Browsing by Author "Martinez, Ricardo"

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    Aurora A–Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy
    (AACR, 2019-12) Du, Jian; Yan, Lei; Torres, Raquel; Gong, Xueqian; Bian, Huimin; Marugán, Carlos; Boehnke, Karsten; Baquero, Carmen; Hui, Yu-Hua; Chapman, Sonya C.; Yang, Yanzhu; Zeng, Yi; Bogner, Sarah M.; Foreman, Robert T.; Capen, Andrew; Donoho, Gregory P.; Van Horn, Robert D.; Barnard, Darlene S.; Dempsey, Jack A.; Beckmann, Richard P.; Marshall, Mark S.; Chio, Li-Chun; Qian, Yuewei; Webster, Yue W.; Aggarwal, Amit; Chu, Shaoyou; Bhattachar, Shobha; Stancato, Louis F.; Dowless, Michele S.; Iversen, Phillip W.; Manro, Jason R.; Walgren, Jennie L.; Halstead, Bartley W.; Dieter, Matthew Z.; Martinez, Ricardo; Bhagwat, Shripad V.; Kreklau, Emiko L.; Lallena, Maria Jose; Ye, Xiang S.; Patel, Bharvin K. R.; Reinhard, Christoph; Plowman, Gregory D.; Barda, David A.; Henry, James R.; Buchanan, Sean G.; Campbell, Robert M.; Pediatrics, School of Medicine
    Although Aurora A, B, and C kinases share high sequence similarity, especially within the kinase domain, they function distinctly in cell-cycle progression. Aurora A depletion primarily leads to mitotic spindle formation defects and consequently prometaphase arrest, whereas Aurora B/C inactivation primarily induces polyploidy from cytokinesis failure. Aurora B/C inactivation phenotypes are also epistatic to those of Aurora A, such that the concomitant inactivation of Aurora A and B, or all Aurora isoforms by nonisoform–selective Aurora inhibitors, demonstrates the Aurora B/C-dominant cytokinesis failure and polyploidy phenotypes. Several Aurora inhibitors are in clinical trials for T/B-cell lymphoma, multiple myeloma, leukemia, lung, and breast cancers. Here, we describe an Aurora A–selective inhibitor, LY3295668, which potently inhibits Aurora autophosphorylation and its kinase activity in vitro and in vivo, persistently arrests cancer cells in mitosis, and induces more profound apoptosis than Aurora B or Aurora A/B dual inhibitors without Aurora B inhibition–associated cytokinesis failure and aneuploidy. LY3295668 inhibits the growth of a broad panel of cancer cell lines, including small-cell lung and breast cancer cells. It demonstrates significant efficacy in small-cell lung cancer xenograft and patient-derived tumor preclinical models as a single agent and in combination with standard-of-care agents. LY3295668, as a highly Aurora A–selective inhibitor, may represent a preferred approach to the current pan-Aurora inhibitors as a cancer therapeutic agent.
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    Endocannabinoids Regulate Cerebellar Granule Cell Differentiation
    (2017-09) Essex, Amanda; Black, Kylie; Baygani, Shawyon; Mier, Tristan; Martinez, Ricardo; Mackie, Ken; Kalinovsky, Anna
    The cerebellum plays a crucial role in learning and execution of complex automated behaviors, including fine motor skills, language, and emotional regulation. Cerebellar development continues throughout an extended postnatal period. The most numerous neurons in the cerebellum, as well as the entire brain, are the cerebellar granule cells (GCs), which are generated in a dedicated secondary proliferative zone, the external granule cell layer (EGL), during the first three postnatal weeks in mice, and over a year in humans. The robust expansion of granule cells during early development is responsible for the majority of cerebellar expansion. Morphological and molecular changes that drive GC proliferation and differentiation have been extensively characterized, starting from the developmental studies by Santiago Ramón y Cajal. GC progenitors (GCPs) proliferate in the outer EGL (oEGL). As they are pushed into the inner EGL (iEGL) by the newly generated GCPs, they exit the cell cycle and begin differentiation, first extending bipolar neurites, followed by tangential migration, and eventually radial migration to the inner granule cell layer (IGL), their target territory. Deregulation of GCPs expansion, proliferation to differentiation switch, or the rate of migration could contribute to abnormal cerebellar size and compartmentalization and disrupt cerebellar circuits’ wiring and function. Endocannabinoids (eCBs) have been identified as key players regulating neuron proliferation and migration in the fore- and mid-brain development, however their role in cerebellar development has not yet been explored in detail. Our preliminary results show robust expression of cannabinoid receptor 1 (CB1) in iEGL GCs, concomitant with expression diacylglycerol lipase α (DGLα) a major enzyme required for the synthesis of eCB 2-arachidonoylglycerol (2-AG), in PCs. Furthermore, our preliminary results show that cerebellar size is reduced in CB1 KOs. In this study we investigate the mechanisms through which eCB signaling may regulate GC proliferation and differentiation, focusing on the GCPs cycle length, rate of differentiation and migration.