bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3189: Targeting NPM1 for controlling growth of Ewing sarcoma
Authors: Traver Geri , Sekhar Konjeti R. , Renthala Narsimha R. , Crooks Peter A. , Ofori Maxwell , Freeman Michael L. 
Published: August 2018

Abstract
Ewing sarcoma is a rare cancer found in children and young adults. Long term survival rates are approximately 70% for patients who present without clinically overt metastases. However, 5 year survival is less than 20% for patients with recurrent tumors or metastasis. Thus, there is a need to improve local tumor control and to treat metastatic disease. Eighty five percent of these cancers are driven by the reciprocal chromosomal translocation t (11;22) (q24;q12), a consequence of a fusion between the 5' portion of Ewing sarcoma breakpoint region 1 on EWSR1 (chromosome 22) and the 3' portion of Friend leukemia virus integration site 1 on FLI1 (chromosome 11). Nucleophosmin1 (NPM1) is a chaperone protein involved in many cellular functions, including DNA repair. NPM1 has been shown to be a novel prognostic biomarker for patients with localized Ewing's sarcoma. Overall survival is significantly lower for patients whose tumors express high levels of NPM1. Besides promoting repair of DNA double strand breaks NPM1 directly interacts with and induces c-Myc-induced hyperproliferation and transformation. Consistent with this knowledge is the observation that relapsed Ewing's patients exhibit high levels of c-Myc expression compared to disease-free patients. Therefore, we wanted to ascertain whether NPM1 represented a molecular target for controlling growth of Ewing's sarcoma. CRISPR/Cas9-mediated targeting of NPM1 exons 3 and 4, as well as lentivirus-mediated shRNA targeting of NPM1 mRNA revealed that targeting of NPM1 expression reduced survival (colony formation) of TC32 and A673 cells (P&lt;0.05). NPM shRNA also reduced TC32 sphere formation under non-adherent conditions. YTR107 and NSC348884 are small molecule inhibitors of NPM1 oligomerization, which is required for NPM1 activity. Both drugs reduced survival of TC32 and A673 Ewing's sarcoma cells in a dose-dependent fashion (P&lt;0.05). We interpret these data to indicate that NPM1 represents a potential molecular target for controlling growth of Ewing's sarcoma. Supported in part by RO1CA140409.
Citation Format: Geri Traver, Konjeti R. Sekhar, Narsimha R. Renthala, Peter A. Crooks, Maxwell Ofori, Michael L. Freeman. Targeting NPM1 for controlling growth of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3189.
Abstract 32: BCL11A is necessary for the expression of extracellular matrix genes and metastatic progression of triple-negative breast cancer
Authors: Seachrist Darcie D. , Ingles Natasha N. , Hannigan Molly M. , Licatalosi Donny D. , Keri Ruth A. 
Published: August 2018

Abstract
Cancer stem cells (CSC) contribute to the high incidence of metastatic recurrence in triple-negative breast cancer (TNBC) and elucidating the mechanisms controlling CSC properties should provide novel targets for therapeutic development that improves patient outcomes. The transcription factor BCL11A is highly differentially expressed in TNBC versus all other subtypes and controls breast CSC phenotypes such as marker expression and tumor initiation. However, the genes that BCL11A targets to control CSC biology and whether BCL11A promotes metastatic progression are unknown. To address these questions, we assessed the impact of transiently silencing the expression of BCL11A in TNBC cells using siRNA transfections. Reducing BCL11A expression did not impact TNBC cell viability or in vitro migratory capacity. However, silencing BCL11A significantly decreased invasion of TNBC cell lines, in vitro. Furthermore, stable shRNA-mediated silencing of BCL11A in the highly metastatic MDA-MB-231 cell line reduced metastatic outgrowth when xenografted into immunocompromised mice, suggesting that BCL11A is critical for metastatic progression of TNBC. To identify the BCL11A-regulated transcriptome in TNBC, we performed RNA-seq analysis of cells transiently transfected with non-targeting or BCL11A-targeted siRNAs in the MDA-MB-231 cell line. Consistent with the impact of BCL11A on invasion, numerous genes involved in adhesion and extracellular matrix were reduced with BCL11A silencing. The gene encoding the matrix metalloproteinase, MMP1, was the most significantly differentially expressed gene, with a 10-fold decrease in RNA expression following BCL11A suppression. We confirmed this down-regulation by both qRT-PCR and western blots of independent samples, as well as in the HCC1143 TNBC cell line. Current studies are assessing the functional impact of MMP1 regulation by BCL11A on invasion and metastatic progression of TNBC.
Citation Format: Darcie D. Seachrist, Natasha N. Ingles, Molly M. Hannigan, Donny D. Licatalosi, Ruth A. Keri. BCL11A is necessary for the expression of extracellular matrix genes and metastatic progression of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 32.
Abstract 3205: Histone tyrosine phosphorylation determines glioblastoma cell survival
Authors: Hossain Mohammad Belayat , Shifat Rehnuma , Kim Debora K. , Rivera-Molina Yiesel , Martinez Francisco Puerta , Jiang Hong , Nguyen Teresa , Johnson David G. , Bedford Mark T. , Hung Mien-Chie , Sulman Erik P. , Lang Frederick , Sawaya Raymond , Fueyo Juan , Gomez-Manzano Candelaria 
Published: August 2018

Abstract
Histone modification is crucial for cell signaling pathways and regulates predominantly chromatin functions related with DNA damage response (DDR) that lead cancer cells to survive upon different therapies. Receptor tyrosine kinases (RTKs) have been extensively studied in cancer progression and DDR and, recently, several reports described the role of RTKs in histone tyrosine modification. We have been focusing on the role of the receptor tyrosine kinase, TIE2, in gliomas. Our study identified the expression of TIE2 in human surgical glioma specimens in relation to malignancy, specifically in brain tumor stem cells. We have revealed that the unexpected membrane-to-nuclear trafficking of TIE2 is related with radioresistance of brain tumor stem cells, functioning as a genotoxic stress sensor to activate DNA repair machinery. Interestingly, TIE2 binds, upon IR stress, to DNA/protein complexes and phosphorylates several core histones. The tandem mass spectrum of H4 and H2B demonstrates that TIE2 directly phosphorylates not previously described H4pY51 and H2BY40 respectively, which reinvigorates TIE2's role in histone code modification. We screened for pY-readers using a SH2 domain array and found that H4pY51 and H2pY40 modifications are read by the proto-oncogenes ABL1 and CRK, respectively. Our data also showed that TIE2/H4pY54/ABL1 complex binds to DNA repair proteins, activating an NHEJ DNA repair mechanism. We summarize that upon IR stress TIE2 localizes to the nucleus where it is involved in key cellular functions by directly phosphorylating core histones, and recruiting SH2 domain proteins to the DNA damage sites, complexing to the DNA repair machinery, which in turns results in radioresistance. Our data highlight the role of epigenetics in modulating the DNA damage response of glioma radiation therapy and open new avenues to find novel targetable pathways for treatment of patients with glioblastomas.
Citation Format: Mohammad Belayat Hossain, Rehnuma Shifat, Debora K. Kim, Yiesel Rivera-Molina, Francisco Puerta Martinez, Hong Jiang, Teresa Nguyen, David G. Johnson, Mark T. Bedford, Mien-Chie Hung, Erik P. Sulman, Frederick Lang, Raymond Sawaya, Juan Fueyo, Candelaria Gomez-Manzano. Histone tyrosine phosphorylation determines glioblastoma cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3205.
Abstract 322: High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with superior survival and platinum sensitivity
Authors: Hollis Robert L. , Churchman Michael , Rye Tzyvia , McCavigan Andrena M. , Knight Laura A. , Kennedy Richard , Herrington C. Simon , Gourley Charlie 
Published: August 2018

Abstract
EMSY, encoding a BRCA2-binding protein, is reportedly amplified in 6-18% of high grade serous ovarian carcinomas (HGSOCs). As a negative regulator of BRCA2, HGSOCs with EMSY overexpression may mimic BRCA-mutant patients, who experience superior clinical outcome and hypersensitivity to platinum chemotherapy and PARP inhibition by virtue of homologous recombination deficiency (HRD).
Here we investigate the impact of EMSY expression, extracted from local and publicly available transcriptomic data, on the outcome and platinum sensitivity of HGSOCs. Platinum response data were collected from the Edinburgh Ovarian Cancer Database. Overall survival (OS) and progression-free survival (PFS) differences were assessed using multivariate cox regression accounting for age, stage at diagnosis and debulking status.
Within the Edinburgh cohort, high EMSY expression was associated with superior OS and PFS (table 1). Datasets from the MRC ICON7 trial control arm, Tothill et al, Mateescu et al, Pils et al, and TCGA cohorts demonstrated similar benefit for high-EMSY patients. Within the Edinburgh cohort, high-EMSY patients displayed significantly superior complete response (CR) rate to platinum at second (radio CR 44.4% vs 12.5%, P = 0.035; CA125 CR 88.0% vs 55.0%, P = 0.002) and third exposure (radio CR 50.0% vs 5.9%, P = 0.080; CA125 CR 53.3% vs 21.3%, P = 0.021), with prolonged time to progression (median 127 vs 83.5 days from second platinum, P = 0.084; median 151.5 vs 60.5 days from third platinum, P = 0.004). Within high-risk (advanced stage suboptimally debulked) HGSOCs, more high-EMSY patients remained recurrence-free 5 and 10 years from diagnosis (17.6% vs 2.7%, P = 0.031; 12.5% vs 0.9%, P = 0.041).
Together these data demonstrate a subgroup of HGSOCs defined by high EMSY expression experience superior clinical outcome and platinum sensitivity, consistent with HRD. This subgroup may therefore represent HGSOCs that are also sensitive to PARP inhibition.
DatasetEventMulti HR95% CIPEdinburghOS0.590.39 – 0.900.013PFS0.600.38 – 0.930.022MRC ICON7 control armOS0.210.07 – 0.680.009Tothill (primary tumour masses)OS0.280.09 – 0.900.032MateescuOS0.430.18 – 0.990.048PilsOS0.270.08 – 0.870.028TCGA advanced stage patientsPFS0.690.45 – 1.050.081
Citation Format: Robert L. Hollis, Michael Churchman, Tzyvia Rye, Andrena M. McCavigan, Laura A. Knight, Richard Kennedy, C. Simon Herrington, Charlie Gourley. High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with superior survival and platinum sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 322.
Abstract 323: DNA damage response (DDR)-targeting strategy by targeting WEE1 and or ATM/ATR works in biliary tract cancer
Authors: Nam Ah Rong , Park Ji Eun , Bang Ju-Hee , Jin Mei Hua , Bang Yung-Jue , Oh Do-Youn 
Published: August 2018

Abstract
Background: Currently, targeting DNA damage response (DDR) is one strategy for new cancer drug development. DDR pathway involves DNA damage repair, cell cycle progression, apoptosis, and regulate the immune system. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. In BTC, DNA repair pathway, which includes BAP1, MSH6, BRCA1, ATM, MLH1, and MSH2, is altered in about 20 % of cases. TP53 module is observed in 33.9% of cases (Nat Genet 2015). The purpose of this study is to evaluate DNA damage response (DDR)-targeting strategy in BTC.
Methods: Using 10 kinds of BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, SNU1196, HuCCT-1, TFK-1, SNU2670, and SNU2773). AZD1775 (Wee1 inhibitor), AZD6738 (ATR inhibitor) and AZD0156 (ATM inhibitor) were tested.
Results: Among 10 cell lines, SNU308 and HuCCT1 were very sensitive to AZD1775, and SNU2670 and SNU2773 were relatively resistant to AZD1775. AZD1775 blocked phosphorylation of CDK1 (Y15) and CDK2 (Y15) in sensitive cells and but increased rH2AX in all cells. AZD1775 significantly increased apoptosis (cleavage of PARP and caspase-7) and G2/M arrest. Interestingly, Wee1 inhibitor increased pATR and pATM levels in resistant cells. AZD1775 in combination with AZD6738 or AZD0156 showed more potent antitumor effect than monotherapy of each drug.
Conclusion: Inhibition of Wee1 has an antitumor effect in some BTC cells. In combination with ATM/ATR inhibitors, the resistance to Wee1 inhibition could be overcome. Taken together, this study supports the further clinical development of DDR-targeting strategy in BTC as monotherapy or in combination.
Citation Format: Ah Rong Nam, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Yung-Jue Bang, Do-Youn Oh. DNA damage response (DDR)-targeting strategy by targeting WEE1 and or ATM/ATR works in biliary tract cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 323.
Abstract 3245: The interplay between patient´s features and mutational processes in tobacco related cancers
Authors: Lima João Paulo da Silveira Nogueira , Drummond Rodrigo Couto Duarte , Santos Monize Nakamoto Provisor , Valieris Renan , Mitrowsky Rafael Andres Rosales , Lima Vladmir Cordeiro , Nunes Diana Noronha , Dias-Neto Emmanuel , Silva Israel Tojal da 
Published: August 2018

Abstract
Background: There is a complex interplay between smoking and patient demographics in the emergence and development of cancer. We vetted the possible relationship between gender, race and age with mutational processes operating on aerodigestive tract cancers, known to be highly associated to tobacco. Methods: We used an empirical Bayesian approach to identify genomic patterns that lead to mutational processes in head and neck, esophageal, and lung cancers from TCGA database followed by confirmation in independent cohorts (cBioPortal). Results: After confronting clinical information and smoking-habits to molecular findings in those cancers, we identified imprints of different mutational processes in a disease-, gender- and race-specific fashion. Black and female patients - despite their lower tobacco consumption in comparison to whites or males - had tumors with the highest enrichment for tobacco-induced DNA damage. The relevance of mutational signatures related to aging varied across race and gender and were independent from chronological age. The activity of smoking signature was different according to disease histotype, and stage. tumors of never-smoker lung cancer patients showed tobacco-specific mutational signatures, which could suggest the influence of second-hand smoking. Patients with tumors enriched for the smoking mutational signature presented longer survival, whereas those with ageing-enriched signature had poorer prognosis. Conclusions: Mutational processes may unravel connections between patient features and tumorigenesis, particular to race, gender, and tumor type. Therefore, it is paramount to assess those details with greater granularity in every effort of personalized medicine either in preventive or therapeutic approaches.
Citation Format: João Paulo da Silveira Nogueira Lima, Rodrigo Couto Duarte Drummond, Monize Nakamoto Provisor Santos, Renan Valieris, Rafael Andres Rosales Mitrowsky, Vladmir Cordeiro Lima, Diana Noronha Nunes, Emmanuel Dias-Neto, Israel Tojal da Silva. The interplay between patient´s features and mutational processes in tobacco related cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3245.
Abstract 3269: Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa)
Authors: Mahalingam Devalingam , Hanni Salih , Fountzilas Christos , Michalek Joel , Sarantopoulos John , Pillai Sureshkumar Mulampurath Achuthan , Kuhn John , Pollak Michael , Thompson Ian 
Published: August 2018

Abstract
Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. Metformin decreases glucose & insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: We analyzed serum and PBMC from a recently completed clinical study of men with advanced PCa on ADT that were randomized 1:1 to metformin at 500mg TID or color matched placebo. Subjects serum insulin/glucose, metformin levels, weight and waist circumference (WC) was assessed at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of metformin vs placebo cohort. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: There were 36 evaluable men. The mean age on study was 68.4. Mean weight, WC and insulin at baseline in metformin cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in placebo cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At week 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. Four men randomized to metformin had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in metformin and 53.3% in placebo cohort achieved undetectable PSA at week 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusion: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT.
Citation Format: Devalingam Mahalingam, Salih Hanni, Christos Fountzilas, Joel Michalek, John Sarantopoulos, Sureshkumar Mulampurath Achuthan Pillai, John Kuhn, Michael Pollak, Ian Thompson. Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269.
Abstract 3269A: 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer
Authors: Singhal Sharad S. , Chikara Shireen , Nagaprashantha Lokesh , Singhal Jyotsana , Horne David , Awasthi Sanjay 
Published: August 2018

Abstract
Breast cancer (BC) remains one of the major causes of cancer deaths in women. 2Hydroxyflavanone (2HF), a constituent of citrus fruits, inhibits growth of human breast cancer cell lines in culture. The present study was undertaken to determine in vivo efficacy of 2HF against MDAMB231 human breast cancer xenografts. The 2HF administration retarded growth of MDAMB231 cells subcutaneously implanted in female nude mice without causing weight loss or any other side effects. The 2HF mediated suppression of MDAMB231 xenograft growth correlated with reduced cell proliferation as revealed by immunohistochemical analysis for Ki67 expression. Analysis of the vasculature in the tumors from 2HF treated mice indicated smaller vessel area compared with control tumors based on immunohistochemistry for angiogenesis marker CD31. The 2HF mediated inhibition of angiogenesis in vivo correlated with downregulation of vascular endothelial growth factor (VEGF) level in the tumor. Consistent with these results, 2HF treatment suppressed cell cycle regulators levels in cultured MDAMB231 cells. Moreover, the 2HF treated MDAMB231 cells exhibited reduced capacity for migration compared with vehicle-treated control cells. In addition, 2HF administration elicits apoptotic response as judged by annexin V and PI staining and TUNEL assay. 2HF treatment reduced the levels of ER alpha in ER positive MCF7 breast cancer cells. In conclusion, the present study demonstrates in vivo anticancer efficacy of 2HF against MDAMB231 xenografts in association with reduced cell proliferation and suppression of neovascularization. Our results indicate that 2HF is a promising anticancer agent for breast cancer due to its ability to collectively inhibit major regulators of breast cancer including RLIP76, ER alpha, and HER2. Interestingly, a spontaneously immortalized non-tumorigenic normal human mammary epithelial cell line (MCF10A) is significantly more resistant to 2HF mediated apoptosis compared with breast cancer cells, demonstrating selectivity of 2HF towards malignant breast cells. These preclinical observations merit clinical investigation to determine efficacy of 2HF against human breast cancers. (This work was supported in part by the Department of Defense grant W81XWH 16 1 0641. Funding from the Beckman Research Institute of City of Hope is also acknowledged).
Citation Format: Sharad S. Singhal, Shireen Chikara, Lokesh Nagaprashantha, Jyotsana Singhal, David Horne, Sanjay Awasthi. 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269A.