tbuckley/cabot-search huggingface dataset:
Abstract 1102: Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth <i>in vivo</i>
Authors: Jessica Wagner, Wafik El-Deiry
Journal: Cancer Research (2017)

Abstract Small molecule imipridone ONC201 is an investigational anti-tumor agent with a wide therapeutic index and broad-spectrum efficacy in vivo. ONC201 upregulates intratumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 as therapy in advanced cancer patients has been completed and the drug has progressed into several Phase II trials in multiple cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease continues to have a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. Bevacizumab is a humanized monoclonal antibody that targets VEGF and is an FDA-approved treatment for advanced CRC patients, in addition to other tumor types. We are investigating the potential combination of VEGF inhibitors such as bevacizumab and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) studies. Our results demonstrate significant tumor regression and occasional tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC-38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Non-invasive angiogenesis imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. With the use of both a murine VEGF inhibitor in syngeneic models, and bevacuzimab in human cell line-derived xenografts, we have demonstrated that combining anti-angiogenic therapies with ONC201 could enhance antitumor efficacy. Thus, ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising combinatorial approach that may be exploited in the clinic for the treatment of CRC. Citation Format: Jessica Wagner, Wafik El-Deiry. Anti-tumor effects of imipridone ONC201 in combination with anti-angiogenic agents significantly impact on colorectal cancer growth in vivo [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 1102. doi:10.1158/1538-7445.AM2017-1102
Abstract 4453: Identification and characterization of oncogenic kinase LASK2 as a diagnostic and therapeutic target for lung cancer
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer deaths worldwide. Since the number of patients responding well to standard therapies is still limited, further development of new anti-cancer agents with minimum risk of adverse event is urgently awaited. To screen oncoantigens which could be used for the development of new diagnostic biomarkers and molecular targeted drugs, we have established a screening system as follows; i) To identify overexpressed genes in 120 lung cancers by genome-wide screening using the microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the genes for their very low or absent expression in normal tissues by northern-blotting, iii) To validate the clinicopathological significance of their expression with tissue microarray covering hundreds of archived lung cancers, iv) To verify whether the target genes are essential for the growth or survival of lung cancer cells by RNAi and cell growth assays. During this process, we selected dozens of druggable oncogenes with various enzymatic activities, and identified overexpression of protein kinase LASK2 (lung cancer-associated kinase 2) in the majority of lung cancers, but not in normal tissues except testis. Immunocytochemical analysis found LASK2 to be mainly localized in the cytoplasm and nucleus of lung cancer cells. Immunohistochemical analysis revealed that strong LASK2 expression was an independent prognostic factor for non-small cell lung cancer (NSCLC) (P&amp;lt;0.0001). Suppression of LASK2 expression with its specific siRNAs caused growth inhibition of lung cancer cells. The enhanced cellular proliferation by introduction of LASK2 in mammalian cells also supported its oncogenic function. Since LASK2 plays a significant role in the cell proliferation and malignant nature of lung cancers, LASK2 is likely to be a prognostic biomarker and a potential therapeutic target for developing new anti-cancer drugs. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Identification and characterization of oncogenic kinase LASK2 as a diagnostic and therapeutic target for 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 4453. doi:10.1158/1538-7445.AM2017-4453
Abstract 2308: Sigma-2 receptor ligands induce apoptosis and inhibit proliferation in breast cancer cell line mda-mb-231
Authors: Gladys Asong, Felix Amissah, Olufisayo Salako, Rosemary Poku, Elizabeth Ntantie, Augustine Nkembo, Nazarius Lamango, Seth Ablordeppey
Journal: Cancer Research (2017)

Abstract Introduction: Despite the reduction in mortality from breast cancer achieved in the last 30 years due to more effective targeted therapies, the survival rate for patients with triple negative breast cancer (TNBC) is poor and has virtually plateaued. Due to the absence of estrogen, progesterone, and human epidermal growth factor receptors 2, no targeted treatment options are currently available for TNBC. Moreover, the current standard systemic treatments are known to cause tremendous side effects. Thus, there is an urgent need to identify novel strategies for treating TNBC. Several reports have revealed that sigma-2 receptors are over-expressed in all solid tumors including TNBC, making it a plausible biomarker to explore for TNBC treatment. In this study, we investigated the effects of novel sigma-2 receptor ligands (XYZ-XI-14 and XYZ-VII-69) synthesized in our lab on the viability and survival of the TNBC, MDA-MB-231. Methods: MDA-MB-231 cells were treated for 48 h with XYZ-XI-14 and XYZ-VII-69, cell viability and proliferation were assessed using resazurin cell titre assay and cell count methods respectively. The effects of the ligands on spheroids formation, cell cycle, and mode of cell death were also investigated. Results: XYZ-XI-14 and XYZ-VII-69 decreased cell viability of MDA-MB-231 cells in a concentration-dependent manner. The EC50 for XYZ-XI-14 and XYZ-VII-69 were 12 and 13 µM respectively; and at 5 µM, the ligands inhibited cell proliferation, induced apoptosis, and arrested MDA-MB-231 cells at the G0/G1 phase of cell cycle. Additionally, concentrations of the ligand as low as 1 µM prevented the formation of spheroids as evidenced by the lack of compact spheroids, and caused the disintegration of preformed spheroids. Conclusion: This study indicates that targeting sigma-2 receptors with novel sigma-2 ligands (XYZ-XII-14 and XYZ-VII-69) effectively inhibits TNBC cancer cell growth by inducing apoptosis and cell cycle arrest, thus presenting a unique and effective pathway for treating TNBC. Additionally, the sigma-2 receptor ligands (XYZ-XI-14 and XYZ-VII-69) have the potential to halt tumor growth and prevent tumor relapse, as seen in our 3D culture assays. Thus, the sigma-2 receptor has the potential to be a valuable target for the development of novel agents for the treatment of TNBC. Citation Format: Gladys Asong, Felix Amissah, Olufisayo Salako, Rosemary Poku, Elizabeth Ntantie, Augustine Nkembo, Nazarius Lamango, Seth Ablordeppey. Sigma-2 receptor ligands induce apoptosis and inhibit proliferation in breast cancer cell line mda-mb-231 [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 2308. doi:10.1158/1538-7445.AM2017-2308
Abstract 3057: Gut microbiome controls liver metastasis
Authors: Chi Ma, Qiong Fu, Tim Greten
Journal: Cancer Research (2017)

Abstract Aim: The gut microbiome can modify tumor immunity and has been suggested to be involved in the development of liver cancer. However, it remains unknown how the gut microbiome controls hepatic immune responses. This study was designed to exam the effect of the gut microbiome on liver antitumor immunity, and to study potential mechanism. Experimental procedure: Antibiotic cocktail in drinking water was given to remove mouse gut microbiota. Control mice were kept on regular water. EL4 thymoma cells were injected s.c. to induce spontaneous liver metastasis. B16 melanoma and CT26 colon cancer cells were injected intrasplenically to form liver metastasis. Lung metastasis was induced by tail injection of tumor cells. Results: Antibiotic cocktail efficiently depleted gut bacteria. Removing gut commensal bacteria did not affect the growth of primary s.c. tumors, but impaired formation of liver metastasis in different models. The inhibitory effect on liver metastasis by removing gut microbiome was found after intrasplenic injection of tumor cells to form liver metastasis using both B16 melanoma and CT26 colon cancer tumor cells. Interestingly, formation of lung metastasis caused by tail vein injection of B16 cells was not impaired by antibiotics treatment, suggesting a liver specific effect. The inhibition of liver metastasis by antibiotic treatment was absent in Rag1 knockout mice, suggesting that the mechanism is mediated by the adaptive immune system. Conclusion: Our results suggest that the gut microbiome affects the liver immune microenvironment and modulates antitumor immunity. Citation Format: Chi Ma, Qiong Fu, Tim Greten. Gut microbiome controls liver metastasis [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 3057. doi:10.1158/1538-7445.AM2017-3057
Abstract 19377: Procedural Success Rates and Outcomes of PCI in the Very Elderly Patients (≥ 90 Years) With NSTE Acute Coronary Syndromes. Results of the Prospective ALKK-Registry
Authors: Uwe Zeymer, Mathias Hochadel, Patrick Riedmaier, Anselm Gitt, Berward Lauer, Harald Darius, Ralf Zahn
Journal: Circulation (2016)

Background: There is a growing number of elderly patients admitted with acute coronary syndromes. However, there is a lack of data on the outcome of the very elderly patients with NSTE-ACS. Therefo...
Abstract 4458: Regulation of MYC protein stability by mutant KRAS in pancreatic ductal adenocarcinoma
Authors: Angelina V. Vaseva, Devon R. Blake, Salma H. Azam, Karim T. Gilbert, Chad V. Pecot, Kenneth H. Pearce, Laura E. Herring, Lee M. Graves, Peter J. Houghton, Channing J. Der
Journal: Cancer Research (2017)

Abstract With the nearly 100% mutation frequency of KRAS in pancreatic ductal adenocarcinoma (PDAC), the development of therapeutic strategies to target KRAS is a high priority for the pancreatic cancer field. In the current study, we aimed to identify signaling changes caused by the acute suppression of mutant KRAS in PDAC cell lines. Strikingly, acute suppression of mutant KRAS in PDAC cell lines caused potent and rapid proteasome-dependent degradation of MYC protein. Ablation of MYC also suppressed PDAC growth both in vitro and in vivo, indicating a critical driver role for MYC in KRAS-dependent PDAC maintenance. A mechanism by which RAS effector signaling regulates MYC protein stability has been described, however we determined that this mechanism cannot fully account for how endogenous mutant KRAS stabilizes MYC protein in PDAC cells. We verified a role for the Raf-MEK-ERK but not the PI3K-AKT-GSK3β effector signaling pathway. Unexpectedly, we also excluded a role for MYC protein phosphorylation at MYC residue T58, and determined that ubiquitin ligases other than FBW7 are involved. These findings prompted us to search for additional KRAS-dependent protein kinases that facilitate MYC protein stability. We applied multiple screening strategies. First, we developed a novel fluorescence-based system to monitor real-time MYC protein degradation in PDAC cells and we adapted this system for use in a high-throughput flow-cytometry based assay. Second, we applied a mass spectrometry-based approach to profile the human kinome for KRAS-dependent changes in protein kinases. Finally, we applied gain-of-function (Cancer Toolkit) and loss-of-function (CRISPR/Cas9) genetic screens to identify signaling regulators of MYC protein stability. The results of these screens will be presented. Citation Format: Angelina V. Vaseva, Devon R. Blake, Salma H. Azam, Karim T. Gilbert, Chad V. Pecot, Kenneth H. Pearce, Laura E. Herring, Lee M. Graves, Peter J. Houghton, Channing J. Der. Regulation of MYC protein stability by mutant KRAS in pancreatic ductal adenocarcinoma [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 4458. doi:10.1158/1538-7445.AM2017-4458
Abstract 4858: AK4 promotes colorectal cancer progression and metastasis
Authors: Yau Hei Yu, Joanna Hung Man Tong, Yi Pan, Raymond Wai Ming Lung, Ka Fai To, Anthony Wing Hung Chan
Journal: Cancer Research (2017)

Abstract Metastatic colorectal cancer (CRC) is a fatal disease with a poor prognosis. It is crucial to understanding the underlying pathogenesis to battle this dismal condition. We previously identified that AK4, a gene on chromosome 1p31.3 encoding a member of adenylate kinase family enzymes, was progressively up-regulated from normal colon, primary CRC to metastasis by mRNA gene expression microarray of paired CRC samples. This study was aimed to validate the overexpression of AK4 and explore in-vitro effects in CRC. We firstly examined the mRNA expression level of AK4 in a panel of CRC cell lines. AK4 mRNA expression was higher in CRC cell lines (n=8) than normal colon cell line, and significantly higher in advanced stage cell lines (n=4, Dukes’ C and D) than early stage ones (n=4, Dukes’ A and B) (P=0.03). We further evaluated expression level of AK4 in two different cohorts of clinical samples. The first cohort consisted of 18 paired primary CRCs and its corresponding normal colonic mucosa, and 27 metastatic CRC (including 15 cases with paired primary CRC and normal colonic mucosa). AK4 mRNA level was significantly higher in metastatic CRC than normal colon (P&amp;lt;0.001), and metastatic CRC than primary CRC (P&amp;lt;0.001). Among 15 cases with paired primary and metastatic tumors, 14 (93.3%) demonstrated higher AK4 in metastatic tumors than their primary counterparts(P&amp;lt;0.05). The second cohort composed of 190 consecutive primary CRCs. Upregulation of AK4 protein expression evaluated by immunohistochemistry was found in 68.4% of CRC, and associated with advanced AJCC stage (P&amp;lt;0.001), poorer overall survival (P=0.002) and worse disease-free survival (P&amp;lt;0.001). To evaluate functional properties of AK4 in CRC, we knocked down AK4 on a CRC cell lines with high endogenous AK4 expression (DLD1, HCT116 and SW620) by siRNA. knockdown of AK4 significantly reduced anchorage-dependent colony forming ability (P&amp;lt;0.05) and eliminated migratory (P&amp;lt;0.05) and invasive (P&amp;lt;0.05) abilities. In conclusion, AK4 is a potential oncogene upregulated in metastatic CRC and exhibiting in-vitro oncogenic properties. AK4 may play an important role in tumor progression and metastasis. Citation Format: Yau Hei Yu, Joanna Hung Man Tong, Yi Pan, Raymond Wai Ming Lung, Ka Fai To, Anthony Wing Hung Chan. AK4 promotes colorectal cancer progression and metastasis [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 4858. doi:10.1158/1538-7445.AM2017-4858
Risk of recurrent venous thromboembolism in COPD patients: results from a prospective cohort study
Authors: Raphael Le Mao, Cécile Tromeur, Amélie Bazire, Maelenn Gouillou, Marie Guegan, Karine Lacut, Aurélien Delluc, Dominique Mottier, Christophe Leroyer, Francis Couturaud
Journal: European Respiratory Journal (2017)

We aimed to assess the risk of recurrent venous thromboembolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) following cessation of anticoagulation therapy. In a prospective cohort of 1468 patients with a documented episode of VTE, followed for up to 5 years after cessation of anticoagulation therapy, the diagnosis of COPD was confirmed in 136. The main outcome was recurrent VTE. The secondary outcome was overall mortality. Univariate and multivariate analyses were performed to identify the risk factors of recurrence. Of the 1468 patients included, recurrent VTE was observed in 306 (34 with COPD and 272 without) during a median follow-up period of 36.5 months. The incidence rate of recurrent VTE was 9.1% (95% CI 6.5–12.8) for COPD patients and 7.0% (95% CI 6.2–7.9) for non-COPD patients. COPD was not associated with an increased risk of VTE recurrence on univariate or multivariate analyses (hazard ratio: 1.0 (95% CI 0.7–1.4)). The risk of death, adjusted for demographic and clinical characteristics, showed no increase in COPD patients, as compared to non-COPD patients. In patients with COPD who had an acute episode of VTE, the risk of recurrent VTE was not any higher than that in non-COPD patients.
Abstract 553: Microsatellite genotyping enables precision lung cancer risk classification
Authors: Robin T. Varghese, Karthik Raja Velmurugan, Natalie C. Fonville, Harold R. Garner
Journal: Cancer Research (2017)

Abstract There remains a large discrepancy between the known genetic contributions to cancer and that which can be explained by genomic variants, both inherited and somatic. Recently, understudied repetitive DNA regions called microsatellites have been identified as genetic risk markers for a number of diseases including various cancers (breast, ovarian and brain). In this study we demonstrate an integrated process for identifying and validating microsatellite based risk markers for lung cancer using data from the cancer genome atlas (TCGA) and the 1000 genomes project. Comparing whole exome germline sequencing data from 488 TCGA lung cancer samples to germline exome data from 390 control samples from the 1000 genomes project, we identified 119 potentially informative microsatellite loci. These loci (risk markers) were found to be able to distinguish between cancer and control samples with sensitivity and specificity ratios over 0.8. Then these loci, supplemented with additional loci from other cancers and controls, were evaluated using a custom target enrichment kit and sample-multiplexed nextgen sequencing. Thirteen of the 119 risk markers were validated using high-depth (579x±315) nextgen sequencing of 30 lung cancer and 89 control samples, resulting in sensitivity and specificity ratios were 0.90 and 0.94, respectively. When 8 loci harvested from the bioinformatic analysis of other cancers are added to the classifier, then the sensitivity and specificity rise to 0.93 and 0.97, respectively. Analysis of the genes harboring these loci revealed two genes (ARID1B and REL) and two significantly enriched pathways (chromatin organization and cellular response to stress) which suggest that the process of lung carcinogenesis is linked to chromatin remodeling, inflammation, and tumor microenvironment restructuring. We illustrate that high-depth nextgen sequencing enables a high precision microsatellite-based risk classifier. Note: This abstract was not presented at the meeting. Citation Format: Robin T. Varghese, Karthik Raja Velmurugan, Natalie C. Fonville, Harold R. Garner. Microsatellite genotyping enables precision lung cancer risk classification [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 553. doi:10.1158/1538-7445.AM2017-553
Abstract P253: Transcriptional Regulation of the IGFBP-1 Gene by RTEF-1 in Endothelial Cells
Authors: Angela F Messmer-Blust, Jiaping Wu, Yi Jin, Shaodong Guo, Jian Li
Journal: Circulation Research (2011)

Background and Objective: Cardiovascular disease is the most important complication of type 2 diabetes, however, its underlying mechanism(s) are poorly understood. Our lab previously reported that RTEF-1 is a transcription factor that promotes angiogenesis via up-regulating HIF-1α and VEGF. In addition to these studies, we recently determined that RTEF-1 upregulates insulin-like growth factor binding protein-1 (IGFBP-1) expression in endothelial cells in vitro and in vivo. IGFBPs are key regulators of insulin-like growth factor (IGF) type 1 and 2 bioavailability at the cellular level. In addition, IGFBP-1 is implicated in cardiovascular health, in terms of blood pressure and glucose tolerance. Methods and Results: RTEF-1 upregulates IGFBP-1 expression in endothelial cells in vitro and in vivo through selectively binding and promoting transcription from the insulin response element (IRE) site on the IGFBP-1 promoter, demonstrated by ChIP assays. In addition to insulin inhibition of IGFBP-1 levels, insulin also dose-dependently inhibits RTEF-1 promoter activity (-2.4 ± 0.3-fold) and expression. In vivo data suggest that Tie2-Cre:RTEF-1 flox/flox transgenic mice, RTEF-1 EC-specific knockout mice, show a significant decrease decrease in IGFBP-1 mRNA levels compared with controls (0.21 ± 0.09 vs. 1.0, respectively), while VE-Cadherin/RTEF-1 overexpressing transgenic mice have increased IGFBP-1 mRNA levels (25.4 ± 0.02-fold). Increased IGFBP-1 levels relate physiologically in our RTEF-1 EC-specific knockout by showing decreased blood glucose tolerance as well as increased insulin resistance as calculated by HOMA-IR compared with littermate controls, (4.1 ± 0.5 vs. 1.1 ± 0.2, respectively). Furthermore, the RTEF-1 EC-specific knockout mice showed a significant increase in systolic blood pressure (10mmHg ± 6mmHg) compared with littermate controls. Conclusion: These results demonstrate that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels and potential cardiovascular function. These findings provide the basis for novel insights into transcriptional regulation of IGFBP-1 and contribute to understanding the role of vascular endothelial cells in metabolism.