tbuckley/cabot-search huggingface dataset:
Abstract 3143: <i>FBW7</i> mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation
Authors: Jingshan Tong, Shuai Tan, Fangdong Zou, Jian Yu, Lin Zhang
Journal: Cancer Research (2017)

Abstract Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7 inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA, or p53. These cells are defective in apoptosis due to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target. Citation Format: Jingshan Tong, Shuai Tan, Fangdong Zou, Jian Yu, Lin Zhang. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation [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 3143. doi:10.1158/1538-7445.AM2017-3143
Abstract 5697: Proteomic analysis of prostate cancer-related exosomes isolated by anti-PSMA antibody beads
Authors: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Kengo Horie, Koji Kameyama, Masafumi Ito, Takashi Deguchi
Journal: Cancer Research (2017)

Abstract Purposes of the study: Exosome has been demonstrated to be a useful non-invasive biomarker for several cancers including prostate cancer. For better understanding cancer-derived exosome, their proteomic analysis is necessary. The aim of this study is to establish the method for isolation and analysis of prostate cancer-related exosomes. Experimental procedures: Total exosomes were isolated from the conditioned media of LNCaP cells by ultracentrifugation. Then, exosomes positive for CD9 or prostate specific membrane antigen (PSMA) were isolated by magnetic beads conjugated with anti-CD9 or -PSMA antibody, respectively. Isolated exosomes were subjected to proteomic analysis. The PSMA positive fraction was also collected by anti-PSMA beads from diluted serum of 3 prostate cancer patients and analyzed by proteomics. Results: A total of 126, 139 and 13 proteins were detected in the LNCaP exosome fractions that were isolated by ultracentrifugation, anti-CD9 beads and anti-PSMA beads, respectively. Out of 126 proteins identified in ultracentrifuge isolated exosome, 56 and 6 protein were found in exosomes that were isolated by anti-CD9 beads and anti-PSMA beads, respectively. Seven proteins were commonly detected in exosomes that were isolated by both beads. Fifty, 54 and 48 proteins were identified in the PSMA positive fraction from serum of 3 prostate cancer patients (P1: localized prostate cancer, P2: advanced prostate cancer and P3: castration resistant prostate cancer). Thirty-three proteins were detected in one patient, 22 in two patients and 25 in three patients. Most proteins detected in all patients were serum- or immunoglobulin-related proteins. The numbers of proteins that were detected only in P2 and P3 were 16 and 8, respectively. Six proteins were found in both P2 and P3 patients. Conclusion: In the present study, we analyzed prostate cancer-related exosomes that were isolated by immunoaffinity-based method. Although most proteins were serum- or immunoglobulin-related proteins, proteins that had been reported as a cancer marker were also detected, which could be candidates for exosomal marker of prostate cancer. Citation Format: Kosuke Mizutani, Kyojiro Kawakami, Yasunori Fujita, Kengo Horie, Koji Kameyama, Masafumi Ito, Takashi Deguchi. Proteomic analysis of prostate cancer-related exosomes isolated by anti-PSMA antibody beads [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 5697. doi:10.1158/1538-7445.AM2017-5697
Abstract 4437: Small non-coding RNA profiling from prostate cancer plasma by deep sequencing
Authors: Xianghua Liu, Andrew Hunter, Qing Zhang, Quanyuan He, Annemarie Benton, Gerri Ortiz, Vaishali Pannu, Nick Xiao, Mark Miglarese, David Spetzler
Journal: Cancer Research (2017)

Abstract Background: Prostate cancer (PCa) is the most common non-skin cancer among American men. MicroRNAs (miRNAs) are critical post-transcriptional regulators and involved in prostate cancer tumorigenesis. The aim of this study is to identify a PCa-specific expression profile of miRNAs from plasma to guide prostate cancer diagnosis and therapeutic treatment. Methods: Plasma was collected from 5 PCa patients and 5 normal men. Circulating RNA was extracted from 1) 200ul plasma or 2) the pellets of anti-Ago2 immunoprecipitations from 500ul plasma using the miRNeasy Serum/Plasma kit (Qiagen), with addition of glycogen as a carrier. Small RNA libraries were constructed using the NEBNext Multiplex Small RNA Prep Set for Illumina® (New England. BioLabs). The cDNA library fragments were purified by Blue Pippin (Sage Science) for extraction of 140-160 bp size fraction containing small RNA inserts. Equimolar amounts of cDNA library samples were pooled and were sequenced in a single flowcell on an Illumina HiSeq2500 with 50 cycle kit and rapid run model. Bioinformatics analysis: Adaptor was firstly removed from the raw reads, and the sequences were mapped to several small RNA databases by using bowtie1 with 1 mismatch. The multiple aligned reads were weighted to the mapped small RNAs based on their unique mapped reads counts. We then calculated the RPM (reads per million) as indicator of the expression levels of the small RNA. To get confident analysis results, we discarded the small RNAs whose averages of the raw reads counts in cancer and normal groups are smaller than 25 and only focus on the mature microRNAs. The moderate t-test is applied to find the differently expressed (DE) microRNAs between normal and cancer group. Results: Two major small RNA classes identified from total plasma are miRNA (47.7%) and yRNA (35.0%). The percentage of miRNA increased to 85.3% by Ago2-IP method. The compositions of categories of small RNAs in cancer and normal samples are similar. We identified 28 and 22 differential miRNAs (&amp;gt;2 fold change between cancer and normal group) by total plasma and Ago-2 IP methods respectively. Conclusions: We discovered a unique expression profile of miRNA detectable in the plasma from prostate cancer patients. Extracted RNA from the pellets of anti-Ago2 immunoprecipitations can enhance the detection of miRNA. Expand study to confirm these findings are needed. Citation Format: Xianghua Liu, Andrew Hunter, Qing Zhang, Quanyuan He, Annemarie Benton, Gerri Ortiz, Vaishali Pannu, Nick Xiao, Mark Miglarese, David Spetzler. Small non-coding RNA profiling from prostate cancer plasma by deep sequencing [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 4437. doi:10.1158/1538-7445.AM2017-4437
Abstract 4455: Identification of novel oncogene, copine-7 (CPNE7), in colorectal cancer
Authors: DONGJUN JEONG, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Sang Byung Bae, Tae Sung Ahn, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek
Journal: Cancer Research (2017)

Abstract Background: CPNE7, a member of copine family, is composed of calcium-dependent membrane-binding proteins. The encoded protein may play a role in calcium-mediated intracellular processes and membrane trafficking mainly. Although this protein was known as tumor suppressor in breast cancer, we identified the possibility as an oncogene in colorectal cancer. In this study, we performed to evaluate the oncogenic functions of CPNE7 in the colorectal cancer cell line and the clinical significance of CPNE7 expression in colorectal cancer patients. Method: The colorectal cancer cell lines (SW480, SW620, HCT116 and HT29) were transfected with siRNA for knockdown CPNE7. The oncogenic functions were identified in the transfected cell lines and compared them with CPNE7 highly expressing control cell lines. In vitro functional studies included cell proliferation assay, migration assay, invasion assay and semisolid agar colony forming assay. The clinical significance of CPNE7 expression was evaluated in 250 cases of colorectal cancer tissue by immunohistochemistry. Results: The knockdowned cell lines significantly showed lower oncogenic function (proliferation, migration, invasion and colony forming) compared to the CPNE7 highly expressing control cell lines (p&amp;lt;0.05). The overall survival rate was decreased in patients of CPNE7 high expression (p=0.03). Multivariate and univariate Cox-regression analysis showed that CPNE7 high expression was an independent prognostic factor in colorectal cancer (HR=1. 54, 95% CI=1. 00-2.38: p=0. 048 / HR=1. 58, 95% CI=1. 03-2.41: p=0. 032). Conclusion: This study announces that CPNE7 is a novel oncogene, an independent prognostic factor and therapeutic target in colorectal cancer. In the future, studies on in vivo assay and identifying oncogenic signal pathways of CPNE7 in colorectal cancer are necessary. Citation Format: DONGJUN JEONG, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Sang Byung Bae, Tae Sung Ahn, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. Identification of novel oncogene, copine-7 (CPNE7), in colorectal 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 4455. doi:10.1158/1538-7445.AM2017-4455
Abstract 2391: Integrated analysis of methylation and expression profile of telomere-related genes in breast cancer patients
Authors: Jianfu Heng, Xinwu Guo, Lili Tang, Fan Zhang, Limin Peng, Ming Chen, Xipeng Luo, Xunxun Xu, Shouman Wang, Jun Wang
Journal: Cancer Research (2017)

Abstract Telomeres at the ends of chromosomes are critical in maintaining the integrity and stability of the genome. Aberrant telomere or telomerase dysfunction participates in tumorgenesis. A majority of human cancers exhibit critically aberrant telomere length, suggesting that tumors can arise from genetically instable cells with dysfunctional telomeres. Many genes are involved in the complex regulatory mechanisms of telomere length and telomerase activity. In addition, the methylation and expression pattern for most of telomere related genes in breast cancer are still unknown. Using microfluidic-PCR based target enrichment and next-generation bisulfite sequencing technology, we explored the promoter methylation profile of 29 telomere-related genes in 184 breast cancer patients with paired tumor and matched normal tissues. The average methylation level was significantly higher in tumor (8.13%) than that in matched normal tissues (7.08%) (P = 4.30E-21). Four genes showed significant hyper-methylation in the breast tumor tissues. All of these 4 genes are annotated with potential TFBSs in the promoter regions. In subtype analysis, RAD51D showed significant methylation difference among four subtypes. In analysis of the association between methylation and clinicopathologic characteristics, TERC showed significant difference between ER+/ER- tumors. The expression profile of the 4 significant hyper-methylated genes was explored in the same cohort using qPCR method. All of them showed significantly lower expression in breast tumor tissues compared with the matched normal tissues. Two genes showed significant and negative cis correlation between methylation and gene expression. These results were also validated in the TCGA database. The 4 genes panel showed a good performance in predicting breast cancer with ROC analysis. In summary, our results revealed the methylation pattern of telomere related genes in breast cancer and illustrated the epigenetic regulatory mechanism on expression of aberrant methylated genes. Our study provides a novel panel of telomere related genes which may be a valuable diagnostic biomarker for breast cancer prediction. Note: This abstract was not presented at the meeting. Citation Format: Jianfu Heng, Xinwu Guo, Lili Tang, Fan Zhang, Limin Peng, Ming Chen, Xipeng Luo, Xunxun Xu, Shouman Wang, Jun Wang. Integrated analysis of methylation and expression profile of telomere-related genes in breast cancer patients [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 2391. doi:10.1158/1538-7445.AM2017-2391
Abstract 692: Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma <i>in vivo</i> and <i>in vitro</i>
Authors: Uwe Thiel, Andreas Kirschner, Melanie Thiede, Thomas GP Grünewald, Rebeca Alba Rubio, Günther Richter, Thomas Kirchner, Dirk Busch, Poul Sorensen, Stefan Burdach
Journal: Cancer Research (2017)

Abstract Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e. IGF binding proteins (IGFBPs), thereby releasing IGFs from IGFBPs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA stimulates normal bone growth, and is also associated with various cancers. In particular, PAPPA is overexpressed and required for proliferation in ES. We isolated HLA-A*02:01+/peptide restricted T cells from A*02:01- healthy donors directed against PAPPA, generated by priming with A*02:01+ PAPPA peptide-loaded dendritic cells. After T cell receptor (TCR) identification, retrovirally TCR transduced CD8+ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2-/-γc-/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity towards HLA-A*02:01+/PAPPA+ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2-/-γc-/- mice and in vivo engraftment of the in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells compared to controls, and tumors from treated mice revealed tumor infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a promising target for TCR based immunotherapy of ES. We demonstrate that TCR transgenic T cells recognize this target, home to the tumor, and causes tumor regression in a preclinical mouse model. Citation Format: Uwe Thiel, Andreas Kirschner, Melanie Thiede, Thomas GP Grünewald, Rebeca Alba Rubio, Günther Richter, Thomas Kirchner, Dirk Busch, Poul Sorensen, Stefan Burdach. Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma in vivo and in vitro [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 692. doi:10.1158/1538-7445.AM2017-692
Abstract 1320: Non-additive and interaction effects of HLA class 2 polymorphism contributing to risk of glioma
Authors: Chenan Zhang, Kyle Walsh
Journal: Cancer Research (2017)

Abstract Although genome-wide association studies have identified a number of susceptibility loci for adult glioma, little is still known regarding whether polymorphisms in the human leukocyte antigen (HLA) region contribute risk. HLA associations have previously been reported for a number of malignancies, with selected HLA polymorphisms investigated in a subset of glioma studies. However, no systematic analysis has been conducted to date, and no investigation into potential non-additive effects of such associations has been described. In this study, we conducted comprehensive genetic analyses of HLA variants in the major histocompatibility complex (MHC) region among 1,746 adult glioma patients and 2,312 controls from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, containing 1,822 SNP probes across the MHC region. We imputed HLA alleles using a reference panel of 5,225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Subjects were of European-ancestry, and case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the MHC region are linked, we created multi-locus haplotypes consisting of genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, DRB1*15:01-DQA1*01:02-DQB1*06:02 showed an improvement in model fit after the inclusion of a non-additive term, which was significant after Bonferroni correction (P = 2.5x10-3). Furthermore, the interaction of DRB1*15:01-DQA1*01:02-DQB1*06:02 with haplotype DRB1*04:01-DQA1*03:01- DQB1*03:01 resulted in a 3.80-fold increase in the odds of glioma (P = 8.8x10-3). Our results indicate that the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype contributes to the risk of glioma via a dominant effect, with heterozygosity conferring greater risk of glioma than expected from homozygote disease risk in an additive model. Citation Format: Chenan Zhang, Kyle Walsh. Non-additive and interaction effects of HLA class 2 polymorphism contributing to risk of glioma [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 1320. doi:10.1158/1538-7445.AM2017-1320
Abstract 2551: Long noncoding RNA <i>HOXA11 antisense</i> promotes tumor progression via the Notch pathway in serous ovarian cancer
Authors: Hee Jung Kim, Ga Won Yim, Kyung Jin Eoh, Lee Kyung Kim, Jung-Yun Lee, Eun Ji Nam, Sang Wun Kim, Young Tae Kim
Journal: Cancer Research (2017)

Abstract The biological function of long noncoding RNAs (lncRNAs) is only partially understood. We investigated the expression of the novel HOXA11 antisense (HOXA11as) lncRNA and its oncogenic role in serous ovarian cancer (SOC). HOXA11as expression was examined in 129 serous ovarian cancer tissue samples by real time RT-PCR. Clinicopathologic factors and patient survival were compared between high (N = 27) and low HOXA11as expression group (N = 102). To investigate the role of HOXA11as in cell proliferation, invasion, and migration, HOXA11as expression in ovarian cancer cells was knocked down using RNA interference. HOXA11as expression in cancer tissue was 77-fold higher than that of noncancerous tissue (P &amp;lt; 0.05). Higher HOXA11as expression significantly correlated with histologic grade (P = 0.017) and preoperative CA125 (P = 0.048). HOXA11as overexpression in SOC cells led to increased cell proliferation, invasion, and migration. In addition, HOXA11as was associated with the expression of genes that involve in cell proliferation, invasion, and migration. Moreover, Knockdown of HOXA11as decreased the expression of vascular endothelial growth factor, matrix metalloproteinase-9 and epithelial-mesenchymal transition (EMT), which are important for cell motility and metastasis. Mechanistic investigation revealed that Notch1, Hes1 and p300 proteins could be inhibited by HOXA11as depletion. In multivariate analysis, HOXA11as was a prognostic factor of progressive disease and mortality (HR = 1.730, 2.170 and P = 0.043, 0.033, respectively). Progression-free and overall survival were significantly shorter in patients with high HOXA11as expression. These findings highlight the clinical significance of HOXA11as in predicting the prognosis of SOC patients and suggest its potential in promoting tumor aggressiveness by regulation of the Notch signaling pathway and EMT-related mechanisms. Note: This abstract was not presented at the meeting. Citation Format: Hee Jung Kim, Ga Won Yim, Kyung Jin Eoh, Lee Kyung Kim, Jung-Yun Lee, Eun Ji Nam, Sang Wun Kim, Young Tae Kim. Long noncoding RNA HOXA11 antisense promotes tumor progression via the Notch pathway in serous ovarian 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 2551. doi:10.1158/1538-7445.AM2017-2551
Abstract 2485: CYP24A1-induced vitamin D insufficiency promotes breast cancer growth
Authors: Makoto Osanai, Yusuke Ono, Akira Takasawa, Kumi Takasawa, Masaki Murata, Norimasa Sawada
Journal: Cancer Research (2018)

Abstract Vitamin D plays a critical role in the maintenance of tissue homeostasis by regulating the expression of genes affecting cell proliferation, differentiation, and apoptosis. The vitamin D 24-hydroxylase CYP24A1 functions in vitamin D target tissues to degrade the hormonal form of vitamin D. Existing knowledge regarding dysregulated CYP24A1 expression supports its candidacy as a putative oncogene. In our presentation, we demonstrate that the suppression of constitutive CYP24A1 expression by CYP24A1-specidic shRNA conferred target cells with increased susceptibility to apoptosis and consequently inhibited anchorage-independent growth in breast carcinoma cells. In addition, suppression of vitamin D metabolism following knockdown of CYP24A1 significantly reduced tumor growth in vivo. Since these data provide substantial evidence for a pro-survival and stimulatory oncogenic effect of CYP24A1 in breast carcinoma cells, we will discuss the potential feasibility of CYP24A1-inhibitory cancer therapies. Citation Format: Makoto Osanai, Yusuke Ono, Akira Takasawa, Kumi Takasawa, Masaki Murata, Norimasa Sawada. CYP24A1-induced vitamin D insufficiency promotes breast cancer growth [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 2485.