bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 382: Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer
Authors: Wyce Anastasia , Degenhardt Yan , Bai Yuchen , Le BaoChau , Korenchuk Susan , Crouthamel Ming-Chih , McHugh Charles F. , Vessella Robert , Creasy Caretha L. , Tummino Peter J. , Barbash Olena
Published: May 2015

BET (bromodomain and extra-terminal) family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in a number of hematologic cancer models, partially through down-regulation of the critical oncogene, MYC. We hypothesized that BET inhibitors will similarly regulate expression of MYC family genes (MYC, MYCN, MYCL1) in solid tumor models characterized by MYC family amplification or over-expression. We and others have recently shown activity for BET inhibitors in MYCN-amplified neuroblastoma models, with concomitant down-regulation of MYCN expression. Here we describe the effects of the highly specific BET inhibitor, I-BET762, on MYC expression and cell growth in prostate cancer models. I-BET762 treatment inhibited MYC expression accompanied by growth inhibition and decreased survival in prostate cancer cell lines that over-express MYC. In addition to MYC signatures, gene expression profiling in cell lines identified numerous cell cycle-associated genes as being significantly down-regulated by I-BET762. Importantly, our data suggests that I-BET762 effects are partially driven by MYC down-regulation and underlines the critical importance of additional mechanisms of I-BET762 induced phenotypes. Consistent with our in vitro observations, BET inhibition reduces MYC expression and tumor burden in a primary model of castration resistant prostate cancer that expresses high levels of MYC. Taken together, our data highlight the potential of BET inhibitors as a novel therapeutic approach to treat prostate tumors driven by MYC over-expression.

Citation Format: Anastasia Wyce, Yan Degenhardt, Yuchen Bai, BaoChau Le, Susan Korenchuk, Ming-Chih Crouthamel, Charles F. McHugh, Robert Vessella, Caretha L. Creasy, Peter J. Tummino, Olena Barbash. Inhibition of BET bromodomain proteins as a therapeutic approach in 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 382. doi:10.1158/1538-7445.AM2014-382
Abstract 3822: Correlation between worse prognosis and lower expression of the TPPP gene in patients with hepatocellular carcinoma, detected by multiarray analysis
Authors: Inokawa Yoshikuni , Nomoto Shuji , Hishida Mitsuhiro , Takano Nao , Kanda Mitsuro , Fujiwara Michitaka , Koike Masahiko , Sugimoto Hiroyuki , Fujii Tsutomu , Nakayama Goro , Yamada Suguru , Tanaka Chie , Kobayashi Daisuke , Iwata Naoki , Kodera Yasuhiro
Published: May 2015

Background. Hepatocellular carcinoma (HCC) patients who undergo liver resection often suffer multicentric occurrence after surgery. Therefore, understanding carcinogenesis in background liver is important.

Methods. Control liver samples (super normal [SN]), were taken from 11 cases of metastatic liver cancer. We selected corresponding normal tissue from typical cases of HCC with chronic hepatitis C (corresponding normal [CN]) for comparison. Expression profiling and methylation arrays were performed to compare SN and CN. Array data showed that the tubulin polymerization promoting protein (TPPP) gene showed differences in both array analyses. The relationship between clinicopathological factors of 179 HCC patients and TPPP expression was investigated.

Results. The expression array showed that the TPPP gene was decreased by 2.236-fold (log2 ratio) in CN compared with SN. The methylation array showed a higher value of methylation for CN (0.730) than SN (0.384). We studied TPPP gene expression by real-time reverse transcription PCR. When compared expression level of TPPP (TPPP value ×103/GAPDH), among SN (n=11), normal liver tissue of HCC patients (n=179), and tumor tissue of HCC (n=179), there were significant differences (median: 116, 4.60, and 2.63, respectively). The group with lower TPPP expression in tumors compared with normal tissue showed a worse prognosis of overall survival than that in the increased expression group (P=0.0317). Strongly reduced TPPP expression in tumor tissue compared with normal tissue (ratio <0.3, n=57) was detected as an independent prognostic factor by multivariate analysis (P=0.0310).

Conclusions. Expression of the TPPP gene in tumor and non-cancerous liver tissue in HCC patients is significantly lower compared with SN. HCC patients with this low TPPP expression show a poor prognosis. This indicates that this gene is a new candidate of tumor suppressor genes in HCC. Low TPPP expression in liver tissue might be a predictor of HCC.

Citation Format: Yoshikuni Inokawa, Shuji Nomoto, Mitsuhiro Hishida, Nao Takano, Mitsuro Kanda, Michitaka Fujiwara, Masahiko Koike, Hiroyuki Sugimoto, Tsutomu Fujii, Goro Nakayama, Suguru Yamada, Chie Tanaka, Daisuke Kobayashi, Naoki Iwata, Yasuhiro Kodera. Correlation between worse prognosis and lower expression of the TPPP gene in patients with hepatocellular carcinoma, detected by multiarray analysis. [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 3822. doi:10.1158/1538-7445.AM2014-3822
Abstract 3825: High DAPK expression is correlated with worse prognosis in colorectal cancer patients
Authors: Ivanovska Jelena , Zlobec Inti , Diamantis-Karamitopoulou Eva , Dawson Heather , Koelzer Viktor Hendrik , Agaimy Abbas , Garreis Fabian , Laqua William , Lugli Alessandro , Hartmann Arndt , Schneider-Stock Regine
Published: May 2015

Objectives: Death-associated protein kinase (DAPK) is a cytoskeleton-associated serine/threonine kinase. It functions as a potent inhibitor of cell polarization and migration. DAPK loss has been shown to be associated with advanced tumor stages and unfavorable prognosis in many tumor types. However, the prognostic relevance of DAPK in patients with colorectal cancer is only poorly understood. Thus, we aimed to investigate the impact of DAPK protein expression on clinical outcome in patients with colorectal cancer.

Methods: Samples from 220 colorectal cancer patients with a median follow-up of 60 months were analyzed for immunohistochemical DAPK protein expression on tissue microarrays. The effect of endogenous DAPK protein expression on cell migration was analyzed applying the ECIS system (electric cell-substrate impedance sensing) with stable DAPK knockdown (shRNA) and DAPK overexpressing cell lines generated from HCT116 wild type colon cancer cells. Colony formation ability was analyzed using soft agar assay.

Results: In Kaplan-Meier-curve analysis DAPK loss was associated with longer survival time (p< 0.001). The 5-year survival rates were 52.3% and 25.6% in patients with DAPK negative tumors and DAPK positive tumors, respectively. 76.1% of DAPK positive tumors showed evidence of tumor budding. After adjusting for TNM stage in multivariate Cox regression analysis, DAPK retained its strong independent prognostic value. Patients with DAPK overexpressing tumors had a 1.9 times increased risk of death from the tumor than those with DAPK negative tumors. DAPK expression in tumor center showed a loss of expression toward the front (p=0.0126). This was in agreement with ECIS migration results indicating higher migration rate for DAPK shRNA cells. DAPK wild type cells showed an increased number of colonies in soft agar assay in comparison to other cell types. Colony formation ability showed time-dependent effects for DAPK overexpression.

Conclusion: In contrast to the well-known function of DAPK as a tumor suppressor, our data showed DAPK overexpression to be associated with aggressiveness of tumors and an unfavorable outcome. This interesting and new finding has to be further evaluated.

Citation Format: Jelena Ivanovska, Inti Zlobec, Eva Diamantis-Karamitopoulou, Heather Dawson, Viktor Hendrik Koelzer, Abbas Agaimy, Fabian Garreis, William Laqua, Alessandro Lugli, Arndt Hartmann, Regine Schneider-Stock. High DAPK expression is correlated with worse prognosis in colorectal 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 3825. doi:10.1158/1538-7445.AM2014-3825
Abstract 3828: An 18-gene signature for vascular invasion is associated with aggressive features and reduced survival in breast cancer
Authors: Mannelqvist Monica , Wik Elisabeth , Stefansson Ingunn M. , Akslen Lars A.
Published: May 2015

Introduction: Vascular invasion, i.e. tumor cells entering the vascular system, is considered to be an early step in the metastatic process and important for the progress of malignant tumors. By microarray and qPCR, we previously constructed an 18-gene signature in relation to vascular invasion among endometrial cancer patients. Here, we wanted to investigate the vascular invasion signature (VIS) among breast cancers patients.

Methods: The 18-gene signature was studied in 11 gene expression data sets of breast cancer including information on 2423 patients. The genes in the signature were investigated in the external data sets and related to clinical data and follow-up information. We also wanted to examine if our signature was associated with other published signatures related to tumor progression.

Results and Conclusions: High VIS showed associations with aggressive features of breast cancer such as high tumor grade, hormone receptor negativity, HER2 positive tumors, presence of a basal-like phenotype, reduced patient survival and response to cytostatic treatment. Correlations between VIS and other signatures for tumor progression indicate an involvement in similar biological processes. In conclusion, the vascular invasion signature showed strong and consistent associations with aggressive features of breast cancer.

Citation Format: Monica Mannelqvist, Elisabeth Wik, Ingunn M. Stefansson, Lars A. Akslen. An 18-gene signature for vascular invasion is associated with aggressive features and reduced survival in breast 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 3828. doi:10.1158/1538-7445.AM2014-3828
Abstract 3830: E2F1-FOXM1 activation predicts progression of non-muscle invasive bladder cancer
Authors: Kim Seon-Kyu , Lee Se-Ra , Roh Yun-Gil , Song Bicna , Park Kiejung , Leem Sun-Hee , Chu In-Sun
Published: May 2015

Backgrounds: Bladder cancer is a genetic disorder driven by the accumulative changes of the multiple genes, such as E2F1, FOXM1, and EZH2. The objective of this study is to estimate a prognostic value of gene expression signature and identify putative signaling pathway for mediating progression of non-muscle invasive bladder cancer (NMIBC).

Methods: Gene expression profiling was performed using primary NMIBC cohort to identify a signature correlated with disease progression. The signature was validated in three independent cohorts. The association between the signature and prognosis of NMIBC patients was assessed using various statistical methods including a leave-one-out cross-validation and multivariate Cox regression analyses. The upstream regulator analysis of the genes in the signature was performed by Ingenuity Pathway Analysis TM. We also confirmed a prognostic relevance of the signature with experimental assays using bladder cancer cell lines.

Results: Kaplan-Meier analysis in the discovery cohort revealed significant differences in disease progression associated with the expression signature of E2F1-associated genes (p = 0.003), which produced consistent prognostic pattern in the validation cohorts. Multivariate Cox regression analysis revealed that the signature was an independent strong predictor of disease progression (hazard ratio = 6.082, 95% confidence interval = 3.280 to 11.279, p < 0.001). In subset analyses, the signature could identify patients who would benefit from intravesical immunotherapy. Lastly, upstream regulator analyses and experimental assays of the signature revealed that NMIBC progression could be mediated by E2F1-FOXM1 pathways.

Conclusion: The prognostic molecular signature defined by activation of E2F1 and FOXM1 represents a promising diagnostic tool to identify high risk NMIBC patients.

Citation Format: Seon-Kyu Kim, Se-Ra Lee, Yun-Gil Roh, Bicna Song, Kiejung Park, Sun-Hee Leem, In-Sun Chu. E2F1-FOXM1 activation predicts progression of non-muscle invasive bladder 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 3830. doi:10.1158/1538-7445.AM2014-3830
Abstract 3832: Characterizing breast cancer CTCs for brain metastasis competence
Authors: Marchetti Dario
Published: May 2015

Mechanisms causing fatal breast cancer brain metastasis (BCBM) remain largely unknown as well as functionalities of brain-colonizing circulating tumor cells (CTCs) in BCBM disease.We have characterized CTCs isolated from peripheral blood mononuclear cells of patients with breast cancer by multi-parametric flow cytometry. In epithelial cell adhesion molecule (EpCAM)-negative CTCs, we identified a “brain metastasis selected marker” (BMSM) profile or HER2+/EGFR+, HPSE+ and Notch1+ CTCs. These CTCs, which are not captured by the CellSearchTM (Veridex, LLC)platform because of their EpCAM negativity, were analyzed for cell invasiveness and metastatic competency in vivo. CTCs expressing the BMSM profile were highly invasive and capable of generating metastases when xenografted in nude mice. Notably, increased brain metastatic capabilities, frequency and quantitation were detected in EpCAM− CTCs overexpressing the BMSM profile. The presence of proteins of this profile was also verified in the metastatic lesions of animals. Further, investigations of viable BMSM CTCs were carried out using the DEPArrayTM, a dielectrophoresis-based platform able to detect and sort pure CTCs which were investigated by whole genome amplification and proteomic content. CTC subsets were derived possessing combinatorial levels of the BMSM profile and distinct abilities to generate BCBM.Collectively, we provide evidence of isolation, culture and characterization of human breast cancer CTCs leading to the description of a BMSM protein profile that is considered necessary for CTC metastatic competency to brain. Studies are presently undergoing to capture multiple CTC subsets and validate the presence of the BMSM profile in longitudinal studies of populations of breast cancer patients with the objective to not only better understand BCBM onset but also to predict disease course for improved and informed clinical treatment.

Citation Format: Dario Marchetti. Characterizing breast cancer CTCs for brain metastasis competence. [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 3832. doi:10.1158/1538-7445.AM2014-3832
Abstract 3834: The National Biomarkers Development Alliance (NBDA): A comprehensive solution
Authors: Compton Carolyn C. , Team The NBDA
Published: May 2015

The development of effective and robust biomarkers is essential to the realization of the vision of precision medicine. Despite huge investments in biomarker discovery and development over decades, less than 100 biomarkers are used routinely in clinical medicine; and approximately 1.3 new protein biomarkers are approved per year by FDA - extremely few new biomarkers are approved by the FDA each year. At present, the high costs and failure rates in biomarker development represent one of the most significant roadblocks to medical progress. The biomarker development process itself requires re-engineering to reduce the massive inefficiencies, fragmentation, and failure rates that now characterize the system.

The NBDA is a nonprofit organization of academic, industry and government partners which aims to create a standards-based, comprehensive end-to-end approach to the development of biomarkers of different categories within a given context of use, guided throughout the development pipeline by regulatory and clinical implementation requirements. The NBDA will work with multi-sector stakeholders across the biomarker development continuum to identify where in the process standards matter, determine the status of existing standards and identify gaps, aggregate information referable to specific biomarkers and biomarker classes, and reproduce the work. NBDA will publish the recommendations it develops by consensus and science, building on the best of current practices. It will act in consultation with the FDA and professional standards organizations in order to meet the levels of evidence for biomarker qualification by regulators and validation in clinical use. Through standards and quality management approaches, it will link and integrate discovery, pre-clinical development, assay development and performance, clinical testing, regulatory approval, and post-market applications. Pilot projects in development are focused on newer classes of biomarkers: e.g., genomic biomarkers such as allelic variance as determined by next generation sequencing technologies; proteomics biomarkers generated by mass spectroscopy; volumetric and functional imaging; and complex biomarkers defined as combinations of different classes of biomarkers, the useful value of which is determined computationally. The ever more rapid development of assay technologies dictates that standards that allow them to be applied successfully to biomarker development keep pace. This can only be accomplished through broad coordination of effort and consensus, which is the goal of the NBDA.

Citation Format: Carolyn C. Compton, The NBDA Team. The National Biomarkers Development Alliance (NBDA): A comprehensive solution. [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 3834. doi:10.1158/1538-7445.AM2014-3834
Abstract 3838: Differential expression of Notch1 in lung, ovarian and breast cancers
Authors: Nguyen Dat , Rubinstein Larry , Sherman Mark E. , Tomaszewski Joseph E. , Takebe Naoko , Ivy Percy , Doroshow James H. , Yang Sherry X.
Published: May 2015

Targeting the Notch signaling pathway for cancer treatment is currently the subject of early clinical trials. However, treatment-related toxicities, particularly gastrointestinal adverse events, have limited clinical development of this class of agents. The development of efficacy biomarkers to gamma-secretase inhibitors and antibodies to Notch ligands and receptors could speed clinical testing. Mutations in Notch1, a dominant Notch receptor, are rare in human solid tumors, and clinical activity has not been observed in patients with tumors bearing Notch1 activating mutations, including T-cell acute lymphoblastic leukemia from available clinical data. Identification of tumors with abundant target expression and/or active Notch signaling status characteristic of Notch intracellular domain (NICD) expression by immunohistochemistry may have clinical utility. All levels of tumor Notch1 expression comprised of low, moderate and high detected by immunohistochemistry and quantitated by digital imaging technology were observed in 52% (34/66) of lung cancers, 51% (35/68) of ovarian cancers, and 11% (7/63) of breast cancers (lung or ovary vs. breast, P<0.0001 by 2-sided Fisher Exact Test). Notch1 was expressed at high levels in 20% of lung cancers including sarcoma, neuroendocrine, small cell and undifferentiated carcinomas, as well as adenocarcinoma and squamous cell carcinomas. High expression of Notch1 was observed in 9% of ovarian tumors including undifferentiated carcinoma, serous adenocarcinoma, and endometrioid adenocarcinoma. In breast cancer, it was noted in one case of infiltrating ductal carcinoma with triple-negative phenotype. Expression of high-level Notch1 varies in lung cancer vs. ovarian cancer vs. breast cancer (P=0.002 by Chi-square statistic), and was frequently associated with NICD expression. Notch1 was not significantly associated with estrogen receptor, progesterone receptor or HER2 status in breast cancer. These data suggest that the frequency of all levels of Notch1 expression is significantly higher in lung cancer and ovarian cancer than breast cancer; and high-level Notch1 is more frequent in lung cancer than in ovarian cancer, and, likewise, more frequent in ovarian cancer than in breast cancer. For the first time, expression of Notch1/NICD has been identified in undifferentiated carcinomas. The findings may provide useful information for the rational design of Notch inhibitor clinical trials.

Citation Format: Dat Nguyen, Larry Rubinstein, Mark E. Sherman, Joseph E. Tomaszewski, Naoko Takebe, Percy Ivy, James H. Doroshow, Sherry X. Yang. Differential expression of Notch1 in lung, ovarian and breast cancers. [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 3838. doi:10.1158/1538-7445.AM2014-3838
Abstract 3842: Relationship between weight change and response to trastuzumab-based neoadjuvant chemotherapy among women with operable HER2 overexpressing breast cancer
Authors: Hajjaji Nawale , Chocteau Dorothee , Gerard Sylvie , Orgerie Marie Brigitte
Published: May 2015

Purpose

Weight change (gain or loss) in early breast cancer patients is associated with worse survival. However, limited research investigates the impact of weight change in the neoadjuvant setting in women with HER2 overexpressing breast cancer. The goals of this study were to examine i) the relationship between weight change during trastuzumab-based neoadjuvant chemotherapy and pathologic response, and ii) determine whether weight change during post-operative trastuzumab was associated with outcome.

Patients and methods

From March 2004 to March 2013, 52 patients diagnosed with invasive non-metastatic HER2 overexpressing breast cancer were recruited from H.S. Kaplan Cancer center, France. They received trastuzumab-based neoadjuvant chemotherapy (NAC) before surgery, followed by adjuvant trastuzumab. Patients were distributed in the “weight loss” or “weight gain/stable” categories according to their relative weight change after NAC, and after adjuvant trastuzumab. Logistic regression was used to examine associations between weight change and pathologic response. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to evaluate the relationship between weight change and progression free survival (PFS).

Results

Median age was 50 years (range 21 to 71 years); 25% of women experienced body weight loss during NAC, 40% had stable body weight, and 35% gained weight. In multivariate analysis, weight loss was significantly associated with worse pathologic complete response (pCR) in tumor compared with the weight gain/stable group (OR = 0.18; 95% CI, 0.04 to 0.84). There was no difference in pCR in nodes according to weight change (OR = 0.34; 95% CI, 0.06 to 1.76). Body mass index was not associated with pCR. At a median follow up time of 3 years, PFS was not associated with weight change during NAC but with weight change during adjuvant trastuzumab. PFS was worse in patients loosing weight during adjuvant trastuzumab (OR = 0.05; 95% CI, 0.01 to 0.34).

Conclusion

Weight loss was associated with worse pCR to trastuzumab-based neoadjuvant chemotherapy. In addition, weight loss during adjuvant trastuzumab was associated with worse PFS. These results suggest that weight control and promotion of weight maintenance in women with HER2 overexpressing breast cancer should be integrated within cancer treatment to optimize patient outcomes.

Citation Format: Nawale Hajjaji, Dorothee Chocteau, Sylvie Gerard, Marie Brigitte Orgerie. Relationship between weight change and response to trastuzumab-based neoadjuvant chemotherapy among women with operable HER2 overexpressing breast 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 3842. doi:10.1158/1538-7445.AM2014-3842
Abstract 3845: Symptoms burden in subjects with cervical cancer and supportive care:A view from a developing country
Authors: Olagunju Andrew T. , Aina Olatunji F. , Sarimiye Foluke O. , Olagunju Tinuke O.
Published: May 2015

Objectives: Cervical cancer is not only a leading gynecologic cancer in the developing countries but disproportionately accounts for the burden due to cancer. In spite of the need for holistic care of cervical cancer, little is known about the experience of the affected populations beyond their cancer treatment. This study aims to investigate the pattern and distribution of symptoms burden in subjects with cervical cancer in a developing context.

Methods: This cross sectional study was carried out among 122 consenting participants with cervical cancer using a designed questionnaire to elicit socio-demographic with clinical profile and symptoms burden. Subsequently, Centre for Epidemiological Studies Depression Scale Revised (CESD-R) was used to ascertain presence of depressive symptoms in participants. Data analyses were done using SPSS-15.

Results: Majority of the subjects, 50(41.0%) and 68(55.7%) were in their fifth decade of life and unmarried respectively. Six (4.9%) participants presented with early stage cancer, while close to two-thirds of the participants made up of 76(62.3%) subjects had advanced stage cancer. The largest proportion, consisting of about 7 in every 10 participants had pain, 70(57.4%) participants reported sexual dysfunction, and common sexual problems that were reported include loss of libido, dyspareunia and anorganism among others. In addition, physical complications like ulcer, weight loss and multiple complaints were seen in 56(45.9%) participants. Significant depressive symptoms based on CESD-R cut-off score of 16 and above was elicited among close to half of the participants, 58(47.5%).

Conclusions: Late presentation and significant burden of diverse symptoms including pain, sexual, physical and depressive were prevalent among individuals with cervical cancer. Health education with proactive health interventions to promote early presentation and supportive care to ensure qualitative overall care are implied.

Citation Format: Andrew T. Olagunju, Olatunji F. Aina, Foluke O. Sarimiye, Tinuke O. Olagunju. Symptoms burden in subjects with cervical cancer and supportive care:A view from a developing country. [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 3845. doi:10.1158/1538-7445.AM2014-3845
Abstract 3850: Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic-Americans: A case control study
Authors: Sun Yuhui , Stroehlein John , Ajani Jaffer , Chang David , Wu Xifeng , Gu Jian
Published: May 2015

Background: Hispanics are the largest non-white ethnic group in the U.S. and account for approximately 17% of U.S. population. Hispanics have higher incidence and mortality rates for gastric cancer than whites or Asians. Association studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for gastric cancer in whites and Asians. However, no studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics. Methods: In a case-control study of 132 Hispanic gastric cancer patients and 125 Hispanic controls, we evaluated the association of 5 previously identified, single nucleotide polymorphisms (SNPs) predisposing to gastric cancer in whites and/or Asians. In addition, two intermediate phenotypic markers in peripheral blood leukocytes, i.e., telomere length and mitochondrial DNA (mtDNA) copy number, were examined with respect to risk for gastric cancer.

Results: The variant C allele of the SNP rs2294008 in PSCA gene was associated with a significantly reduced risk of gastric cancer (per allele OR=0.60, 95%CI, 0.41-0.88; P=0.009) after adjusting for age, gender, and smoking status. Low mtDNA copy number was associated with a significantly increased risk of gastric cancer (OR=6.83; 95%CI, 3.33-14.00; P <0.01). Telomere length was not significantly associated with the risk of gastric cancer (OR=1.25, 95% CI, 0.70-2.24; P=0.450).

Conclusion: Hispanics share certain genetic susceptibility loci and intermediate phenotypic biomarkers with whites and Asians, but may also have distinct genetic susceptibility factors related to risk for gastric cancer

Citation Format: Yuhui Sun, John Stroehlein, Jaffer Ajani, David Chang, Xifeng Wu, Jian Gu. Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic-Americans: A 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 3850. doi:10.1158/1538-7445.AM2014-3850
Abstract 3857: Induction of ALDH1A2 expression is critical for cancer stem cell properties in neuroblastoma
Authors: Nishimura Noriyuki , Hartomo Tri Budi , Pham Thi Van Huyen , Yamamoto Nobuyuki , Hrase Satoshi , Hayakawa Akira , Hasegawa Daiichiro , Kawasaki Keiichiro , Kosaka Yoshiyuki , Matsuo Masafumi , Takeshima Yasuhiro , Iijima Kazumoto , Nishio Hisahide
Published: May 2015

Neuroblastoma is an aggressive tumor characterized by its heterogeneity ranging from spontaneous regression to malignant progression, and accounts for ∼15% of all cancer-related deaths in children. Despite current aggressive therapies, over 50% of high-risk neuroblastoma patients have experienced a tumor relapse. As in most cancers, recurrent neuroblastoma is primarily driven by chemoresistant cancer stem cells (CSCs), which are identified as a subpopulation of cancer cells with the multipotent ability to self-renew, generate differentiated progeny, and recapitulate a heterogeneous population of cancer cells in xenograft cancers. An increasing number of studies isolated CSCs as spheres, side population cells, and cell-surface marker-positive cells based on the markers associated with stem cell populations in a variety of cancers. Although high activity of aldehyde dehydrogenase (ALDH), which catalyzed the oxidation of aldehydes to carboxylates and comprised 19 isoforms in human cells, was used to identify and isolate CSCs from many types of cancers, it remained to be characterized in neuroblastoma. In the present study, we investigated the ALDH activity and the expression profile of 19 ALDH isoforms in spheres and parental cells of neuroblastoma. The ALDH activity was enriched in spheres compared to parental cells, while the expression profile was considerably varied among different neuroblastoma cells. Among ALDH isoforms consistently induced in spheres, ALDH1A2 knockdown most severely impaired the sphere and colony formation. Reciprocally, increased expression of ALDH1A2 enhanced these functions in neuroblastoma cells. ALDH1A2 expression was further correlated with the differentiation of neuroblastoma xenografts, the resistance to 13-cis-retinoic acid (13-cRA), and the overall survival of neuroblastoma patients. These results suggest that the induction of ALDH1A2 expression is critical for CSC properties in neuroblastoma.

Citation Format: Noriyuki Nishimura, Tri Budi Hartomo, Thi Van Huyen Pham, Nobuyuki Yamamoto, Satoshi Hrase, Akira Hayakawa, Daiichiro Hasegawa, Keiichiro Kawasaki, Yoshiyuki Kosaka, Masafumi Matsuo, Yasuhiro Takeshima, Kazumoto Iijima, Hisahide Nishio. Induction of ALDH1A2 expression is critical for cancer stem cell properties in 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 3857. doi:10.1158/1538-7445.AM2014-3857
Abstract 3862: Isolation and nanoscale visualization of glioblastoma stem-like cells utilizing the Notch1 receptor
Authors: Pohlmann Elliot , Murphy Susan , Kelly Debbie , Sheng Zhi
Published: May 2015

Tumor eradication is an elusive goal in modern medicine. This unmet goal is in part due to the imprecise therapeutic targeting of a specific population of cells having “stem-like” properties. These stem-like tumor cells can remain almost senescent during chemotherapeutic interventions to evade treatment and produce genetically different secondary tumor lineages than their parental tumors. Here we develop a novel approach that utilizes the Notch1 receptor, found on the surface of glioma cells, to isolate a population of cells bearing stem-like properties. We identified this population to be Nestin+GFAP-, capable of serum differentiation into Nestin-GFAP+ cells, and self-regenerating. In addition, this unique population of cells has increased stem-like qualities compared to the CD133 marker. Utilizing affinity nanocapture grids, we were able to visualize Notch1+ stem-like cells and the perforation of their plasma membranes by unlabeled gold nanorods via electron microscopy. Previous studies have shown that tumor stem-like cells can exist within the larger tumor milieu, representing a potential threat to recurrence. We propose that 1) Notch1 may serve as a novel marker to define glioblastoma stem-like cells, capable of being used for targeting chemotherapeutic approaches in the future, and 2) affinity nanocapture grids represent a unique method for examining individual living cells at the nanoscale.

Citation Format: Elliot Pohlmann, Susan Murphy, Debbie Kelly, Zhi Sheng. Isolation and nanoscale visualization of glioblastoma stem-like cells utilizing the Notch1 receptor. [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 3862. doi:10.1158/1538-7445.AM2014-3862
Abstract 3874: Loss of DDB2 enhances the tumorigenicity of ovarian cancer cells through expanding cancer stem-like cell population
Authors: Han Chunhua , Zhao Ran , Liu Xingluo , Srivastava Amit Kumar , Gong Li , Mao Hsiaoyin , Qu Meihua , Zhao Weiqiang , Yu Jianhua , Wang Qi-En
Published: May 2015

Ovarian cancer is an extremely aggressive disease associated with a high percentage of recurrence and chemotherapy resistance. DNA damage binding protein 2 (DDB2) is a 48-kDa protein originally identified as a component of the damage-specific DNA-binding heterodimeric complex DDB. Besides the known ability of DDB2 protein to bind ultraviolet (UV)-damaged DNA and serving as the initial damage recognition factor during nucleotide excision repair (NER), DDB2 was also reported to be involved in the promotion of apoptosis to reduce cisplatin resistance of ovarian cancer cells, control of cell migration, invasiveness and breast tumor progression, as well as suppression of metastasis of colon cancer through a transcriptional regulatory mechanism. Here we show that DDB2 is downregulated in human ovarian serous adenocarcinomas. DDB2 overexpression in human ovarian cancer cell line CP70 suppressed its capability to recapitulate tumors in athymic nude mice, as well as the growth of these cells cultured in semisolid media. Flow cytometry analyses indicate that DDB2 overexpression in CP70 cells reduced the abundance of ALDH+ cells, which are believed to be cancer stem-like cells (CSCs) in ovarian cancer. In contrast, downregulation of DDB2 in ovarian cancer cell line A2780 increased the percentage of ALDH+ cells. In addition, we analyzed the expression level of DDB2 in the putative CSCs isolated from various ovarian cancer cell lines, and demonstrated that DDB2 expression is downregulated in all tested CSCs in comparison with their parental bulk tumor cells. Overexpression of DDB2 in the ovarian CSCs reduced the expression of CSC marker Nanog, as well as inhibited the self-renewal of these CSCs. In addition, overexpression of DDB2 in CSCs isolated from ovarian cancer cell line SKOV-3 also decreased the tumorigenicity of these cells in NOD/SCID mice. Further analysis of publicly available gene expression array datasets revealed that low DDB2 expression correlates with poor outcomes among ovarian cancer patients, suggesting that loss of DDB2 may promote ovarian tumor relapse through expanding CSC population. Given that the DDB2 protein level is downregulated in ovarian tumor cells, targeting DDB2 expression could be a promising strategy to eradicate CSCs, and helps to halt ovarian cancer relapse. (Supported by NIH R01 grant CA151248 to QEW)

Citation Format: Chunhua Han, Ran Zhao, Xingluo Liu, Amit Kumar Srivastava, Li Gong, Hsiaoyin Mao, Meihua Qu, Weiqiang Zhao, Jianhua Yu, Qi-En Wang. Loss of DDB2 enhances the tumorigenicity of ovarian cancer cells through expanding cancer stem-like cell population. [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 3874. doi:10.1158/1538-7445.AM2014-3874
Abstract 3877: Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype
Authors: Nakano Ichiro
Published: May 2015

High grade glioma (HGG) is a life-threatening brain tumor. Among heterogeneous tumor cells, glioma stem cells (GSCs) are defined as a subpopulation resistant to chemo- and radiotherapy with prominent tumorigenic ability. Identification of novel therapeutics designed to target the GSC population in HGGs is a challenge. The recent genome-wide transcriptome analysis identified 3 subtypes, proneural (PN), proliferative, and mesenchymal (MES), in HGGs. These HGG subtypes harbor distinct gene signatures and altered signaling pathways with some clinical relevance. During malignant transformation, HGGs appear to gain therapy resistance, at least in part, through their phenotypic drift into mesenchymal tumors. In addition, some of the current therapies, if not all, appear to induce mesenchymal transformation of HGGs resulting in more therapy-resistant tumors. Nonetheless, identification of subtype-specific GSCs remains elusive.

My lab recently identified clinical HGG sample-derived two mutually-exclusive GSCs: PN and MES GSCs with striking phenotypic differences with clinical relevance (Mao et al., PNAS 2013). Transcritpome microarray analysis, miRNA profiling, and subsequent functional analysis demonstrated that distinct signaling pathways regulate tumorigenesis and propagation of the individual GSC subtypes. For example, PN GSCs are dependent on the oncogenic transcription factor c-Myb (Miyazaki et al., Clinical Cancer Res. 2012) and MES GSCs are dependent on the oncogene/mitotic kinase MELK and Survivin (Guvenc et al., Clinical Cancer Res. 2012; Gu et al., Stem Cells 2013; Joshi et al., Stem Cells 2013). Intriguingly, upon radiation treatment, PN GSCs gain the phenotypes of MES GSCs (PN-to-MES transformation; PMT), which are much more aggressive and radioresistant than original PN GSCs. Of note, targeting the MES-specific pathways partially blocks PMT of GSCs. These results may patially explain the molecular mechanisms underlying mesenchymal transformation of HGGs to promote therapy resistance. Here I summarize our latest data to elucidate the molecular mechanisms that drive GSC evolution to promote their therapy resistant phenotype.

Citation Format: Ichiro Nakano. Evolution of cancer stem cells in glioma to promote their therapy-resistant phenotype. [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 3877. doi:10.1158/1538-7445.AM2014-3877
Abstract 3880: Targeting the root of cancer: a data-driven approach for identification of lung cancer stem cell biomarkers
Authors: Fan-Minogue Hua , Butte Atul
Published: May 2015

Cancer stem cells (CSCs) are a small group of cancer cells with stem cell-like properties and have been revealed to be the drive force of tumorigenesis, metastasis and drug resistance in many cancers. Current CSC surface biomarkers, such as CD133, CD44 and CD166, have been used to isolate CSC population. However, they are often not specific and unassociated with tumor outcome. Here, we applied a data-driven approach to identify new and functional biomarkers of CSC. We systematically screened for genes whose expressions are statistically correlated with CSC surface biomarkers. Normalized DNA microarray data of 160 cases of squamous carcinoma and 33 cases of adenocarcinoma and 8 cases of normal lung were analyzed for association with CD133, CD44 and CD166 respectively. Multiple hypothesis testing was corrected with the false discovery rate (FDR) less than 1%. We find CD133, CD44 and CD166 each has a different set of statistically associated genes in either adeno or squamous subtypes. Moreover, correlated genes with each of the surface marker are different between adeno and squamous subtypes. Among the highly correlated receptor genes with CD133 in squamous subtype is a hormone receptor of the reproduction regulator oxytocin (OXTR, r=0.4276, p=1.699e-8). We experimentally validated the correlation between OXTR and CD133 in human lung cancer tissues and cell lines. Further with functional assays, we discovered a new role of OXTR in promoting the self-renewal and differentiation of lung CSC. Our study suggests highly heterogeneous molecular features of CSC in different lung cancer types and demonstrates that association studies of CSC surface markers can be applied to identify new CSC biomarkers, which can be potentially used for development of probes for CSC imaging and targeting.

Citation Format: Hua Fan-Minogue, Atul Butte. Targeting the root of cancer: a data-driven approach for identification of lung cancer stem cell biomarkers. [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 3880. doi:10.1158/1538-7445.AM2014-3880
Abstract 3896: The Hippo coactivator YAP1 upregulates SOX9 and endows cancer stem cell properties in non-transformed cells and esophageal cancer cells
Authors: Song Shumei , Ajani Jaffer A. , Honjo Soichiro , Maru Dipen M. , Chen Qiongrong , Jin Jiankang , Scott Ailing W. , Heallen Todd R. , Xiao Lianchun , Hofstetter Wayne L. , Weston Brian , Lee Jeffrey H. , Wadhwa Roopma , Sudo Kazuki , Martin James F. , Stroehlein John R. , Hung Mien-Chie , Johnson Randy L.
Published: May 2015

Cancer stem cells are proposed to initiate and maintain tumor growth. Dysregulation of normal stem cell signaling may lead to the generation of cancer stem cells (CSCs), however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional co-activator YAP1 through direct regulation of SOX9 promotes the generation of CSCs and that the inhibition of YAP1 and SOX9 attenuates CSC formation. SOX9 transcripts and expression are upregulated upon YAP1 activation and several lines of evidence indicate that SOX9 is a direct target of YAP1. The Chromatin Immunoprecipitation analysis and luciferase assays demonstrate direct binding of YAP1 to the SOX9 promoter through a conserved TEAD binding site. Mutation of this site abrogates transcriptional regulation of SOX9 by YAP1 and Tead2. Functional studies demonstrate that YAP1 regulation of SOX9 is necessary and sufficient to confer CSC properties and tumorigenesis in vitro and in vivo. The small molecule inhibitor of YAP1, Verteporfin (VP) significantly blocks CSC self-renewal properties in cells with high YAP1 and a high proportion of the CSC marker aldehyde dehydrogenase 1 (ALDH1) indicating that VP targets the CSC population. These data identify YAP1 as a driver of esophageal cancer (EC) stem cells, in part, by regulation of SOX9 and suggest that pharmacological inhibition of YAP1 may be an effective means of specifically targeting EC stem cells.

Citation Format: Shumei Song, Jaffer A. Ajani, Soichiro Honjo, Dipen M. Maru, Qiongrong Chen, Jiankang Jin, Ailing W. Scott, Todd R. Heallen, Lianchun Xiao, Wayne L. Hofstetter, Brian Weston, Jeffrey H. Lee, Roopma Wadhwa, Kazuki Sudo, James F. Martin, John R. Stroehlein, Mien-Chie Hung, Randy L. Johnson. The Hippo coactivator YAP1 upregulates SOX9 and endows cancer stem cell properties in non-transformed cells and esophageal 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 3896. doi:10.1158/1538-7445.AM2014-3896
Abstract 3909: Cisplatin resistant head and neck cancer cells are susceptible to growth inhibition by CDF curcumin
Authors: Basak Saroj K. , Zinabadi Alborz , Venkatesan Natarajan , Duarte Victor M. , Dalgard Clifton L. , Srivastava Meera , Wang Marilene B. , Sarkar Fazlul H. , Srivatsan Eri S.
Published: May 2015

Head and neck (H&N) cancer is the sixth most common type of cancer, with about 650,000 new cases in the world every year. Platinum-based agents (cisplatin/carboplatin) are the most common chemotherapeutic agents for H&N cancer; however the five year survival rate is only 50% and development of drug resistance is one of the major challenges for effective therapy. Thus, development of new strategies to overcome drug resistance will help in H&N cancer treatment. Our studies using H&N cancer cisplatin resistant cell lines in vitro have indicated that Cancer Stem cell (CSC) specific markers such as CD44 and cytokines (IL-8, IL-10) are up-regulated during the development of drug resistance. Furthermore, our in vitro studies indicated that the treatment of drug resistant cell lines with a novel synthetic curcumin analog known as CDF in liposomal encapsulation (liposomal CDF) resulted in statistically significant growth inhibition (p<0.05). Similarly, our studies in a nude mouse xenograft drug resistant H&N cancer tumor model showed that treatment with liposomal CDF (1 mg/100 µl in saline, i.v. injection 5 days a week for 3 weeks) resulted in greater than 50% tumor growth inhibition. The CDF treated cell lines and xenograft tumors showed a statistically significant reduction in the expression of CD44 (p<0.05), indicating an inhibitory effect of CDF on cancer stem cells, which is consistent with previously published data on other tumor models. These results demonstrate that CDF can be useful for the treatment of drug resistant H&N cancer.

Citation Format: Saroj K. Basak, Alborz Zinabadi, Natarajan Venkatesan, Victor M. Duarte, Clifton L. Dalgard, Meera Srivastava, Marilene B. Wang, Fazlul H. Sarkar, Eri S. Srivatsan. Cisplatin resistant head and neck cancer cells are susceptible to growth inhibition by CDF curcumin. [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 3909. doi:10.1158/1538-7445.AM2014-3909