GBM cells death. Therefore, we sought to investigate if the PI3K inhibitor, ZSTK474, would enhance the effectiveness of PS-341 in anticancer therapy. Three GBM cells lines (U87, U251, U138) were exposed to Velcade (10-7 M, 24 hr). We found that phosphorylation of Akt, 4E binding protein-1 (4EBP1), and mammalian target of rapamycin (mTOR) was induced by Valcade in these GBM cells compared to the controls. To study the role of the PI3K/Akt signal pathway in the Velcade induced growth arrest in GBM cells, this pathway was blocked using the PI3K inhibitor ZSTK474. These three cell lines were treated with serial dilutions of either Velcade or ZSTK474 or both drugs together, and MTT [3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide] assay results showed that combination of ZSTK474 and Velcade synergistically inhibited proliferation of GBM cell lines. In the presence of ZSTK474, the phosphorylation of Akt, 4EBP1, and mTOR was markedly decreased in all cell lines. Cells apoptosis was increased when exposed to Velcade and ZSTK474 in combination as shown by Annexin V analysis. To confirm the decrease of p-4EBP1 in the presence of both drugs, the unphosphorylated binding protein 4EBP1 was also detected. In all cell lines in the presence of Velcade and ZSTK474, 4EBP1 becoming unphosphorylated. Cyclin D1, another protein promoting proliferation in the PI3K/Akt pathway, was up-regulated in the presence of Velcade alone, but down-regulated in the presence of both Valcade and ZSTK474 together. In summary, the anticancer ability of Valcade is increased by combination with PI3K pathway inhibitor ZSTK474 in glioblastoma multiforme.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2801. doi:1538-7445.AM2012-2801