tbuckley/cabot-search huggingface dataset:
MELK Inhibition in Diffuse Intrinsic Pontine Glioma
Authors: Michaël H. Meel, Mark C. de Gooijer, Miriam Guillén Navarro, Piotr Waranecki, Marjolein Breur, Levi C.M. Buil, Laurine E. Wedekind, Jos W.R. Twisk, Jan Koster, Rintaro Hashizume, Eric H. Raabe, Angel Montero Carcaboso, Marianna Bugiani, Olaf van Tellingen, Dannis G. van Vuurden, Gertjan J.L. Kaspers, Esther Hulleman
Journal: Clinical Cancer Research (2018)

Purpose: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG.Experimental Design: We evaluated the antitumor efficacy of the small-molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells. In addition, we determined the blood-brain barrier (BBB) penetration of OTSSP167 and evaluated its translational potential by treating mice bearing patient-derived DIPG xenografts.Results: This study shows that MELK is highly expressed in DIPG cells, both in patient samples and in relevant in vitro and in vivo models, and that treatment with OTSSP167 strongly decreases proliferation of patient-derived DIPG cultures. Inhibition of MELK in DIPG cells functions through reducing inhibitory phosphorylation of PPARγ, resulting in an increase in nuclear translocation and consequent transcriptional activity. Brain pharmacokinetic analyses show that OTSSP167 is a strong substrate for both MDR1 and BCRP, limiting its BBB penetration. Nonetheless, treatment of Mdr1a/b;Bcrp1 knockout mice carrying patient-derived DIPG xenografts with OTSSP167 decreased tumor growth, induced remissions, and resulted in improved survival.Conclusions: We show a strong preclinical effect of the kinase inhibitor OTSSP167 in the treatment of DIPG and identify the MELK-PPARγ signaling axis as a putative therapeutic target in this disease. Clin Cancer Res; 24(22); 5645-57. ©2018 AACR.
Abstract 14660: Xeno-Free Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Cell Sheet Transplantation Promise the Safety and Effectiveness in the Treatment for Heart Failure
Authors: Motoko Shiozaki, Shigeru Miyagawa, Satsuki Fukushima, Itsunari Minami, Shin Yajima, Keitaro Domae, Atsuhiro Saito, Takashi Asada, Norio Nakatsuji, Yoshiki Sawa
Journal: Circulation (2016)

Background: Human Induced pluripotent stem cells (hiPSC) have a potential to propose new era for the treatment for cardiovascular disease, while the safety in hiPSC have great concern for clinical ...
Abstract LB-316: Dynamic live cell imaging of tumor migration and invasion
Authors: Ross Booth, Cindy Chen, Victor Yeh, Deepika Verma, Jun Park
Journal: Cancer Research (2018)

Abstract Migration and invasion activities of metastasizing cancer cells are of immense significance to the field of cancer research, often leading to fatal spread of the disease. While much understanding has been gained regarding the underlying molecular and cellular mechanisms governing these processes, the direct observations of associate morphological and biochemical features are limited by the current methodologies which largely rely on endpoint micro-porous membrane-based assays or various live cell imaging assays performed on 2D/3D substrates- neither of which enable dynamic control over the tumor microenvironment. Microfluidic technologies enable high-resolution time-lapse imaging while providing exceptional experimental control to maintain a physiologically relevant microenvironment. Here we demonstrate the value of the CellASIC ONIX2 “dynamic live cell imaging system”, where microenvironmental parameters such as flowrates, the perfusion of nutrients and reagents, and temperature and gas compositions can be precisely controlled on demand by software during the entire duration of a given experiment. We now show the value of this system for imaging of metastatic processes with a novel microfluidic design comprising two parallel chambers separated by a micro-porous wall. One chamber contains MDA-MB-231 breast cancer cells embedded in 3D hydrogel culture or simply grown in 2D fashion, and the other chamber contains HUVEC endothelial cells in a monolayer. The device enables exceptionally clear real-time imaging of the migration of MDA-MB-231 cells, as well as invasion of these cells through and out of the gel into the “vascular” channel, enabling the monitoring of the adhesion and interaction of these cells with the HUVEC cells once the tumor cells had left the gel. Unlike the state-of-the-art endpoint or static culture imaging assays, the microfluidics system described herein enables the investigation of wider microenvironmental parameters and their interplay with cellular processes in unprecedented precision and permutations, and is also suitable for the studies of wider biological applications outside of cancer biology. Citation Format: Ross Booth, Cindy Chen, Victor Yeh, Deepika Verma, Jun Park. Dynamic live cell imaging of tumor migration and invasion [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 LB-316.
Abstract 5269: Body mass index may not have causal association with thyroid cancer risk: A Mendelian randomization study
Authors: Jeongseon Kim, Soo Ji Lee, Quy N. Nguyen, Jeonghee Lee, Eun Kyung Lee, Yul Hwangbo, Joohon Sung
Journal: Cancer Research (2018)

Abstract Background: Thyroid cancer (TC) is one of the endocrine tumors of which incidence rates have shown an upward trend worldwide. Obesity, another endemic health issue, has been recently reported in the association with increased TC risk. We attempted to examine if there is a causal association between body mass index (BMI) and TC using a Mendelian randomization approach. Methods: Total 17,935 healthy individuals from the Korean Genome Epidemiology Study and 1,214 TC cases from National Cancer Center, Korea, and Seoul National University Hospital were selected with age, sex, BMI, and genetic information. Based on the thirteen previously reported single nucleotide polymorphisms associated with BMI, we constructed a genetic risk score (GRS) as a genetic instrumental variable (IV) representing BMI independent of possible confounding. IV analysis was performed using the ratio (or, Wald) method to test causal association. Results: The odds of TC were 2.6 times higher in females than males. The cases were younger than the controls. The F-statistic from the regression of BMI on BMI GRS (IV) was 157.2 (usually, F larger than 10 indicates a strong and valid IV), and the IV explained 1.10% of the phenotypic variance for BMI. From IV analysis, genetically instrumented BMI was not associated with TC risk (causal odds ratio per 1kg/m2 increase in BMI 0.98 [0.79 - 1.20 95% confidence interval]). Conclusion: Our analysis suggests that positive association between obesity and TC risk repeatedly reported from several meta-analyses may be null. Further investigation is needed as the incidence rates differ in different ethnicity. Citation Format: Jeongseon Kim, Soo Ji Lee, Quy N. Nguyen, Jeonghee Lee, Eun Kyung Lee, Yul Hwangbo, Joohon Sung. Body mass index may not have causal association with thyroid cancer risk: A Mendelian randomization study [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 5269.
Abstract PR06: Functional genomics of CIC-DUX4 fusions in zebrafish recapitulates the spectrum of human CIC-rearranged cancers
Authors: Sarah Watson, Genevieve C. Kendall, Whitney A. Murchison, Olivier Delattre, Franck Tirode, James F. Amatruda
Journal: Clinical Cancer Research (2018)

Abstract CIC-DUX4 sarcomas are aggressive soft-tissue malignancies characterized by frequent metastases and poor survival. Histologically, CIC-DUX4 sarcomas resemble Ewing sarcomas but do not express EWS-FLI1 or other FET-ETS fusion genes typical of Ewing sarcoma. The tumors arise from chromosomal translocations that fuse the transcriptional repressor CIC with the homeodomain-containing protein DUX4, creating an aberrant transcription factor. However, the critical targets of CIC-DUX4 have been only partly described, the cell of origin and mechanism of transformation are unknown, and animal models of the disease are lacking. Owing to this poor biologic understanding, patients with CIC-DUX4 sarcomas are treated with the same regimens used for classical Ewing sarcoma, despite generally poor outcomes. To comprehensively address these problems, we are taking a cross-species comparative oncology approach via analysis of human CIC-DUX4 sarcomas and genetically engineered in vivo zebrafish models. Human CIC-DUX4 transgenes exerted strong effects on zebrafish embryonic development. Beginning at 5 weeks of age, almost 40% of injected animals developed invasive, rapidly growing tumors. Strikingly, two classes of tumors emerged: small round blue cell sarcomas developed in soft tissues including the trunk musculature and the ventral abdomen, and CNS-PNETs arose in the head. This recapitulates the spectrum of human tumors with CIC gene rearrangements. To further understand the molecular mechanisms of tumorigenesis, we performed RNASeq on zebrafish CIC-DUX4 sarcoma and zebrafish EWS-FLI1 sarcomas alongside human tumors and nonmalignant tissues. This analysis revealed pathways conserved between fish and human, including RAS-MAPK signaling, and highlighted the central importance of ETV4 in this disease. Further studies established ETV4 as a valuable new marker of the human disease. Taken together these findings demonstrate that CIC-DUX4 expression is sufficient to promote the development of tumors, give insight into the cellular origins of CIC-DUX4 tumors, and provide a valuable new animal model for translational research. Citation Format: Sarah Watson, Genevieve C. Kendall, Whitney A. Murchison, Olivier Delattre, Franck Tirode, James F. Amatruda. Functional genomics of CIC-DUX4 fusions in zebrafish recapitulates the spectrum of human CIC-rearranged cancers [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR06.
Use of Palliative Care Earlier in the Disease Course in the Context of the Opioid Epidemic
Authors: Yael Schenker, Jessica S. Merlin, Timothy E. Quill
Journal: JAMA (2018)

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Abstract 4903: AXL inhibition overcomes erlotinib resistance in AXL-activated non-small cell lung cancer cells
Authors: Feng Wang
Journal: Cancer Research (2018)

Abstract Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are present in 10-35% patients with NSCLC. In patients with EGFR-mutated NSCLC, EGFR tyrosine kinase inhibitors, including erlotinib, have demonstrated excellent initial responses. However, despite improved outcomes observed in patients treated with EGFR TKIs, most patients eventually develop drug resistance. We and others recently demonstrated that the activation of oncogene AXL is necessary to confers erlotinib resistance in both cell and mouse models as well as in human tumor tissues. While genetic aberrations affecting AXL appear rare, we recently identified two patients with EGFR-mutated lung cancer who simultaneously harbor AXL A273V or AXL V289M mutation. Both patients were resistant to erlotinib treatment (one case of primary and one case of acquired resistance). In this study, we first evaluated whether these AXL mutations conferred resistance to erlotinib treatment. Using HCC827 and PC-9 NSCLC cell lines stably expressing the AXL A273V or V289M mutation, we confirmed that AXL A273V significantly increased resistance to erlotinib treatment. Subsequently we also conducted a preclinical study to test if a new AXL inhibitor MGCD265 could overcome such erlotinib resistance in NSCLC cells. Using an in vitro MTS assay, we first validated that administration of MGCD265 in combination with erlotinib significantly inhibited the viability of erlotinib-resistant HCC827-ER cells, compared to erlotinib- or MGCD265-alone treatment. Through conducting an array of cell functional studies, we found that combination of MGCD265 and erlotinib significantly decreased cell cycle progression in S phase, enhanced apoptosis, and repressed cell migration relative to single-agent erlotinib or MGCD265 treatment in HCC827-ER cells. We further performed RNA-sequencing to evaluate the gene expression profile and the cellular pathways altered in cells treated with erlotinib alone, MGCD265 alone or a combination of erlotinib and MGCD265. RNA-sequencing analysis identified that several groups of genes involved in cell survival inhibition or apoptosis promotion were upregulated, whereas genes involved in cell cycle process, DNA replication or cancer metabolism were downregulated in cells treated with the combination of erlotinib and MGCD265. Taken together, our results indicated that AXL mutations may confer resistance to EGFR TKI treatment, and effective blockade of the AXL pathway may represent a novel strategy to overcome erlotinib resistance for the treatment of NSCLC patients. Citation Format: Feng Wang. AXL inhibition overcomes erlotinib resistance in AXL-activated non-small cell lung cancer cells [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 4903.
New Cell Cycle Inhibitors Target Aneuploidy in Cancer Therapy
Authors: Masanori Kawakami, Xi Liu, Ethan Dmitrovsky
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Aneuploidy is a hallmark of cancer. Defects in chromosome segregation result in aneuploidy. Multiple pathways are engaged in this process, including errors in kinetochore-microtubule attachments, supernumerary centrosomes, spindle assembly checkpoint (SAC) defects, and chromosome cohesion defects. Although aneuploidy provides an adaptation and proliferative advantage in affected cells, excessive aneuploidy beyond a critical level can be lethal to cancer cells. Given this, enhanced chromosome missegregation is hypothesized to limit survival of aneuploid cancer cells, especially when compared to diploid cells. Based on this concept, proteins and pathways engaged in chromosome segregation are being exploited as candidate therapeutic targets for aneuploid cancers. Agents that induce chromosome missegregation and aneuploidy now exist, including SAC inhibitors, those that alter centrosome fidelity and others that are under active study in preclinical and clinical contexts. This review explores the therapeutic potentials of such new agents, including the benefits of combining them with other antineoplastic agents.
Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis
Authors: Johannes Waage, Marie Standl, John A. Curtin, Leon E. Jessen, Jonathan Thorsen, Chao Tian, Nathan Schoettler, Carlos Flores, Abdel Abdellaoui, Tarunveer S. Ahluwalia, Alexessander C. Alves, Andre F. S. Amaral, Josep M. Antó, Andreas Arnold, Amalia Barreto-Luis, Hansjörg Baurecht, Catharina E. M. van Beijsterveldt, Eugene R. Bleecker, Sílvia Bonàs-Guarch, Dorret I. Boomsma, Susanne Brix, Supinda Bunyavanich, Esteban G. Burchard, Zhanghua Chen, Ivan Curjuric, Adnan Custovic, Herman T. den Dekker, Shyamali C. Dharmage, Julia Dmitrieva, Liesbeth Duijts, Markus J. Ege, W. James Gauderman, Michel Georges, Christian Gieger, Frank Gilliland, Raquel Granell, Hongsheng Gui, Torben Hansen, Joachim Heinrich, John Henderson, Natalia Hernandez-Pacheco, Patrick Holt, Medea Imboden, Vincent W. V. Jaddoe, Marjo-Riitta Jarvelin, Deborah L. Jarvis, Kamilla K. Jensen, Ingileif Jónsdóttir, Michael Kabesch, Jaakko Kaprio, Ashish Kumar, Young-Ae Lee, Albert M. Levin, Xingnan Li, Fabian Lorenzo-Diaz, Erik Melén, Josep M. Mercader, Deborah A. Meyers, Rachel Myers, Dan L. Nicolae, Ellen A. Nohr, Teemu Palviainen, Lavinia Paternoster, Craig E. Pennell, Göran Pershagen, Maria Pino-Yanes, Nicole M. Probst-Hensch, Franz Rüschendorf, Angela Simpson, Kari Stefansson, Jordi Sunyer, Gardar Sveinbjornsson, Elisabeth Thiering, Philip J. Thompson, Maties Torrent, David Torrents, Joyce Y. Tung, Carol A. Wang, Stephan Weidinger, Scott Weiss, Gonneke Willemsen, L. Keoki Williams, Carole Ober, David A. Hinds, Manuel A. Ferreira, Hans Bisgaard, David P. Strachan, Klaus Bønnelykke
Journal: Nature Genetics (2018)
Abstract 3604: Centrosome amplification in epcam-captured circulating tumor cells from metastatic cancer patients
Authors: Ashok Singh, Ryan A. Denu, Jamie M. Sperger, Beth A. Weaver, Mark E. Burkard, Joshua M. Lang
Journal: Cancer Research (2018)

Abstract Background: Genomic instability and evolution of cancers is linked to chemotherapy sensitivity and resistance in patients with metastatic cancer. Taxane-based chemotherapies operate by promoting chromosomal instability (CIN) by increasing multipolar mitoses. Breast tumors with CIN are more sensitive to paclitaxel compared to tumors without CIN. There is a critical need for new biomarkers based on biological evaluation of mechanisms of response and resistance in metastatic cancer. Although CIN is difficult to detect directly, centrosome amplification (CA) is a common mechanism of CIN. In this study, we develop an assay to detect CA in circulating tumor cells (CTCs) as a minimally invasive assay to evaluate sensitivity to taxane-based chemotherapies. Methods: Blood samples from patients with metastatic breast and prostate cancer were collected and processed for nucleated cells using a Ficoll gradient and magnetic depletion of CD45-positive cells. EpCAM-positive CTCs were captured using an exclusion-based sample preparation technology known as the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. CTCs were defined as cells positive for Hoechst, cytokeratin and negative for multiple immune and endothelial cell markers (CD45/CD11b/CD14 and CD34). EpCAM-captured CTCs were also stained with pericentrin and centrin to identify CA and evaluated for pericentrin (whole centrosome marker) and centrin (centriole marker) protein-staining intensity, number and size. Results: CA was detected in a subset of CTCs from patients with metastatic breast and prostate cancer patients. As a control, centrosomes were also analyzed in matched peripheral blood mononuclear cells from the same patients. CA was heterogeneous with 100% of patients demonstrating some degree of CA (&amp;gt;4 centrioles), ranging from 15-48% of CTCs. Conclusion: In conclusion, we report the presence of CA in EpCAM-captured CTCs from metastatic cancer patients. Evaluation of CA in CTCs using pericentrin and centrin staining may serve as a predictive biomarker of taxane based chemotherapy response and resistance. We are recruiting taxane-naïve metastatic cancer patients to test the hypothesis that CA and/or CIN predict taxane sensitivity. Citation Format: Ashok Singh, Ryan A. Denu, Jamie M. Sperger, Beth A. Weaver, Mark E. Burkard, Joshua M. Lang. Centrosome amplification in epcam-captured circulating tumor cells from metastatic cancer patients [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 3604.
Abstract 6: Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma
Authors: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi
Journal: Cancer Research (2018)

Abstract Tumor angiogenesis occurs in the setting of a defective vasculature, which is associated with increased vascular permeability and enhanced tumor permeability. Bevacizumab is used to treat malignant glioma and was found to reduce microvascular density and prune abnormal tumor microvessels. Using electron microscopic observation of two autopsy cases, we investigated the effects of blood vessel normalization in glioblastomas treated with bevacizumab. Notch-1 and SMA immunostaining were used to compare initial surgical specimens with postmortem specimens obtained after bevacizumab treatment. Postmortem samples showed marked proliferation of SMA-positive cells (pericytes) in tumor vessels and marked proliferation of Notch-1–positive cells around vessels. Electron microscopic images confirmed the presence of pericytes surrounding the vascular endothelium. These findings suggest that bevacizumab treatment promotes vascular normalization by recruiting mature pericytes. Next, we investigated the effects of bevacizumab on VEGF inhibition in glioma stem cells. Bevacizumab treatment attenuated activation of VEGFR2 and increased Notch signaling expression. VEGF inhibition by bevacizumab treatment attenuated proliferation and self-renewal of glioma stem cells and induced endothelial and pericyte differentiation. In tumor angiogenesis, vascular endothelial growth factor induces sprouting angiogenesis and recruitment of vascular endothelial cells such as tip cells, stalk cells, and phalanx cells. Fully mature phalanx cells are in close contact with pericytes. Our results suggest that bevacizumab treatment induces glioma stem cells to differentiate to endothelium and pericytes. These mechanisms might be important in normalizing tumor vasculature after bevacizumab treatment and could be useful in improving the effectiveness of current glioma therapy. Citation Format: Norihiko Saito, Kazuya Aoki, Nozomi Hirai, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai, Satoshi Iwabuchi. Role of Notch signaling in bevacizumab-induced vascular normalization in glioblastoma [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 6.