Browsing by Author "Marshall, Mark S."

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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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    Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant
    (Wolters Kluwer, 2020-04-30) Tramontana, Timothy F.; Marshall, Mark S.; Helvie, Amy E.; Schmitt, Morgan R.; Ivanovich, Jennifer; Carter, Jacquelyn L.; Renbarger, Jamie L.; Ferguson, Michael J.; Pediatrics, School of Medicine
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    Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma
    (MDPI, 2020-08-26) Pandya, Pankita H.; Cheng, Lijun; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Tang, Shan; Sinn, Anthony L.; Trowbridge, Melissa A.; Coy, Kathryn L.; Bailey, Barbara J.; Young, Courtney N.; Ding, Jixin; Dobrota, Erika A.; Dyer, Savannah; Elmi, Adily; Thompson, Quinton; Barghi, Farinaz; Shultz, Jeremiah; Albright, Eric A.; Shannon, Harlan E.; Murray, Mary E.; Marshall, Mark S.; Ferguson, Michael J.; Bertrand, Todd E.; Wurtz, L. Daniel; Batra, Sandeep; Li, Lang; Renbarger, Jamie L.; Pollok, Karen E.; Pediatrics, School of Medicine
    Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.