bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3989: High throughput screening highlights NFkB signaling in Ewing sarcoma
Authors: Surdez Didier , Stoll Gautier , Tirode Franck , Laud Karine , Barillot Emmanuel , Delattre Olivier
Published: May 2015

Ewing sarcoma (ES) is the second most frequent pediatric bone tumor and still remains of poor prognosis especially for metastatic patients. Genetically, ES is characterized by a chromosomal translocation between EWSR1 and ETS family members (FLI1 in 85% of cases). This leads to the expression of EWS-FLI1 chimeric oncogene transcription factor. Aiming at identifying EWS-FLI1 regulated genes with potential therapeutic targets, a genome wide method was developed to rank these potential hits by combining Ewing sarcoma transcriptome and ChIPSeq data. Accordingly, 273 selected genes were further investigated using a siRNA approach for their impact on cell cycle phases and apoptosis using high throughput imaging methods. 133 of these genes displayed a phenotype and bioinformatics tools were used to connect these genes. NFkB turned out to be a major hub in this network and upstream activation pathways were further investigated. Interleukin-1 pathway may account for this observed effect and in vitro and in vivo experiments are currently on going to validate this hypothesis. Interestingly, preliminary results indicate that both tumor and tumor microenvironment are of prime importance for the activation of this pathway.

Citation Format: Didier Surdez, Gautier Stoll, Franck Tirode, Karine Laud, Emmanuel Barillot, Olivier Delattre. High throughput screening highlights NFkB signaling in Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2014-3989
Abstract 3990: Chemerin and chemerin receptors in neuroblastoma tumor microenvironment
Authors: Tuemmler Conny , Snapkov Igor , Moens Ugo L. , Sveinbjørnsson Baldur
Published: May 2015

Tumor promoting inflammatory cells as well as inflammatory mediators such as chemokines are important contributors to the tumor microenvironment as they can support tumor progression, angiogenesis and metastasis. Chemerin (also known as TIG-2 or RARRES2) is a chemoattractant factor for macrophages, immature DCs and NK-cells and a known adipokine involved in inflammation, metabolism and adipogenesis. Synthesized as a 163aa preproprotein, chemerin is N-terminally cleaved and secreted as inactive prochemerin. Following secretion, chemerin can be cleaved at the C-terminus by a variety of extracellular proteases resulting in several isoforms with varying length and biological activity. During inflammation initiation, maintenance and resolution the different chemerin isoforms may function pro- and/ or anti- inflammatory. Chemerin is a natural ligand for the G protein- coupled receptors CMKLR1 (Chem23) and GPR1. The role of chemerin and CMKLR1 in the tumor microenvironment has not been extensively studied.

The aim of this work is to study the function of chemerin and its receptors in neuroblastoma (NB). Screening of mRNA expression arrays showed a correlation between high expression of CMKLR1 and GPR1 and a worsened prognosis in NB. Chemerin, CMKLR1 and GPR1 expression was detected in different neuroblastoma cell lines by RT-PCR, immunocytochemistry and Western Blot. Stimulation with chemerin resulted in rapid and transient ERK1/2 and Akt phosphorylation.

TNF-α and IL-1β treatment increased chemerin and CMKLR1 protein levels. The functional significance of chemerin/ CMKLR1 in NB will be assessed by the use of NB animal models using cell clones silenced for chemerin/ CMKLR1.

Citation Format: Conny Tuemmler, Igor Snapkov, Ugo L. Moens, Baldur Sveinbjørnsson. Chemerin and chemerin receptors in neuroblastoma tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3990. doi:10.1158/1538-7445.AM2014-3990
Abstract 3992: Modes of metastasis evolution in human and murine cancer revealed by whole exome sequencing
Authors: Carter Scott L. , Brastianos Priscilla K. , McFadden David G. , Papagiannakopoulos Thales , Taylor-Weiner Amaro , Cibulskis Kristian , Jacks Tyler , Hahn William , Getz Gad
Published: May 2015

Despite that fact that 90% of cancer deaths are due to metastasis, relatively little is known about how metastases evolve from primary cancers. We subjected 101 trios consisting of primary tumor, brain metastasis, and normal reference tissue to whole exome sequencing (WES). To analyze the data, we developed novel computational tools to derive high quality allelic copy-number profiles directly from the WES data. These were used to perform an integrative analysis of somatic copy-number alterations (SCNAs) and somatic single nucleotide variants (SSNVs). This analysis allowed us to estimate the clonal architecture of the primary and metastatic samples from each patient, and to reconstruct a single phylogenetic tree relating all of the subclones detected in both samples.

We determined that all of the matched metastases analyzed likely formed from a single clone. In all cases, we observed a sibling relationship between the metastasis and primary tumor samples, indicating that they share a common ancestor, but ongoing evolution in the primary tumor resulted in fully clonal mutations in the primary biopsy that were not present in the metastasis sample. An important corollary of this is that in no case was a metastasis-founding subclone detected in a primary tumor sample. Using mutational spectra associated with tobacco exposure in lung cancers, we determined that most of the evolution leading up to the brain metastasis like occurred within the lung.

In contrast with these findings, analysis of related primary tumor and metastasis families in a mouse model of small cell lung cancer using identical methodology revealed evidence of more variable patterns of metastatic spread. Analysis of draining lymph nodes revealed that multiple subclones of the primary contributed to these metastases. In addition, we uncovered evidence for the sequential spread of metastases, consistent with multiregion sequencing of primary and metastatic human pancreatic cancer. The extension of this finding to a mouse cancer model suggests this may be a more frequent feature of cancer metastasis, and raises the possibility of genetically dissecting these processes in this experimental system.

Citation Format: Scott L. Carter, Priscilla K. Brastianos, David G. McFadden, Thales Papagiannakopoulos, Amaro Taylor-Weiner, Kristian Cibulskis, Tyler Jacks, William Hahn, Gad Getz. Modes of metastasis evolution in human and murine cancer revealed by whole exome sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3992. doi:10.1158/1538-7445.AM2014-3992
Abstract 4032: Targeting the isoprenoid biosynthetic pathway in a murine model of metastatic prostate cancer
Authors: Reilly Jacqueline E. , Neighbors Jeffrey D. , Bannick Nadine , Henry Michael D. , Kuder Craig H. , Hohl Raymond J.
Published: May 2015

The isoprenoid biosynthetic pathway (IBP) provides substrates for the post-translational modification of key proteins in regulating malignant cell properties, including proliferation, migration, and invasion. Several studies have found broad inhibitors of the IBP, such as statins, to significantly reduce the risk of advanced prostate cancer (PCa), potentially through their induced-reduction of geranylgeranylated proteins. However, such inhibition of the entire IBP is limited by side effects resulting from depletion of all isoprenoids and their products. We have developed a novel compound, geranylgeraniol bisphosphonate (GGOHBP), selectively targeting geranylgeranyl diphosphate synthase (GGDPS) and reducing the post-translational modification of geranylgeranylated proteins. Luciferase-expressing human-derived 22Rv1 PCa cells were injected into the left ventricle of 20 mice using bioluminescence imaging (BLI) to visualize tumor development. After three weeks 18/20 mice had developed tumors and daily subcutaneous (SQ) injections of 1.5mg/kg GGOHBP were given for one month. All 18 mice developed mandible tumors, 13 developed adrenal gland tumors, 4 developed intestinal tumors, 2 developed femoral tumors, 2 developed liver tumors, and 1 developed a tumor in an unidentified location in the chest cavity. Ex vivo photon count analyses revealed an 80% (p=0.1458) reduction in adrenal gland tumors of the treated mice as compared to vehicle-treated controls. This corresponded to a 54% (p=0.0007) reduction in total adrenal gland tumor weight in the treated as compared to the control mice. Western blot analysis of the adrenal gland tumors and one intestinal tumor showed a reduction in Rap1A geranylgeranylation in the treated mice and not the control mice, while non-tumorous tissues showed no Rap1A alteration. A follow-up study of non-tumor bearing mice given SQ injections of 1.25 or 1.5 mg/kg GGOHBP daily did not reveal alterations in Rap1A geranylgeranylation in the adrenal glands, kidneys, liver, or heart. Our findings detail a novel compound capable of preferentially altering the IBP in the adrenal gland tumors of a murine model of metastatic PCa. Future work defining the mechanism behind this focal effect and the adrenal gland isoprenoid environment will allow compound optimization and further understanding of the IBP's role in PCa metastasis.

Citation Format: Jacqueline E. Reilly, Jeffrey D. Neighbors, Nadine Bannick, Michael D. Henry, Craig H. Kuder, Raymond J. Hohl. Targeting the isoprenoid biosynthetic pathway in a murine model of metastatic prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4032. doi:10.1158/1538-7445.AM2014-4032
Abstract 4074: Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation
Authors: Kim Hyemin , Kim Yejin , Choi Jiwon , Jang Mirim , Choi Jiyea , Hwang Young-il , Kang Jae Seung , Lee Wang Jae
Published: May 2015

It is recently reported that CD40-CD40 ligand (CD40L) interaction is important to Th17 development. Also, it is known that transforming growth factor-beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial for the development of Th17. In this study, we investigated the role of CD40 on breast cancer cells and its role on the immune suppressive function and tumor progression. CD40 stimulation on breast cancer cell line, MDA-MB231, caused up-regulation of TGF-β, and direct CD40-CD40L interaction between breast cancer cells and activated T cells increased TFG-β production. Moreover, direct interaction of CD40-CD40L induced the production of IL-17, which increased the proliferation of MDA-MB231 cells via the activation of STAT3. Therefore, direct CD40-CD40L interaction of breast tumor and activated T cells increases the TGF-β production and the differentiation of Th17 cells, which promote the proliferation of breast cancer cells.

Citation Format: Hyemin Kim, Yejin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Young-il Hwang, Jae Seung Kang, Wang Jae Lee. Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2014-4074
Abstract 4075: LAG3 and PD1 co-inhibitory molecules directly interact to limit CD8+ T cell signaling
Authors: Huang Ruea-Yea , Eppolito Cheryl , Fadiel Ahmed , Hamza Adel , Lele Shashikant , Mastuzaki Junko , Odunsi Kunle
Published: May 2015

Increasing evidence indicate that dual blockade of Lymphocyte Activation Gene-3 (LAG3) and programmed cell death 1 (PD1) synergistically enhances autoimmunity and anti-tumor immunity. Despite the fact that these co-inhibitory receptors individually attenuate T cell receptor signaling, it is not clear whether they interact at the physical, biochemical and/or molecular levels, to regulate the functional fate of T cells. To answer these questions, we first simulated possible direct interaction of LAG3 and PD1 using in-silico molecular docking techniques. Using confocal microscopy and ImageStream analyses, we demonstrated that LAG3 and PD1 molecules co-localized in a subset of activated murine CD8+ T cells. The co-localization occurred at the trans-Golgi vesicles, early/recycling endosomal compartments, lysosomes, and microtubule organizing center (MTOC). Importantly, LAG3 and PD1 cluster with pLck at the immunological synapse of CD8+ T cell and dendritic cell conjugates. Reciprocal immunoprecipitation of the T cell extracts with specific antibodies for LAG3 and PD1 revealed a physical association between LAG3 and PD1 and this interaction was absent in T cells isolated from LAG3 and PD1 knockout mice. Finally, LAG3 protein was also associated with Src family tyrosine phosphatase-2 (SHP2) that is recruited by PD1 during T cell signaling. The recruitment of phosphatases is additively reduced in CD8+ T cells deficient in both LAG3 and PD1. Taken together, our data suggest that LAG3 interacts and collaborates with PD1, following T cell activation, for rapid translocation from early/recycling endosomal compartments to the immunological synapse, leading to a synergistic inhibitory effect on T cell signaling.

Citation Format: Ruea-Yea Huang, Cheryl Eppolito, Ahmed Fadiel, Adel Hamza, Shashikant Lele, Junko Mastuzaki, Kunle Odunsi. LAG3 and PD1 co-inhibitory molecules directly interact to limit CD8+ T cell signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4075. doi:10.1158/1538-7445.AM2014-4075
Abstract 4078: EZH2 marks polyfunctional memory T cells and controls tumor immunity
Authors: Zhao Ende , Maj Tomasz , Kryczek Ilona , Zhao Lili , Wei Shuang , Wan Shanshan , Crespo Joel , Szeliga Wojciech , Vatan Linda , Wu Ke , Chinnaiyan Arul M. , Welling Theodore H. , Marquez Victor E. , Kotarski Jan , Zhang Yi , Liu Rebecca , Tao Kaixiong , Wang Guobin , Zou Weiping
Published: May 2015

Polyfunctional T cells mediate potent anti-viral immunity. However, the nature and molecular mechanisms controlling their functional signature remain poorly understood. Here we report that polyfunctional T cells are characterized by high proliferative capacity and apoptotic resistance. Enhancer of zeste homolog 2 (EZH2) phenotypically marks them and functionally controls their survival and expansion. Notch signaling regulates effector T cell function. We show that EZH2 represses Numb and Fbxw7, two Notch repressors, activates Notch signaling, and Notch subsequently stimulates Bcl-2 expression and protects EZH2+ T cells from apoptosis via trimethylating histone H3 on lysine 27. Moreover, EZH2 targets T cell cycling repressors and promotes their expansion. EZH2+CD8+ T cells mediate anti-tumor immunity and are associated with improved long-term cancer survival. Together, the data reveal a novel role and mechanism for EZH2 in controlling polyfunctional T cells. Thus, manipulation of EZH2 signaling in T cells may have therapeutic potential in treating cancer patients.

Citation Format: Ende Zhao, Tomasz Maj, Ilona Kryczek, Lili Zhao, Shuang Wei, Shanshan Wan, Joel Crespo, Wojciech Szeliga, Linda Vatan, Ke Wu, Arul M. Chinnaiyan, Theodore H. Welling, Victor E. Marquez, Jan Kotarski, Yi Zhang, Rebecca Liu, Kaixiong Tao, Guobin Wang, Weiping Zou. EZH2 marks polyfunctional memory T cells and controls tumor immunity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4078. doi:10.1158/1538-7445.AM2014-4078
Abstract 41: 47 kda CXCR4: A marker for highly invasive neuroblastoma
Authors: Shankar Vipin , Qi Lei , Kihira Kentaro , Komada Yoshihiro , Hori Hiroki
Published: May 2015

Neuroblastoma; a pediatric cancer of the sympathetic nervous system, which accounts for 15% of childhood cancer deaths, presents with metastatic disease of the bone and the bone marrow at diagnosis in 70% of the cases. Although studies have shown that the CXCL12 chemokine receptor CXCR4 mediates the process of metastasis in many cancer types, its role in the bone marrow metastasis of neuroblastoma is unclear. In an effort to better understand the role of the CXCR4- CXCL12 axis in bone marrow metastasis of neuroblsatoma, we screened 20 neuroblastoma cell lines for their invasive potential, and expression of CXCR4, and sought to identify a correlation between tumor invasiveness and CXCR4 expression. Western blot analyses of cell lysates revealed the presence of multiple CXCR4 isoforms with 3 prominent species at about 35 kda, 47 kda and 62 kda. Cell lines expressing the 47 kda isoform showed higher secretion of MMP9 in gelatin zymography and higher migration and invasion towards mesenchymal stem cells (MSCs) and MSC-conditioned-RPMI, in transwell migration/invasion studies. Far western blot analysis with immuno-precipitated CXCR4, showed that the 47kda protein bound with CXCL12 at a higher rate. Blocking CXCR4 with AMD3100 or a neutralizing antibody against the 47 Kda isoform decreased the secretion of MMP9, the expression of integrin α3 and integrin β1 and the invasive potential of the cell. These data suggest that the 47 kda CXCR4 plays a prominent role in the bone marrow metastasis of neuroblastoma and could possibly be used as a diagnostic marker for highly invasive neuroblastoma and the development of minimal residual disease.

Citation Format: Vipin Shankar, Lei Qi, Kentaro Kihira, Yoshihiro Komada, Hiroki Hori. 47 kda CXCR4: A marker for highly invasive neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 41. doi:10.1158/1538-7445.AM2014-41
Abstract 4103: Biomarkers of thyroid function and autoimmunity associated with thyroid cancer risk: A nested case-control study
Authors: Kim Jeongseon , Cho Young Ae , Shin Aesun , Lee Jeonghee , Kong Sun-Young , Lee Eun Kyung , Lee You Jin
Published: May 2015

Background & Objective: The incidence of thyroid cancer has been increased in several countries. However, the markers to predict for high-risk group have not been fully established. We aim to investigate the potential association between the biomarkers of thyroid function/autoimmunity and the risk of thyroid cancer in Korean population, where the incidence rate of thyroid cancer is one of the highest in the world.

Design: This study was a nested case-control study within the Cancer Screenee Cohort study, which consisted of 257 incident thyroid cancer patients who were ascertained during mean of 2.2 years of follow-up and 257 controls. Total triidothyronine (TT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and thyroglobulin (Tg), and two markers of thyroid autoimmunity (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb] antibodies) were measured. Logistic regression models were used to examine the association between these biomarkers and thyroid cancer risk. Stratified analyses were conducted by sex, BMI, and smoking status.

Results: When the markers were categories by tertile distribution of the levels of controls group, highest tertile of FT4 (OR [95% CI] = 1.73[1.11, 2.69]) and middle tertile of TSH (OR [95% CI] = 1.77[1.14, 2.74]) were associated with thyroid cancer risk in multivariate analyses. In addition, normal (30-60 U/mL) (OR [95% CI] = 8.47 [5.39, 13.33]) or elevated levels (60 > U/mL) (OR [95% CI] = 4.48 [2.59, 7.76]) of TPOAb showed an elevated risk for thyroid cancer. Stratified analyses implied that some of these associations could be differed by sex, BMI, or smoking status.

Conclusions: This study represented that the levels of biomarkers of thyroid function/autoimmunity, particularly the presence of TPOAb, may be used as diagnostic adjuncts for predicting thyroid cancer risk.

Citation Format: Jeongseon Kim, Young Ae Cho, Aesun Shin, Jeonghee Lee, Sun-Young Kong, Eun Kyung Lee, You Jin Lee. Biomarkers of thyroid function and autoimmunity associated with thyroid cancer risk: A nested case-control study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4103. doi:10.1158/1538-7445.AM2014-4103
Abstract 4107: Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells
Authors: Mishra Manoj K. , Stokes James A. , Salaam Amanee , Nyairo Elijah , Singh Udai , Dean Derrick
Published: May 2015

Monocyte chemo-attractant protein (MCP-1) is a chemokine, which recruits monocytes, neutrophils, and lymphocytes in response to trauma and proinflammatory cytokines such as TNF-α. MCP-1 generally is not expressed in healthy individuals, but in response to various stressful stimuli it gets up-regulated, which in turn contributes to increased inflammation. MCP-1 has been implicated in mediating apoptosis by producing a proapoptotic protein designated MCP-induced protein (MCPIP). Resveratrol (RES), a polyphenolic compound found in the skin of red fruits, exhibits anti-inflammatory, anti-oxidative, anti-cancer, and anti-proliferative characteristics. In this study, we hypothesized that the functionalization of RES with detonated nano-diamond (DND, hereafter called fDND) will enhance the effective delivery of RES to tumor cell and impact the modulation of molecular mechanisms in murine prostate cancer (PCa) cells. This hypothesis was tested on mouse PCa cell lines, derived from transgenic adenocarcinoma of mouse prostate (TRAMP), in C57/B6 mice. Interestingly, TRAMP-C1 and TRAMP-C2 form tumor while TRAMP-C3 fails to develop tumor. TRAMP cells were treated with different concentrations of fDND at different time points and analyzed for underlying cellular and molecular mechanisms such as cell viability/proliferation, mitochondrial membrane potential, cytokines and growth factors production. The initial results indicate that the fDND significantly induce molecular signatures in TRAMP-C3 cells in comparison with TRAMPC1 and C2. Interestingly, the level of MCP-1 was significant elevated in TRAMP C1 and C2 cells. Thus, suggesting a major role of MCP-1 in the regulation of cancer progression and clearance. This data also suggest that the functionality of dietary compounds can be enhanced by conjugating or functionalizing them with DND, which can be used as a therapeutic carrier.

Citation Format: Manoj K. Mishra, James A. Stokes, Amanee Salaam, Elijah Nyairo, Udai Singh, Derrick Dean. Efficient delivery of dietary compound modulates mcp-1 in murine prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4107. doi:10.1158/1538-7445.AM2014-4107
Abstract 4124: Ovarian cancer survival by tumor subtype
Authors: Poole Elizabeth M. , Cramer Daniel W. , Vitonis Allison F. , Terry Kathryn L.
Published: May 2015

Introduction: Epithelial ovarian cancer is heterogeneous, with subgroups defined by cell of origin (ovary vs. fallopian tube), histology, and carcinogenic pathway (the etiologic pathway through which tumors arise: type I tumors develop on the ovarian surface and are low grade serous or mucinous histology; type II tumors develop through endometriotic implantation and are clear cell or endometrioid histology; type III tumors originate in the fallopian tube and are high grade serous histology). Although differences in associations have been observed with risk of incident ovarian cancer, few studies have examined differences in survival by subtype. In the New England Case-Control Study of ovarian cancer (NECC), we examined differences in survival by tumor dominance (a surrogate for cell of origin), histology, and carcinogenic pathway.

Methods: Among 2076 women with epithelial ovarian cancer (1991-2008), 892 deaths were observed. Cox proportional hazards regression was used to calculate hazards ratios (HRs) and 95% confidence intervals (95% CI) for the association of ovarian cancer subtype with overall survival, adjusting for age at diagnosis, study phase, year of diagnosis (as a proxy for treatment), BMI, and smoking status.

Results: Serous invasive tumors were more likely to be non-dominant (likely fallopian origin) and type III. Compared to serous invasive tumors, all other tumor histologies had statistically significantly improved survival. Similarly, dominant tumors (i.e., likely ovarian origin) had greater survival than non-dominant tumors (HR: 0.38; 95% CI: 0.31-0.47). Type I (mucinous and low grade serous) and type II (endometrioid and clear cell) tumors had better survival than type III (high grade serous) tumors (HR: 0.21; 95%CI: 0.16-0.28 and HR: 0.23; 95% CI: 0.18-0.29, respectively).

Conclusion: Regardless of how subtype was defined, high grade, invasive serous tumors had worse survival compared to other tumor subtypes. This underscores the need for prevention and treatment targeted at these aggressive tumors.

Table.Associations between tumor subtype and overall survivalSubtypeDeaths/CasesMedian Survival (years)HR (95% CI)HistologySerous invasive654/9683.21.00 (ref.)Serous borderline25/25010.10.35 (0.18-0.67)Mucinous36/2427.10.38 (0.25-0.58)Endometrioid68/3314.70.28 (0.21-0.37)Clear cell29/1163.40.30 (0.21-0.44)DominanceNon-dominant268/3853.31.00 (ref.)Dominant162/6034.00.38 (0.31-0.47)PathwayType III596/8563.21.00 (ref.)Type II97/4474.00.23 (0.18-0.29)Type I60/2915.70.21 (0.16-0.28)

Citation Format: Elizabeth M. Poole, Daniel W. Cramer, Allison F. Vitonis, Kathryn L. Terry. Ovarian cancer survival by tumor subtype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2014-4124
Abstract 4136: Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based study
Authors: Beiggi Sara , Banerji Versha , Deneka Angela , Griffith Jane , Gibson Spencer , Johnston James
Published: May 2015

Chronic Lymphocytic Leukemia (CLL) patients in Manitoba are either referred to the CancerCare Manitoba (CCMB) CLL clinic or receive care from other hematologists/general practitioners. However, it is unknown whether referral to the CLL-specialized clinic alters patients' outcome.

All CLL/SLL diagnoses in Manitoba 2007-2011 were obtained from the Manitoba Cancer Registry to create an immunophenotipically confirmed population-based cohort. Referred patients to the CLL-specialized clinic were identified from the CCMB charts. Association between age and treatment was measured by chi-squared test. Hazard ratio (HR) was determined using Cox Proportional Hazard Regression model.

Of 555 CLL/SLL diagnoses, 281 (51%) were referred to the CLL-specialized clinic. For referred and non-referred patients the median age was 68y (39-99) and 72y (45-96), treated patients were 77 (27%) and 31 (11%), time to first treatment was 5m (0-5.5y) and 3m (0-2.5y), respectively. M:F was 1.7:1 for both groups. CLL was the primary cause of death in both referred and non-referred patients (57% and 35%, respectively). Comorbidities such as cardiovascular diseases had equal contributions to mortality in both populations (7% and 9.5% in referred and non-referred patients, respectively). When patients older than 70 years were investigated, elderly patients that were referred to the clinic were more likely to receive treatment (p = 0.0002).

When adjusted for age (≥80y HR 10.79, p: >0.0001; 71-79y HR 5.44, p: 0.0007; 62-70y HR 4.07, p: 0.0051; <62 HR 1.00), gender (male HR 1.61, p: 0.0414), pre-CLL cancer (HR 1.85, p: 0.0187) and post-CLL Cancer (HR 2.31 p: 0.0208), patients seen by CLL-specialists had a >2-fold increased OS compared to non-referred patients (HR 2.39, p: 0.0003) in the Manitoba population. In the non-referred population, there was a striking correlation between advancing age and decreasing OS. This correlation was almost eliminated in the referred population.

Thus, patients seen in a specialized clinic have an improved survival compared to non-referred patients and this appears to be primarily related to improved OS in the elderly. Whether this observation is related to improved therapy/supportive care in the specialized clinic or to referral bias is under investigation.

Citation Format: Sara Beiggi, Versha Banerji, Angela Deneka, Jane Griffith, Spencer Gibson, James Johnston. Comparison of overall survival of Chronic Lymphocytic Leukemia (CLL) patients referred or not referred to a specialized CLL clinic: A Canadian population-based study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4136. doi:10.1158/1538-7445.AM2014-4136
Abstract 416: New technology to detect DNA methylation in plasma sample from lung cancer patients
Authors: Shinjo Keiko , Kondo Eisaku , Kondo Yutaka
Published: May 2015

Epigenetic alterations have emerged as a common hallmark of many types of human cancers including lung cancers. Therefore, detection of aberrant DNA methylation from blood samples may be a promising diagnostic tool for cancers. We have been developing a highly sensitive plasma-based approach to detect aberrant DNA methylation in lung cancer patients. First, we identified seven markers from genome-wide methylation analysis, which can diagnose lung cancer in tissue samples with high accuracy (sensitivity, 91%; specificity, 100%). Next, we evaluated DNA methylation status in tissue samples and corresponding plasma samples in each patient using pyrosequencing analysis and qMSP. However, DNA methylation status between tissue and plasma samples were not concordant by both methods (pyrosequencing, 0/19 cases; qMSP, 3/9 cases). Given the concentration of DNA in plasma originated from cancerous tissue might theoretically be very low, we need to use more sensitive and accurate methods. We used digital PCR and next generation sequencer to analyze the methylation status of plasma DNA. These methods are both highly sensitive. Now we invent a new technology using specific probes, which can recognize sequence information including methylated cytosine even in one DNA molecule. This new technology might be applicable as a practical tool for lung cancer diagnosis.

Citation Format: Keiko Shinjo, Eisaku Kondo, Yutaka Kondo. New technology to detect DNA methylation in plasma sample from lung cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 416. doi:10.1158/1538-7445.AM2014-416
Abstract 4164: The druggable proteome: Identifying novel target families for cancer
Authors: Razaz Parisa , Workman Paul , Al-Lazikani Bissan
Published: May 2015

Cancer drug attrition rates in the clinic continue to be unacceptably high (1). As most failures are due to lack of observed efficacy, greater focus is being placed on target validation (1), which in turn is driving drug discovery efforts towards safer targets and pathways. Meanwhile, large scale ‘omic efforts are showing us that there are hundreds of potential cancer drivers outside of the key targets known to the cancer field. Furthermore, cancer drugs can function through the exploitation of non-oncogenes (2). To mirror the systematic, large-scale and objective identification of potential cancer drivers, we have applied a large-scale, objective, systematic and multifaceted chemogenomic approach. This combines biological, chemical, pharmacological and 3D structural data (3,4) to prioritize druggable proteins and protein families, identifying novel untapped families with potential for cancer drug discovery. We have carried out computational druggability assessment of the human proteome (∼35’854 RefSeqs) using ligand-, structure-, network-, precedence- and feature-based druggability analysis methods. This has identified over 20 families that are likely to be druggable and, as can be gleaned from the literature, have had little or no chemical exploration efforts. We combine this with bioinformatics analysis of multiomic data from 18 different cancer types, with a focus on GI cancers of unmet medical need, in order to rank the families based on potential evidence of deregulation in these cancers. Here we present the results of this analysis, along with preliminary RNAi knockdown results of some of the families. Application of these objective methodologies allows identification of previously untapped druggable families for cancers, in addition to establishment and application of a computational pipeline for druggability assessment.

1. Arrowsmith, J. & Miller, P. Trial Watch: Phase II and Phase III attrition rates 2011-2012. Nat Rev Drug Discov 12, 569 (2013).

2. Workman, P. & Al-Lazikani, B. Drugging cancer genomes. Nat Rev Drug Discov 12, 889-890 (2013).

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Citation Format: Parisa Razaz, Paul Workman, Bissan Al-Lazikani. The druggable proteome: Identifying novel target families for cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4164. doi:10.1158/1538-7445.AM2014-4164
Abstract 4168: Dissect the clinical utility of TCGA genomic data across tumor types
Authors: Liang Han ,   TCGA Pan-Cancer Clinical/Predictor Group
Published: May 2015

A central question for the cancer research community is how to use genomic and proteomic data to guide cancer care. We investigated two potential clinical applications of The Cancer Genome Atlas (TCGA) data: predicting patient prognosis and identifying clinically actionable alterations. For four TCGA cohorts, we systematically evaluated the power of molecular data with or without clinical variables in predicting patient survival; and to facilitate further community efforts, we established an open-access model evaluation platform. We demonstrate that incorporating molecular data with clinical variables can improve predictive power. Interestingly, one model derived from ovarian cancer can predict outcomes in kidney cancer, suggesting the potential utility of cross-tumor analysis. Across 12 cancer types, we identified 10,281 somatic alterations in clinically relevant genes in 2,928 out of 3,277 patients (89.4%), revealing recurrent and potentially targetable alterations not revealed in single-tumor datasets. Our study represents the first systematic and comprehensive analysis evaluating the prognostic power of different types of molecular data across multiple cancer types. In addition, the clinically actionable alterations we identified may inform novel clinical trial design and treatment choice.

Citation Format: Han Liang, TCGA Pan-Cancer Clinical/Predictor Group. Dissect the clinical utility of TCGA genomic data across tumor types. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4168. doi:10.1158/1538-7445.AM2014-4168
Abstract 4196: An RNA aptamer-based approach for human glioma treatment
Authors: Camorani Simona , Esposito Carla L. , Catuogno Silvia , Amero Paola , Rienzo Anna , Vita Gennaro D. , Condorelli Gerolama , Franciscis Vittorio de , Cerchia Laura
Published: May 2015

Gliomas are the most common primary central nervous system tumors with a dismal prognosis. Despite recent advances in surgery, radiotherapy, and chemotherapy, current treatment regimens have a modest survival benefit.

Due to a combination of its complex phenotype and organ-specific clinical manifestations, efforts to refine glioma treatment with targeted therapies have largely been frustrated. Hence, finding specific ligands capable of detecting and measuring the altered pattern of gene expression and to discriminate between different tumor phenotypes, is a strategic and plausible objective for the diagnosis and therapy of glioma. To date, antibody-based approaches have been developed for in vivo applications but, in most cases, they show toxicity in vivo and do not reach adequate sensitivity. Thanks to their unique characteristics (low size, good affinity for the target, no immunogenicity, chemical structures that can be easily modified to improve their in vivo applications), single-stranded nucleic acid ligand molecules, named aptamers, represent a valid alternative to antibodies for in vivo targeted recognition as therapeutics or delivery agents for nanoparticles, small interfering RNAs, chemotherapeutic cargos and molecular imaging probes.

By applying cell-SELEX on cancer cells we have generated and characterized different nuclease resistant 2′fluoro-pyrimidines RNA aptamers as high affinity ligands and inhibitors of human receptor tyrosine kinases (RTKs) with a crucial role in glioma, including EGFR, EGFRVIII, EphB3, Axl and PDGFRβ. All the aptamers are able to efficiently and specifically inhibit tumor growth in cell based assays and in animal models of human glioma. Further, some of these aptamers strongly cooperates in inducing inhibition of tumor growth thus providing the basis for further development of antitumor combination therapies.

Citation Format: Simona Camorani, Carla L. Esposito, Silvia Catuogno, Paola Amero, Anna Rienzo, Gennaro De Vita, Gerolama Condorelli, Vittorio de Franciscis, Laura Cerchia. An RNA aptamer-based approach for human glioma treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4196. doi:10.1158/1538-7445.AM2014-4196
Abstract 4200: Interaction between mPGES-1 and iNOS promotes human melanoma progression
Authors: Kim Sun-Hee , Hashimoto Yuuri , Ekmekcioglu Suhendan , Grimm Elizabeth A.
Published: May 2015

Melanoma cells in vivo are well known to express varying inflammatory features, which is not limited by somatic mutational subclass. Among the most prevalent of inflammatory markers are iNOS (inducible Nitric Oxide Synthase) generated NO production and COX-2/PGE2, and for which their active pathways have been shown to enhance carcinogenesis and tumor progression, stimulate angiogenesis, support tumor growth, and promote metastasis. COX-2 inhibitors are well studied agents that inhibit tumor growth and prevent tumor development including melanoma, but the focus of research has shifted to develop inhibitors for enzymes, which are downstream of COX-2, especially microsomal PGE2 synthase-1 (mPGES-1), due to the cardiovascular risk associated with the initial COX-2 inhibitory drugs. Here, we demonstrate crosstalk between iNOS/NO and mPGES-1/PGE2 signaling pathways and suggest that mPGES-1 is a novel potential therapeutic target in human melanoma employing a spectrum of well-defined human cell lines, as well as human tissues. Our melanoma stage III survival Tissue MicroArray analysis shows that the expression of mPGES-1 is elevated in 65% of human stage III melanomas and intense expression of mPGES-1 is significantly associated with the short-term survival of patients. More interestingly, about 90 % of patient samples which express mPGES-1 were also positive for iNOS. In addition, treatment of human melanoma cells with NO donors or constitutively-driven expression of iNOS resulted in increased PGE2 production, which was suppressed by mPGES-1 inhibition, indicating that the pathway is active and targetable. Moreover, iNOS was found to interact directly with mPGES-1, and iNOS or NO donors enhance mPGES-1 activity in melanoma cells and in vitro, suggesting that iNOS-mediated NO promotes PGE2 production through mPGES-1 activation. mPGES-1 inhibition by its shRNA or specific inhibitors suppressed human melanoma cell viability and migration. Collectively, these findings suggest that the interaction between iNOS and mPGES-1 is associated with human melanoma progression and could be considered as a novel target for translational application in melanoma growth regulation.

Citation Format: Sun-Hee Kim, Yuuri Hashimoto, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Interaction between mPGES-1 and iNOS promotes human melanoma progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2014-4200
Abstract 4205: Mass-spectroscopy phosphorylation profiling identified differential activation of signaling molecules via spleen tyrosine kinase in B-cell receptor signaling and stromal cell stimulation in DLBCL and CLL cells that are inhibited by GS-9973
Authors: Paolo Julie A. Di , Clarke Astrid , Rong Hong , Rousseau Emma
Published: May 2015

Dysregulation of protein kinase activity leading to aberrant or excessive downstream signaling is widely believed to underlay the pathogenesis of multiple cancers. The purpose of this study was to identify the spleen tyrosine kinase (SYK)-dependent phosphoproteins that were activated in a diffuse large B-cell lymphoma (DLBCL) cell line, DHL4, and primary chronic lymphocytic leukemia (CLL) cells, upon either B-cell receptor (BCR) activation, stromal cell contact, or in a resting state and demonstrate inhibition with a selective SYK inhibitor, GS-9973. A commercial PTMScan Direct procedure from Cell Signaling Technology was utilized in this assessment. Cell lysates generated from resting, αIgG treatment or HS-5 human stromal cell line contact were digested with trypsin and the resultant peptides were enriched by immunoprecipitation with either an anti-phosphotyrosine or anti-phosphoserine/threonine antibody cocktail, and subjected to mass spectrometric analysis to identify and quantify phosphorylated peptides. The phosphorylated peptide profile was then compared to a similarly treated lysate after incubation with 1 μM GS-9973. Protein phosphorylations that were significantly changed by < or > 2.5-fold with GS-9973 treatment were identified and confirmed, where possible, by western blot of DHL-4 lysates or in primary CLL samples with antibodies specific for the identified sites. PTMScan Direct analysis showed overlapping, but not equivalent, patterns of phosphorylated peptides upon αIgG or stromal cell activation. A shared set of GS-9973 inhibited phosphoproteins were identified including pSyk, pAkt, pMek, pErk, pJnk2, pPKCδ, and pS6 kinase. Western blot analysis validated 13 out of 14 proteins as being modulated by 1 μM GS-9973 treatment. Furthermore, dose-response inhibition was demonstrated for pAkt-T473, pBCR-Y177, pBlnk-Y84, pMek-S217/221, and pErk-T202/Y204 with EC50s ranging from 23 to 50 nM. These data support the concept that Syk inhibition can block multiple signaling pathways known to be important in malignant B-cells function. Furthermore, identification of these sites elucidates possible pharmacodynamic signatures of GS-9973 inhibition that may be followed in clinical investigations of GS-9973 in oncology.

Citation Format: Julie A. Di Paolo, Astrid Clarke, Hong Rong, Emma Rousseau. Mass-spectroscopy phosphorylation profiling identified differential activation of signaling molecules via spleen tyrosine kinase in B-cell receptor signaling and stromal cell stimulation in DLBCL and CLL cells that are inhibited by GS-9973. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4205. doi:10.1158/1538-7445.AM2014-4205
Abstract 4223: Combined PI3K-AKT and MEK-ERK pathway inhibition provides broad antitumor efficacy in HER2+ breast tumor models
Authors: De Pradip , Sun Yuliang , Carlson Jennifer , Friedman Lori , Dey Nandini , Leyland-Jones Brian
Published: May 2015

Background: The PI3K-AKT-mTOR and the RAS-RAF-MEK-ERK pathways are thought to be the central transducers of oncogenic signals in cancer. Combined targeting of these two pathways may be necessary for optimal therapeutic activity in solid tumors. This study evaluated the PI3K inhibitor GDC-0941, the MEK1/2 inhibitor GDC-0973 and the combination of both in different HER2+ breast cancer cell lines. Methodology: Growth inhibition/survival, apoptosis, signal transduction and antitumor efficacy were examined using MTT assays, 3D-ON-TOP assays, annexinV staining and mouse xenografts respectively, in BT474 (trastuzumab sensitive), BT474HR (trastuzumab-resistant) and HCC1954 (PIK3CA mutated) breast cancer cell lines. Results: (1) GDC-0941 and GDC-0973 exhibited in vitro cell killing activity in MTT assays with IC50's ranging from 0.35 µM to 1 µm and from 8 µM to 20 µM respectively, (2) the initiation of apoptotic activity (annexin V) in GDC-0941 plus GDC-0973 was significantly superior to that of either drug alone, (3) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46) was observed following GDC-0941 treatment, and the combination of GDC-0941 plus GDC-0973 more effectively blocked p-S6RP and p-4EBP1, especially in BT474HR and HCC1954 cells, (4) GDC-0973 abrogated activation of ERK, and this ERK inactivation was sustained when combined with GDC-0941, (5) a combination of GDC-0941 and GDC-0973 more effectively blocked 3D-ON-TOP clonogenic growth of HER2+ cells than either agent alone, and (6) xenograft data show that the combination of GDC-0941 and trastuzumab has an enhanced anti-tumor effect in both sensitive (almost 100%) and resistant models (85%), and tumor regression was observed in both sensitive and resistant models when mice were treated with GDC-0941 plus GDC-0973 plus trastuzumab. Conclusions: Therapy with dual PI3K and MEK combination is more efficient than with either drug alone in all three cell lines. Our data provide stronger evidence that the addition of MEK inhibitor along with pan-PI3K inhibitor to HER2-directed treatment could augment the clinical benefit in breast cancer patients.

Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Combined PI3K-AKT and MEK-ERK pathway inhibition provides broad antitumor efficacy in HER2+ breast tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4223. doi:10.1158/1538-7445.AM2014-4223