tbuckley/cabot-search huggingface dataset:
Abstract 2474: The mechanistic role of polyamines in DNA double-strand break repair
Authors: Chih-Ying Lee, Guan-Chin Su, Min-Yu Ko, Wen-Yen Huang, Geen-Dong Chang, Sung-Jan Lin, Peter Chi
Journal: Cancer Research (2017)

Abstract Polyamines are essential organic cations for cell growth, proliferation and tissue remodeling. The rate-limiting step in the biosynthesis of polyamines is catalyzed by ornithine decarboxylase (ODC). The activity of ODC and the level of intracellular polyamines significantly increase in many cancers, indicating the critical role of polyamines in tumorigenesis. Depletion of polyamines sensitizes cells to DNA damage agents that lead to DNA double-strand breaks (DSBs), suggesting that endogenous polyamines may participate in DNA repair process. However, the mechanistic role of polyamines in DSB repair remains largely unknown. Here, we wish to ascertain the role of polyamines in DSBs repair pathway and to delineate the underlying mechanism by combining biochemical analyses, cell-based and animal approaches. Our cell-based experiments demonstrated that polyamines indeed participate in DNA double-strand break repair. Specifically, the level of intracellular polyamines regulates homologous recombination (HR) repair pathway rather than non-homologous end joining (NHEJ). Furthermore, our in vitro reconstitution system and functional analyses demonstrated that polyamines significantly enhance RAD51-mediated DNA strand exchange reaction. Importantly, we reveal that the stimulatory effect of polyamines by RAD51 stems from the enhancement of duplex DNA captures in the DNA exchange reaction. Finally, the physiological role of polyamines in DSBs repair was examined by using mouse hair follicle as a model system. The animal model clearly highlights the significant contribution of polyamines to the DNA repair in vivo. Our findings thus furnish valuable insight into the mechanistic basis of polyamines in DNA repair. Citation Format: Chih-Ying Lee, Guan-Chin Su, Min-Yu Ko, Wen-Yen Huang, Geen-Dong Chang, Sung-Jan Lin, Peter Chi. The mechanistic role of polyamines in DNA double-strand break repair [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 2474. doi:10.1158/1538-7445.AM2017-2474
Abstract 306: Antitumor effect of Wee1 inhibitor in gastric cancer cells
Authors: Seongyeong Kim, Ahrum Min, So Hyeon Kim, Dong Hyeon Ha, Hyemin Jang, Yu JIn Kim, Hee Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Journal: Cancer Research (2017)

Abstract Background: A cell cycle checkpoint is a key step to watch any damages and, it is needed to maintain genomic stability. Thus, to jeopardize cell cycle checkpoint is an attractive strategy for cancer treatment. Wee1 is a G2 cell cycle regulator that phosphorylate cdc2 on tyrosine 15 for inhibiting its activity. The activation of Wee1 can delay G2 phase progression and cells can have a chance to repair DNA damages. Therefore, to inhibit wee1 can accelerate DNA damage accumulation in the cell. AZD1775 is a first-in-class wee1 inhibitor. So far, previous studies showed the antitumor effect of AZD1775 as a mono-therapeutic agent or combination treatment with other chemo-agents. However, the activity of wee1 in gastric cancer (GC) cells is not yet fully understood. Thus, we would like to study whether AZD1775 has an antitumor effect against GC or not. Materials and methods: We determined the antitumor effects of AZD1775 on GC cells using a cytotoxicity assay, cell cycle analysis, immunofluorescence assay and western blotting by AZD1775 treatment. Results: AZD1775 effectively inhibit GC cell proliferation. The TP53 gene status or p-Wee1 expression levels were not associated with AZD1775 sensitivity. AZD1775 effectively down-regulated p-Wee1 and p-cdc2 expressions in SNU-601, a sensitive cell line. However, these effects were not significant in KATO-III cells, which is less sensitive to AZD1775. Cell cycle analysis revealed that the cells had different responses by AZD1775 treatment. SNU-601 cells were enriched in S phase when we decide cell cycle only by its DNA contents. However, KATO-III cells were arrested in G2/M phase. The sub-G1 population was dramatically increased only in SNU-601 cells. A population of BrdU-positive and p-HH3 positive cells was significantly increased in the SNU-601 cells which indicate that premature mitosis was increased. However, no differences were observed in KATO-III cells. Moreover, due to premature mitotic entry, multi-nucleated cells were observed only in SNU-601 cells. Conclusion: AZD1775 effectively inhibited the growth of GC cell lines. The inhibition of cdc2 by AZD1775 was observed only in a sensitive cell line. Moreover, early mitotic entry was induced by AZD1775, and it led the induction of mitotic catastrophe. This result indicates that AZD1775 have an antitumor effect on GC and the possibility of adoption to the clinical trial design. Citation Format: Seongyeong Kim, Ahrum Min, So Hyeon Kim, Dong Hyeon Ha, Hyemin Jang, Yu JIn Kim, Hee Jun Kim, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im. Antitumor effect of Wee1 inhibitor in gastric cancer cells [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 306. doi:10.1158/1538-7445.AM2017-306
Abstract 5138: Development of a gold nanoparticle platform capable of selective homing to tumor tissues for intravenous antitumor therapy
Authors: Zhen Han
Journal: Cancer Research (2017)

Abstract Intratumoral administration of high mobility group nucleosome-binding protein 1 (HMGN1) and R848/resiquimod together with a checkpoint inhibitor can eradicate large established tumors. However, the intratumoral route of administration is difficult to use on cancers of internal organs. To improve potential clinical use of HMGN1 and R848, it is necessary to deliver HMGN1 and R848 systemically to the tumor tissue. Gold nanoparticles (AuNP) have been extensively studied as a vehicle for various types of drugs, including anticancer compounds. In this study, we established a means of generating PEGylated Au-HMGN1-R848 (Au-PEG-HMGN1-R848) complexes, which, upon intravenous IV administration, preferentially target ectopic hepatoma or colon tumor tissue and avoids uptake of the particles by liver and spleen of tumor-bearing mice. Additionally, Au-PEG-HMGN1-R848 complexes were stable and preserved the capacity of HMGN1 and R848 to stimulate the maturation of dendritic cells. IV administration of Au-PEG-HMGN1-R848 complexes plus a checkpoint inhibitor had effective antitumor activity in curing 80% of C57BL/6 mice bearing large (1 cm in diameter) Hepa1-6 hepatoma and Balb/c mice bearing CT26 colon tumors. Therefore, an Au nanoparticle platform capable of selectively delivering HMGN1 and R848 systemically to tumor tissues can be used to effectively to cure ectopic Hepa1-6 hepatoma and CT26 colon carcinoma. Note: This abstract was not presented at the meeting. Citation Format: Zhen Han. Development of a gold nanoparticle platform capable of selective homing to tumor tissues for intravenous antitumor therapy [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 5138. doi:10.1158/1538-7445.AM2017-5138
Abstract 3450: Identification of a novel lncRNA involved in Bcr-Abl mediated cellular transformation
Authors: Jilong Chen, Xuefei Wang
Journal: Cancer Research (2017)

Abstract Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, little information is available about functional involvement of lncRNAs in tumorigenesis of chronic myeloid leukemia (CML) induced by Bcr-Abl oncogene. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray combined with drug treatment. We identified an lncRNA termed lncRNA-up38 that was critically involved in Bcr-Abl-mediated cellular transformation. We found that expression of lncRNA-up38 was greatly upregulated by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Furthermore, our experiments demonstrated that lncRNA-up38 acted as a key regulator of 4EBP1 functioning during Bcr-Abl-mediated cellular transformation. Moreover, silencing lncRNA-up38 promoted leukemic cells survival and enhanced Bcr-Abl-mediated tumorigenesis, whereas forced expression of lncRNA-up38 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Additionally, our experiments have begun to address the mechanism of how lncRNA-up38 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-up38 expression through c-Myc-dependent signaling. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation is associated with downregulation of tumor-suppressor lncRNA-up38 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia. Note: This abstract was not presented at the meeting. Citation Format: Jilong Chen, Xuefei Wang. Identification of a novel lncRNA involved in Bcr-Abl mediated cellular transformation [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 3450. doi:10.1158/1538-7445.AM2017-3450
Probe-based endomicroscopy for in vivo detection of gastric intestinal metaplasia and neoplasia: a multicenter randomized controlled trial
Authors: Xiu-Li Zuo, Zhen Li, Chang-Qing Li, You-You Zheng, Li-Dong Xu, Jie Chen, Rong Lin, Jun Song, Chao-Hui Yu, Min Yue, Qi Zhou, Zhi-Yan Liu, Yan-Qing Li
Journal: Endoscopy (2017)

Abstract Background and study aims Owing to the indistinctive endoscopic appearance of gastric intestinal metaplasia (GIM), gastric intraepithelial neoplasia (GIN), and early gastric cancer (EGC), a significant number of such lesions may be missed during surveillance endoscopy. The aim of this clinical trial was to assess the value of combined computed virtual chromoendoscopy (flexible spectral imaging color enhancement [FICE]) and probe-based confocal laser endomicroscopy (pCLE) for in vivo detection of GIM, GIN, and EGC. Patients and methods This was a multicenter, randomized controlled trial performed in 238 patients at four tertiary centers. Patients were randomized to FICE-guided pCLE with targeted biopsies (group A) or FICE with standard biopsies (group B). The diagnostic yield of GIM, GIN, or EGC was compared between the two groups. Results On a per-patient assessment, the diagnostic yield for GIM/GIN/EGC was 73.3 % (88/120) in group A and 63.6 % (75/118) in group B (P = 0.09). On a per-biopsy analysis, FICE-guided pCLE with targeted biopsies significantly increased the diagnostic yield of GIM/GIN/EGC vs. FICE with standard biopsies, from 31.5 % (252/800) to 75.1 % (313/417) (P &lt; 0.001). In addition, pCLE-guided targeted biopsies led to a significant 48.5 % decrease in the number of biopsies per patient vs. FICE with standard biopsies (P &lt; 0.001). Conclusions Real-time pCLE and targeted biopsies after FICE improved the diagnostic yield for the detection of GIM, GIN, and EGC, and only required about half the number of biopsies vs. FICE with standard biopsies. This may allow a better regimen for endoscopic surveillance and subsequent treatment of patients with premalignant and malignant gastric abnormalities. Trial registered at ClinicalTrials.gov (NCT02515721).
Abstract 4939: Activation of GSK3β/β-catenin pathway promotes organ-specific metastasis in prostate cancer
Authors: Siyuan Qin, Qiong Song, Jinlu Dai, Haibo Tong, Evan Keller, Jian Zhang, Yi Lu
Journal: Cancer Research (2017)

Abstract Metastasis is the major cause of treatment failure in various malignancies, including prostate cancer (PCa). Accumulating data has suggested that primary cancer cells prefer to spread to certain distant organs. To explore the mechanisms of different cancer cells preferentially metastasizing to certain organs, we established a prostate cancer lung metastasis model. Murine prostate cancer cells (RM1), which labeled with luciferase, were used in this study. RM1 cells were injected into left tibia of mouse (C57BL/6J), and monitored the tumor growth and metastasis every week by Bioluminescence Imaging. The mice would be sacrificed when metastatic tumor appeared in multi-organs. We isolated the lung metastatic tumor, made single cell suspension and amplified. The lung metastatic tumor cells were specifically metastasized to lung when the tumor cells were injected intratibially again. After several cycles we obtained highly lung metastatic tumor cells, named RM1-LM cells. Further, we investigated property and function changes in RM1-LM cells compared to parental cells (RM1) using in vitro assays. We firstly found the highly lung metastatic tumor cells showed more mesenchymal properties. Western blot results showed that hallmarks of EMT including E-cadherin, vimentin, snail, and ZO-1 were altered significantly in RM1-LM cells. Then, we observed that the highly lung metastatic tumor cells exhibited increased proliferative, colony formation, migratory and invasive abilities. Mechanistic analyses indicated that prostate cancer organ-specific metastasis mediated by the activation of GSK-3β/β-catenin pathway. The current study may provide potential therapeutic targets and diagnostic biomarkers of PCa metastasis. This work was supported by Natural Science Foundation of China (NSFC) Key Project (81130046); NSFC (81171993; 81272415); Guangxi Projects of China (2013GXNSFEA053004; 2012GXNSFCB053004). Note: This abstract was not presented at the meeting. Citation Format: Siyuan Qin, Qiong Song, Jinlu Dai, Haibo Tong, Evan Keller, Jian Zhang, Yi Lu. Activation of GSK3β/β-catenin pathway promotes organ-specific metastasis in 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 4939. doi:10.1158/1538-7445.AM2017-4939
Abstract 5636: Targeting of NOXA overexpression in anaplastic thyroid cancer (ATC)
Authors: Niklas K. Finnberg, Junaid Abdulghani, Hormoz Ehya, Wafik El-Deiry
Journal: Cancer Research (2017)

Abstract Anaplastic thyroid cancer (ATC) is a rare, aggressive and fatal cancer with a median survival of 3-5 months after diagnosis. Our long-term goal is to develop better therapies based on the biology of ATC that contributes to improved tumor response and a reduced risk of potential side-effects. We recently showed that the anti-apoptotic BCL2 family member MCL1 is overexpressed in a subset of ATC and that targeting of MCL1 with quinacrine leads to increased sensitization to the BRAF inhibitor sorafenib. To further investigate the importance of BCL2 family proteins in ATC, we analyzed gene expression data from several published independent gene expression studies. We discovered that both papillary thyroid cancer (PTC) and ATC surprisingly overexpress the mRNA of the pro-apoptotic BCL2 family member NOXA. However, despite the observed overexpression of NOXA mRNA in several ATC cell lines, we find that NOXA protein expression, by contrast, is low. NOXA protein has previously been shown to be subject to ubiquitination and proteasomal degradation. Indeed, through bioinformatics, we find overexpression of several ubiquitin enzymes in ATC suggesting that the half-life of NOXA protein may be selectively reduced in this tumor type. We are further assessing differences in the turnover of NOXA protein in ATC cells and are investigating if restoring NOXA protein expression may synergize with the pharmacologic targeting of MCL1 and other anti-apoptotic BCL2 family members. Interestingly, through TCGA analysis, we discovered that BCL2 overexpression is associated with a poor prognosis in thyroid cancer (THCA) patients. Indeed, treatment with the BCL2/BCLXL inhibitor navitoclax showed encouraging efficacy and synergized with the neddylation inhibitor MLN4924 in the ATC cell line 8505C. This was based on the expectation that MLN4924 would rescue NOXA protein expression. We are pursuing mechanistic studies in a larger panel of thyroid cancer cell lines and in vivo efficacy and toxicity studies. We conclude that restoring NOXA protein expression can together with the rational targeting of anti-apoptotic BCL2 family members may allow for the expansion of the limited ATC-selective treatment strategies currently available. Citation Format: Niklas K. Finnberg, Junaid Abdulghani, Hormoz Ehya, Wafik El-Deiry. Targeting of NOXA overexpression in anaplastic thyroid cancer (ATC) [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 5636. doi:10.1158/1538-7445.AM2017-5636
Abstract 3002: Therapeutic targeting of PGBD5-induced DNA repair dependence in pediatric solid tumors
Authors: Anton Henssen, Casie Reed, Eileen Jiang, Wong Wai, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Johannes H. Schulte, Neil Ganem, John Petrini, Alex Kentsis
Journal: Cancer Research (2017)

Abstract Despite intense efforts, the cure rates of childhood solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined, particularly for tumors caused by aberrant developmental and epigenetic factors. We have now found that the majority of childhood solid tumors, rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5. Using functional genetic approaches, we observed that mouse and human cells deficient in non-homologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA repair inhibitors, we identified the ATR/ATM inhibitor AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. Ectopic expression of PGBD5 was sufficient to induce hypersensitivity to AZD6738, and endogenous PGBD5 was necessary for its anti-tumor effects. We found that PGBD5-expressing tumor cells accumulate unrepaired DNA damage in response to AZD6738 treatment, and undergo apoptosis in both dividing and G1 phase cells in the absence of measureable DNA replication stress. Accordingly, AZD6738 exhibits nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro. Finally, AZD6738 exhibits excellent single-agent activity against high-risk neuroblastoma and medulloblastoma xenografts, with induction of apoptosis and tumor regression in vivo. These findings delineate a therapeutically actionable synthetic lethality for the majority of childhood solid tumors. Citation Format: Anton Henssen, Casie Reed, Eileen Jiang, Wong Wai, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Johannes H. Schulte, Neil Ganem, John Petrini, Alex Kentsis. Therapeutic targeting of PGBD5-induced DNA repair dependence in pediatric solid tumors [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 3002. doi:10.1158/1538-7445.AM2017-3002
Chelator-Free Radiolabeling of SERRS Nanoparticles for Whole-Body PET and Intraoperative Raman Imaging
Authors: Matthew A. Wall, Travis M. Shaffer, Stefan Harmsen, Darjus-Felix Tschaharganeh, Chun-Hao Huang, Scott W. Lowe, Charles Michael Drain, Moritz F. Kircher
Journal: Theranostics (2017)

A single contrast agent that offers whole-body non-invasive imaging along with the superior sensitivity and spatial resolution of surface-enhanced resonance Raman scattering (SERRS) imaging would allow both pre-operative mapping and intraoperative imaging and thus be highly desirable.We hypothesized that labeling our recently reported ultrabright SERRS nanoparticles with a suitable radiotracer would enable pre-operative identification of regions of interest with whole body imaging that can be rapidly corroborated with a Raman imaging device or handheld Raman scanner in order to provide high precision guidance during surgical procedures.Here we present a straightforward new method that produces radiolabeled SERRS nanoparticles for combined positron emission tomography (PET)-SERRS tumor imaging without requiring the attachment of molecular chelators.We demonstrate the utility of these PET-SERRS nanoparticles in several proof-of-concept studies including lymph node (LN) tracking, intraoperative guidance for LN resection, and cancer imaging after intravenous injection.We anticipate that the radiolabeling method presented herein can be applied generally to nanoparticle substrates of various materials by first coating them with a silica shell and then applying the chelator-free protocol.
Abstract 3569: Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer
Authors: Parameet Kumar, Joyeeta Chakraborty, Raghunath Chatterjee, Gauthaman Sukumar, Clifton L. Dalgard, Kevin Babcock, Albert Dobi, Taduru L. Sreenath, Roopa Biswas
Journal: Cancer Research (2017)

Abstract Prostate Cancer (CaP) is the most common non-cutaneous form of cancer in men and is the second leading cause of cancer mortality in men in the USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5' untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of the prostate tumors. To identify and investigate the underlying mechanisms of ERG-associated CaP, we developed ERG-inducible LNCaP cell system. In this present study, we investigated the unique cellular transcriptome associated with over-expressed ERG in CaP cells. Our data from comprehensive transcriptome analyses, illustrate a distinct signature that distinguishes ERG-dependent and ERG-independent CaP. The data highlight the significant heterogeneity among the transcript. Out of the 527 differentially expressed genes, 232 genes were up-regulated and 295 genes were down-regulated in response to ERG. Subsequent, in silico analyses indicate that these differentially expressed genes were associated with many pathways and functions. The most significantly differentially expressed genes were associated with cell cycle regulation. The top-ranked biological functions affected by ERG over-expression include Cell Cycle (p &amp;lt; 1.42E-04), Cellular Growth and Proliferation (p &amp;lt; 1.23E-04), Cellular Development (p &amp;lt;1.23E-04), Cell Death and Survival (p &amp;lt; 1.37E-04), and Cellular Assembly and Organization (p &amp;lt; 1.42E-04). Further analyses indicate a strong association with known cancer networks. The top-ranked canonical pathways enriched in ERG-positive compared to ERG-negative LNCaP cells include, Cell Cycle Control of Chromosomal Replication (p=2.69E-16), Role of CHK Proteins in Cell Cycle Checkpoint Control (p=3.16E-11), Cell Cycle: G2/M DNA Damage Checkpoint Regulation (p=1.34E-09), Role of BRCA1 in DNA Damage Response (p=4.05E-08) and Estrogen-mediated S-phase Entry (p =5.51E-08). These findings indicate new insights into the complexity of TMPRESS2-ERG gene fusion, and may help understand mechanistic pathways which promote growth and progression of CaP. Citation Format: Parameet Kumar, Joyeeta Chakraborty, Raghunath Chatterjee, Gauthaman Sukumar, Clifton L. Dalgard, Kevin Babcock, Albert Dobi, Taduru L. Sreenath, Roopa Biswas. Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of 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 3569. doi:10.1158/1538-7445.AM2017-3569