tbuckley/cabot-search huggingface dataset:
Abstract 1580: Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer
Authors: Leah C. Rider, Lindsey U. Rodrigues, Anis Karimpour-Fard, Lina Romero, Claire Gillette, James C. Costello, Scott D. Cramer
Journal: Cancer Research (2017)

Abstract We recently functionally validated a clinically aggressive subtype of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. This subtype accounts for up to 25% of prostate cancer deaths. Androgen signaling is a critical component of prostate tumorigenesis and disease progression, which is exploited in treatment of prostate cancer with androgen deprivation and anti-androgen therapies. Neuroendocrine differentiation is thought to provide a selective growth advantage of prostate cancer in androgen-depleted conditions such as surgical or chemical castration. REST is a transcriptional repressor of neuronal gene expression and has been implicated in neuroendocrine differentiation of prostate cancer. The impact of combined MAP3K7 and CHD1 loss on androgen signaling and neuroendocrine differentiation has not been determined. Here, we demonstrate that dual loss of MAP3K7 and CHD1 simultaneously stimulates enhanced androgen signaling and enhanced neuronal differentiation correlated with enhanced growth in both androgen-depleted and androgen-replete conditions. These changes occur via increased androgen receptor chromatin binding, loss of CHD1 chromatin binding, loss of REST expression, and reduced chromatin binding by REST. Suppression of CHD1 and MAP3K7 attenuates the antiproliferative activity of the anti-androgen Enzalutamide. Furthermore, we translate these findings to clinical samples and show that decreased expression of CHD1, MAP3K7, and REST is associated with previous therapeutic intervention, castrate-resistant disease, and progression to a neuroendocrine phenotype. Overall, patients with low expression of all three have poorer disease-free survival. Together these data support the lineage plasticity of prostate tumors with loss of CHD1 and MAP3K7 exhibiting both androgen-dependent and -independent phenotypes leading to poor clinical outcome, which poses challenges to conventional therapeutic approaches. Citation Format: Leah C. Rider, Lindsey U. Rodrigues, Anis Karimpour-Fard, Lina Romero, Claire Gillette, James C. Costello, Scott D. Cramer. Combined neuroendocrine differentiation and androgen receptor hyperactivity in MAP37 and CHD1 null prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1580. doi:10.1158/1538-7445.AM2017-1580
Abstract 3444: <i>LINC00152</i> regulates cell proliferation via p38 signaling and overexpression predicts poor patient survival in lung cancer
Authors: Shumei Feng, Jie Zhang, Wenmei Su, Shengbin Bai, Lei Xiao, Zhuwen Wang, Jules Lin, Rishindra Reddy, Andrew Chang, David Beer, Guoan Chen
Journal: Cancer Research (2017)

Abstract Lung cancer is a molecularly-heterogenous disease and the leading cause of cancer mortality. The molecular basis for this heterogeneity remains incompletely understood. In the past few years, long non-coding RNAs (lncRNAs) have emerged as novel mechanisms in mediating cancer biology, although most lncRNAs are still undiscovered. LINC00152 has been identified as highly associated with the tumorigenesis and development in gastric cancer, colon cancer and hepatocellular carcinoma, however, the expression level and its oncogenic roles in lung cancer remains unknown. In the present study, we employed next generation RNA sequencing analysis to reveal dysregulated lncRNAs in lung cancer utilizing datasets of 461 lung adenocarcinomas (LUAD) and 156 normal lung tissues from 3 separate institutions. We found that LINC00152 was 4-fold (p &amp;lt;0.001) overexpressed in lung tumors as compared to their adjacent normal tissues with AUC &amp;gt; 0.8 in these 3 data sets. Patients with high LINC00152 expression have significantly poorer survival than those with low expression (log-rank test, p = 0.003). We verified this diagnostic/prognostic potential in an independent cohort of lung tumor tissues by quantitative RT-PCR. Cell proliferation and colony formation ability were decreased after knockdown of LINC00152 using siRNAs in lung cancer cell lines. The expression of LINC00152 was found primarily in the cytoplasm by qRT-PCR analysis. Trichostatin A treatment indicated that histone acetylation could be one of the mechanisms underlying LINC00152 overexpression in NSCLC and cell-based analyses showed p38 signaling was mainly affected by LINC00152 in vitro. Taken together, our study suggests that LINC00152 is involved in lung tumor growth, may have potential as diagnostic/prognostic marker and that further characterization of this lncRNA as a novel therapeutic target for lung cancer is warranted. Note: This abstract was not presented at the meeting. Citation Format: Shumei Feng, Jie Zhang, Wenmei Su, Shengbin Bai, Lei Xiao, Zhuwen Wang, Jules Lin, Rishindra Reddy, Andrew Chang, David Beer, Guoan Chen. LINC00152 regulates cell proliferation via p38 signaling and overexpression predicts poor patient survival in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3444. doi:10.1158/1538-7445.AM2017-3444
Abstract 2115: Therapeutic potential of fingolimod against prostate cancer cells is partly attributed to interrupting the cross talk between estrogen and sphingolipid metabolisms
Authors: Rasha M. Allam, Ahmed M. Al-Abd, Alaa Khedr, Ola A. Sharaf, Salwa M. Nofal, Amani E. Khalifa, Hisham A. Mosli, Ashraf B. Abdel-Naim
Journal: Cancer Research (2017)

Abstract Sphingolipids influence tumor microenvironment in different malignancies. Estrogen and estrogen metabolites are involved in prostate cancer. Fingolimod is Sphingokinase-1 (SphK1) inhibitor which possesses anticancer properties in various tumor types. The aim of the current study is to investigate the interference of Fingolimod with the cross talk between sphingolipid and estrogen metabolisms within prostate cancer cells as a novel therapeutic strategy. The design is based on determining the mutual influence between estrogen metabolism/signaling and sphingolipid metabolism within prostate cancer cells. Cytotoxicity using SRB-U assay; cell cycle analysis using DNA cytometry and intracellular caspase-3 concentration were assessed. Estrogen metabolites and estrogen metabolizing enzymes were determined using LC/MS and RT-PCR, respectively. Estrogen receptor (ERα and ERβ) expression and their downstream signaling (CXCR4 and Cyclin-D1, respectively) were measured using immunocytochemical staining and RT-PCR, respectively. Fingolimod showed antiproliferative/cytotoxic effects against different prostate cancer cells (LNCaP, DU145 and PC3) with IC50 ranging from 3.0±0.3 to 6.8±1.7 µM. Fingolimod induced significant decrease in estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone concentrations with reciprocal increase in 2-methoxyestrone and 2-methoxyestradiol concentrations. This was mirrored by significant down expression for the enzymes, aromatese, CYP1A1 and CYP1B1 and over expression for the enzyme COMT. Additionally, Fingolimod suppressed the expression of ERα and ERβ within prostate cancer cells as well as their downstream signaling (CXCR4 and Cyclin-D1, respectively). Reciprocally, it was found that estradiol and catechol estrogens induce the expression of SphK1 while methoxylated catechol estrogen suppresses its expression. Our results give compelling evidence that Fingolimod has therapeutic potential by modulating the estrogenic micromilieu and interrupting its cross talk with sphingolipid metabolism in prostate cancer cells. Citation Format: Rasha M. Allam, Ahmed M. Al-Abd, Alaa Khedr, Ola A. Sharaf, Salwa M. Nofal, Amani E. Khalifa, Hisham A. Mosli, Ashraf B. Abdel-Naim. Therapeutic potential of fingolimod against prostate cancer cells is partly attributed to interrupting the cross talk between estrogen and sphingolipid metabolisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2115. doi:10.1158/1538-7445.AM2017-2115
Abstract 2563: LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3
Authors: Xin Hu, Dongxi Xiang, Luwei Tao, Ying Xie, Yue Jin, Yidi Guo, Luca Pinello, Guo-Cheng Yuan, Zhe Li
Journal: Cancer Research (2017)

Abstract LSD1 (also known as KDM1A) is a histone demethylase that has been shown to play both oncogenic and tumor suppressor roles in breast cancer. However, the exact context under which it functions as a tumor suppressor or oncoprotein remains largely elusive. To address this, we characterized its role in normal mammary epithelial cells (MECs) and found MEC-specific ablation of Lsd1 largely phenocopied that of Gata3, which encodes a master regulatory transcription factor for luminal MECs. In the luminal lineage, LSD1-loss led to reduction in both mature ductal and alveolar luminal subpopulations. In human luminal breast cancer cells, we found LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. In particular, we found LSD1 might be recruited by GATA3 to the GATA3 promoter region, to positively regulate GATA3 expression via demethylation of H3K9me2. Knockdown of LSD1 led to increased invasion of luminal breast cancer cells, in part via downregulation of GATA3 and multiple cell junction genes (e.g., CDH1, VCL, CTNNA1), as well as upregulation of mammary stem/progenitor cell genes (e.g., ELF5, ITGB1). However, LSD1 knockdown also led to reduced proliferation of luminal breast cancer cells, in part via downregulation of RBBP4 (encoding a Histone-binding protein) and upregulation of CDKN1A (encoding p21). Collectively, our data suggest that LSD1 is required for maintaining luminal MEC differentiation and survival and for suppressing luminal breast cancer cell invasion, in part via GATA3. As inhibitors of LSD1 are currently under clinical trials (e.g., in leukemia), our data suggest that although treatment of luminal breast cancer by the LSD1 inhibitor may lead to reduced tumor cell proliferation (and thus tumor shrinkage), the treatment may also lead to increased invasion of surviving breast cancer cells. Thus, our study is expected to have important implications for developing better epigenetic therapy in an individualized, context-dependent fashion. Citation Format: Xin Hu, Dongxi Xiang, Luwei Tao, Ying Xie, Yue Jin, Yidi Guo, Luca Pinello, Guo-Cheng Yuan, Zhe Li. LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2563. doi:10.1158/1538-7445.AM2017-2563
Abstract 1335: Deubiquitinase OTUD6B isoforms are important regulators of growth and proliferation
Authors: Maurizio Bocchetta, Clodia Osipo, Anna Sobol
Journal: Cancer Research (2017)

Abstract Deubiquitinases (DUBs) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressors signaling. Here evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non-small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1 isoform is inhibitory, while the short OTUD6B-2 isoform stimulates protein synthesis. These properties affect NSCLC cell proliferation, since OTUD6B-1 represses DNA synthesis while OTUD6B-2 promotes it. Mutational analysis and downstream mediators suggest that the two OTUD6B isoforms modify different cellular targets. OTUD6B-2 influences the expression of cyclin D1 by promoting its translation while regulating (directly or indirectly) c-Myc protein stability. This phenomenon appears to have clinical relevance as NSCLC cells and human tumor specimens have a reduced OTUD6B-1/OTUD6B-2 mRNA ratio compared to normal samples. The global OTUD6B expression level does not change significantly between non-neoplastic and malignant tissues, suggesting that modifications of splicing factors during the process of transformation are responsible for this isoform switch. Because protein synthesis inhibition is a viable treatment strategy for NSCLC, these data indicate that OTUD6B isoform 2, being specifically linked to NSCLC growth, represents an attractive, novel therapeutic target and potential biomarker for early diagnosis of malignant NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Maurizio Bocchetta, Clodia Osipo, Anna Sobol. Deubiquitinase OTUD6B isoforms are important regulators of growth and proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1335. doi:10.1158/1538-7445.AM2017-1335
Abstract 384: The implications of splicing variant of AIMP2 lacking exon 2 among various cancer types: An analysis of the ICGC/TCGA database and clinical validation
Authors: Dong Chan Kim, Ryul Kim, Daeyoon Kim, Hyojin Song, Dong-Yeop Shin, Inho Kim, Kwang-Sung Ahn, Nam Hoon Kwon, Sunghoon Kim, Sung-Soo Yoon, Youngil Koh
Journal: Cancer Research (2017)

Abstract Aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMP) is the multiple tRNA synthetase complex protein called the multi-tRNA complex (MRC). In cancer, the splicing variant of AIMP2 derives a several signaling cascades, which are crucial for cancer proliferation. Detecting an exon-2 depleted splicing variant (AIMP2-DX2) is an issue of growing importance in cancer therapy. This study suggests the evidence for interrelation between the AIMP2-DX2 and cancer development. We analyzed AIMP2 and AIMP2-DX2 gene expression and their ratio on 7 commercial cancer cell lines and Multiple myeloma patient derived 536MM cell line by RT-PCR and targeted RNA sequencing. Extended this profile, the distribution of AIMP2-DX2/AIMP2 ratio and AIMP2-related major cancer pathways were analyzed using the samples in the ICGC/TCGA database. Over 23 cancer types, 753 samples were used in WTS analysis. In the DEG set analysis, 10 pre-defined major cancer pathways were analyzed among 16 cancer types. Some cancer types, especially acute myeloid leukemia (AML) showed most significant association with AIMP2-DX2 in terms of cancer signaling pathways. We focused on clinical implications of AIMP2-DX2/AIMP2 ratio in the ICGC/TCGA database. 19 AML samples were used, Overall survival (OS) showed that patients with AIMP2-DX2/AIMP2 ratio higher than Q1 shows poor OS and Most of the genes including MEK1/2, ERK, MNK1/2 in this pathway had positive association with AIMP2-DX2/AIMP2 ratio. In colon carcinoma and hepatocellular carcinoma, OS curves had a tendency in a similar way to AML. For the clinical validation of the prognostic value of AIMP2-DX2, 51 AML patients were included in this analysis. The correlation between AIMP2-DX2 expression and survival outcomes was investigated in clinical validation cohort of AML. The AIMP2-DX2-positive group had significantly inferior OS rate and had worse RFS compare to AIMP2-DX2-negative group. Our sequential data shows that the AIMP2-DX2/AIMP2 expression and their ratio can possibly be an indicator to measure malignancy of various cancer types. Citation Format: Dong Chan Kim, Ryul Kim, Daeyoon Kim, Hyojin Song, Dong-Yeop Shin, Inho Kim, Kwang-Sung Ahn, Nam Hoon Kwon, Sunghoon Kim, Sung-Soo Yoon, Youngil Koh. The implications of splicing variant of AIMP2 lacking exon 2 among various cancer types: An analysis of the ICGC/TCGA database and clinical validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 384. doi:10.1158/1538-7445.AM2017-384
Abstract 1204: Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models
Authors: Hye Yeon Jang, Haeng Jung Lee, Yeo Jin Nam, Won Dong Kim, Yong Ju Bae, Jin Hwang Jung, Seung Jin Lee, Dae Hyuk Moon
Journal: Cancer Research (2017)

Abstract Optimal strategy for the application of MEK inhibitor as combination therapy has not been established in Ras/Raf-mutant colorectal cancer (CRC). As we preliminary observed that 5-FU-induced pharmacodynamic changes were restored by ERK inhibition, we hypothesized that post-treatment of MEK inhibitor would enhance antitumor activity of 5-FU. Treatment of 5-FU for 2 days followed by selumetinib for another 2 days (FS schedule) exhibited synergism for cell viability, whereas reverse or concomitant combination showed antagonism or inconsistent response, respectively, in 8 kinds of CRC cell lines including BRAFV600E colo205, BRAFV600E RKO, or KRASG13D HCT8 cells. Combination as FS schedule persistently down-regulated the phosphorylation of ERK and pS6 throughout treatment period, whereas selumininib alone or reverse combination transiently decreased within 24 hr. The cells treated as FS schedule exhibited higher apoptosis and lower capacity of anchorage-independent cell growth than the cells under single or reverse combination. Microarray analysis revealed the distinct groups of genes underlying different efficacy by schedule-dependent treatment. Tumor growth in mice administered 5-FU at 10 mg/kg/day for colo205 and at 30 mg/kg/day for HCT8 for 7 days followed by selumetinib at 10 mg/kg/day for colo205 and 25 mg/kg/day for HCT8 for another 7 days was significantly retarded than that in mice treated with single agents. But the combination in reverse sequence induced comparable tumor growth to single agents. Decreased expression of Ki67 was observed in tumors from mice treated as FS scheduling. Our results suggest that the schedule-dependent combination of 5-FU and selumetinib may be benefit in patients having CRC with hyper-activation of Ras/RAF pathway. Citation Format: Hye Yeon Jang, Haeng Jung Lee, Yeo Jin Nam, Won Dong Kim, Yong Ju Bae, Jin Hwang Jung, Seung Jin Lee, Dae Hyuk Moon. Enhanced efficacy of selumetinib by pretreatment of 5-FU in preclinical Ras/Raf-mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1204. doi:10.1158/1538-7445.AM2017-1204
Abstract 988: Effect of a supervised exercise intervention on sarcopenic obesity and metabolic syndrome in prostate cancer patients: A randomized pilot study
Authors: Jacqueline L. Kiwata, Tanya B. Dorff, E. T. Schroeder, Christina M. Dieli-Conwright
Journal: Cancer Research (2017)

Abstract Purpose: Prostate cancer survivors (PCS) on androgen deprivation therapy (ADT) experience adverse side effects such as skeletal muscle loss and adiposity gain, together called sarcopenic obesity, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance exercise can increase skeletal muscle mass, but no exercise interventions to date in PCS on ADT have concomitantly improved sarcopenic obesity and cardiometabolic risk factors. Utilizing a 12-week intervention of progressive resistance exercise designed to target skeletal muscle mass, this ongoing pilot trial investigates sarcopenic obesity and as a secondary analyses, MetS components, in PCS on ADT. Methods: Eighteen PCS (65.6±8.8 yr) on current or previous ADT were recruited from the USC Norris Comprehensive Cancer Center and randomized to resistance training (RT; n=9) or a control stretching program (CS; n=9). Body composition, measured through dual-x-ray absorptiometry, and MetS outcomes, including waist circumference, blood pressure, fasting blood glucose, triglycerides and HDL, were assessed at baseline and after the 12-week intervention. Appendicular skeletal muscle index (ASMI), a common index of sarcopenia, was calculated from body composition. RT performed a supervised total-body resistance exercise and stretching program 3 times/week. CS performed home-based stretching 3 times/week. Baseline differences were tested with univariate ANOVA. Differences in all outcomes were tested with 2(group) x 2(time) ANOVA. Results: No significant differences in ADT duration, Gleason score, body fat, skeletal muscle mass, or MetS components were found between groups at baseline (P&amp;gt;0.05). RT program compliance was 98.3%, while CS program compliance was 75.5%. Post-intervention, significant increases were observed in RT compared to CS for appendicular skeletal mass (mean±SE; 0.8±.4 kg; P=0.04) and ASMI (0.3±.1 kg/m2; P=0.041). A nonsignificant decrease in body fat (%) was observed in RT compared to CS (1.3±.7 %; P=.067; d=0.89). No differences were found in MetS components. Conclusions: While 12 weeks of resistance exercise in PCS on ADT improved skeletal muscle mass, no changes in adiposity and MetS variables were observed. Future interventions are needed for PCS to determine the optimal exercise prescription to target both sarcopenic obesity and cardiometabolic risk factors. Citation Format: Jacqueline L. Kiwata, Tanya B. Dorff, E. T. Schroeder, Christina M. Dieli-Conwright. Effect of a supervised exercise intervention on sarcopenic obesity and metabolic syndrome in prostate cancer patients: A randomized pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2017-988