Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Total Page:16

File Type:pdf, Size:1020Kb

Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells Published OnlineFirst September 14, 2016; DOI: 10.1158/1535-7163.MCT-16-0172 Small Molecule Therapeutics Molecular Cancer Therapeutics Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells Gema Santamaría Nunez~ 1, Carlos Mario Genes Robles2, Christophe Giraudon2, Juan Fernando Martínez-Leal1, Emmanuel Compe2,Fred eric Coin2, Pablo Aviles1, Carlos María Galmarini1, and Jean-Marc Egly2 Abstract We have defined the mechanism of action of lurbinectedin, a ubiquitin/proteasome machinery; and (iii) the generation of marine-derived drug exhibiting a potent antitumor activity DNA breaks and subsequent apoptosis. The finding that inhi- across several cancer cell lines and tumor xenografts. This drug, bition of Pol II phosphorylation prevents its degradation and currently undergoing clinical evaluation in ovarian, breast, and the formation of DNA breaks after drug treatment underscores smallcelllungcancerpatients,inhibits the transcription pro- the connection between transcription elongation and DNA cess through (i) its binding to CG-rich sequences, mainly repair. Our results not only help to better understand the high located around promoters of protein-coding genes; (ii) the specificity of this drug in cancer therapy but also improve our irreversible stalling of elongating RNA polymerase II (Pol II) understanding of an important transcription regulation mech- on the DNA template and its specific degradation by the anism. Mol Cancer Ther; 15(10); 1–14. Ó2016 AACR. Introduction derivatives, anthracyclines, etc.; ref. 10). Currently, several laboratories are developing inhibitors of cyclin-dependent Cancer cells aberrantly deregulate specific gene expression kinases (CDK) that have a critical role in regulating transcrip- programs with critical functions in cell differentiation, prolifer- tion initiation, pause release, and elongation (e.g., CDK7, ation, and survival (1). Differently from noncancer cells, those CDK8, or CDK9), the three main steps involved in RNA altered gene programs in cancer cells have a striking dependence synthesis (11, 12). Other approaches are inhibition of DNA on continuous active transcription. For example, small cell lung repair mechanisms (e.g., irinotecan, topotecan, olaparib; cancer (SCLC) cells are addicted to lineage-specific and proto- ref. 13) or chromatin remodeling (HDAC inhibitors or oncogenic transcription factors that support their growth (2–7). demethylating agents; refs. 14, 15). Although these compounds Similarly, triple-negative breast cancer (TNBC) is highly depen- have already entered clinical trials, the mechanisms by which dent on uninterrupted transcription of a specific key set of genes they disturb transcription as well as those driving to cancer cell (8, 9). Pharmacologic modulation of transcription of protein- death are far from being understood. coding genes may thus provide an approach to identify and treat Here, we describe the inhibition of transcription by lurbi- tumor types that are dependent on deregulated transcription for nectedin (PM01183; Fig. 1A), an anticancer agent that is being maintenance of their oncogenic state. evaluated in late-stage (phases II and III) clinical trials. Lurbi- Targeting DNA in tumor cells happened to be the most nectedin is structurally related to trabectedin, containing the explored therapeutic strategy to block DNA processing enzymes same pentacyclic skeleton of the fused tetrahydroisoquinoline such as those involved in transcription (e.g., cisplatin and rings, but differing by the presence of a tetrahydro-B-carboline replacing the additional tetrahydroisoquinoline of trabectedin. The pentacyclic skeleton is mostly responsible for DNA minor 1Cell Biology and Pharmacogenomics Department, Pharmamar SA, groove recognition and binding. Lurbinectedin reacts with the 2 Colmenar Viejo, Madrid, Spain. Department of Functional Genomics exocyclic amino group of guanines in the minor groove of DNA and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France. forming a covalent bond. The resulting adduct is additionally stabilized through the establishment of van der Waals interac- Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). tions and one or more hydrogen bonds with neighboring nucleotides in the opposite strand of the DNA double helix G. Santamaría Nunez~ and C.M. Genes Robles are first coauthors. (16). The additional tetrahydro b-carboline moiety protrudes Corresponding Author: C.M. Galmarini, Pharmamar SA, Avda de los Reyes 1, from the DNA minor groove and could be interacting directly Colmenar Viejo 28770, Madrid, Spain. Phone: 34 918466158; Fax: 34 918466001; with specific factors involved in DNA repair and transcription E-mail: [email protected] pathways. Indeed, it is possible that this part of the molecule doi: 10.1158/1535-7163.MCT-16-0172 interacts directly with TC-NER factors and could interfere with Ó2016 American Association for Cancer Research. the repair mechanism. In this sense, lurbinectedin is able to www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 14, 2016; DOI: 10.1158/1535-7163.MCT-16-0172 Santamaría Nunez~ et al. attenuate the repair of specific nucleotide excision repair (NER) in the article have been authenticated in the laboratory in the last 6 substrates (17, 18). In addition to its activity in tumor cells, it months. was recently shown that lurbinectedin affects the inflammatory microenvironment, with a selective apoptotic-inducing effect Cell proliferation on mononuclear phagocytes and a specific inhibition of pro- Cell proliferation was studied by [3-(4,5-dimethythiazol-2-yl)- duction of inflammatory cytokines (19, 20). In this work, we 2,5-diphenyl] tetrazolium bromide (MTT) assays that were per- show that, following its specific target on CG-rich sequences formed following the manufacturer's instructions (MTT Cell located at promoters of protein-coding genes, lurbinectedin Proliferation Kit I; Roche Diagnostics). Briefly, cells were seeded induces the specific degradation of elongating (phosphorylat- in 96-well trays. Serial dilutions of lurbinectedin, PM030779, or ed) RNA polymerase II (Pol II) by the ubiquitin-proteasome PM120306 were added to the medium. Exposure to the drugs was fi machinery. This process occurs speci cally on activated genes maintained during 72 hours. Determination of IC50 values was and is associated with the formation of DNA breaks that drive performed by iterative nonlinear curve fitting using the Prism 5.0 tumor cells to apoptosis. Inhibition of Pol II phosphorylation statistical software (GraphPad). The data presented are the aver- prevents its degradation and the formation of DNA breaks. age of three independent experiments performed in triplicate. These investigations not only show how lurbinectedin causes a cascade of events on the transcription process that can explain DNA electrophoretic mobility shift assay its antiproliferative activity on tumor cells, but also improve The binding assay was performed with a 250 pb PCR product our understanding of the fate of Pol II when it encounters a from the human adiponectin gene. After incubation with lesion on the DNA. appropriate concentrations of the compounds at 25Cduring 1 hour, the DNA was subjected to electrophoresis in a 2% (w/v) Materials and Methods agarose/TAE gel, stained with ethidium bromide (Sigma) and photographed. Reagents Lurbinectedin was produced by PharmaMar through a semi- DNase I footprinting assays synthetic method. Z-Leu-Leu-Leu-al (MG-132), 5,6-dichloro- Radiolabeled AS/CGG and OS/CCG were bound to magnetic fl benzimidazole-1-a-D-ribofuranoside (DRB), and avopiridol beads (Dynabeads) and incubated for 30 minutes at room tem- were purchased from Sigma. The following antibodies were perature with the indicated drug concentrations (21). After exten- used for Western blotting: POLR2A (RPB1, Pol II) (clones N-20 sive washings, DNase I digestion was performed for 45 seconds at and H-224), POLR1A (RNA Pol I), POLRMT (B-1), CCNH room temperature. Purified nucleic acids were resolved on an 8% (Cyclin H) (B-1), CDK9 (C-20), ERCC2 (p80-TFIIH) denaturing Urea-polyacrylamide gel. (H-150), TP53 (FL-393) from Santa Cruz Biotechnology; TBP, GTF2H1 (TFIIH), POLR2D (RPB4, RNA Pol II), POLR2B (RPB2, In vitro transcription assays RNA Pol II), CRCP (RNA Pol III) from Abcam; CDK7 from Cell Run-off transcription assays were performed using recombi- – Signaling Technology; and anti phospho-Ser2Pol II (clone H5) nant TFIIB, TFIIE, TFIIF, TBP, TFIIH, and RNA pol II, as previously – and anti phospho-Ser5 Pol II (clone H14) from Covance. The described (22). following antibodies were used for chromatin immunoprecip- itation (ChIP) and immunoprecipitation (IP) experiments: RNA synthesis quantification in tumor cells Antibodies against phospho-Ser2 Pol II (clone 3E8) and phos- A549 (3.5 Â 104 cells/well), A673 (2.6 Â 105), HCT116 (1.8 pho-Ser2 Pol II (clone 3E10) were from Active Motif. Poly- Â 105), HeLa (1.5 Â 105), and MDA-MB-231 (2 Â 105)were clonal antibodies against POLR2A (H-224), CDK7 (C-19), seeded in 24-well plates and incubated with lurbinectedin or CDK9 (H-169), UBB (Ubiquitin clone FL-76 or clone A-5), vehicle (DMSO) for 30, 45, 60, and 90 minutes and pulsed with Biotin(33), and ERCC4 (XPF, clone H-300) were from Santa 5 mCi [3H] uridine (Perkin Elmer) for
Recommended publications
  • Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights
    cancers Article Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights 1, 1, 1 Adrián Povo-Retana y, Marina Mojena y, Adrian B. Stremtan , Victoria B. Fernández-García 1, Ana Gómez-Sáez 1, Cristina Nuevo-Tapioles 2,3 , José M. Molina-Guijarro 4 , José Avendaño-Ortiz 5, José M. Cuezva 2,3 , Eduardo López-Collazo 5, Juan F. Martínez-Leal 4 and Lisardo Boscá 1,5,6,* 1 Instituto de Investigaciones Biomédicas Alberto Sols (Centro Mixto CSIC-UAM), 28029 Madrid, Spain; [email protected] (A.P.-R.); [email protected] (M.M.); [email protected] (A.B.S.); [email protected] (V.B.F.-G.); [email protected] (A.G.-S.) 2 Centro de Biología Molecular (Centro Mixto CSIC-UAM), Nicolás Cabrera S/N, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain; [email protected] (C.N.-T.); [email protected] (J.M.C.) 3 Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain 4 Pharma Mar SA, 28770 Colmenar Viejo, Spain; [email protected] (J.M.M.-G.); [email protected] (J.F.M.-L.) 5 Instituto de Investigación Sanitaria La Paz (IdiPaz), Hospital Universitario La Paz, 28046 Madrid, Spain; [email protected] (J.A.-O.); [email protected] (E.L.-C.) 6 Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-9149-72747 These authors have equal contribution. y Received: 28 August 2020; Accepted: 16 October 2020; Published: 20 October 2020 Simple Summary: Trabectedin and lurbinectedin are two potent onco-therapeutic drugs for the treatment of advanced soft tissue sarcomas.
    [Show full text]
  • A Phase I Dose-Finding, Pharmacokinetics and Genotyping
    www.nature.com/scientificreports OPEN A phase I dose‑fnding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors Andres Poveda1*, Ana Oaknin2, Ignacio Romero3, Angel Guerrero‑Zotano3, Lorena Fariñas‑Madrid2, Victor Rodriguez‑Freixinos4, Pedro Mallol5, Raquel Lopez‑Reig6,7 & Jose Antonio Lopez‑Guerrero6,7,8 The poly (ADP‑Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double‑strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efcacy. A 3 + 3 dose‑escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose‑limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efcacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defned as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%.
    [Show full text]
  • The Essentials of Marine Biotechnology. Frontiers in Marine Science [Online], 8, Article 629629
    ROTTER, A., BARBIER, M., BERTONI, F. et al. 2021. The essentials of marine biotechnology. Frontiers in marine science [online], 8, article 629629. Available from: https://doi.org/10.3389/fmars.2021.629629 The essentials of marine biotechnology. ROTTER, A., BARBIER, M., BERTONI, F. et al. 2021 Copyright © 2021 Rotter, Barbier, Bertoni, Bones, Cancela, Carlsson, Carvalho, Cegłowska, Chirivella-Martorell, Conk Dalay, Cueto, Dailianis, Deniz, Díaz-Marrero, Drakulovic, Dubnika, Edwards, Einarsson, Erdoˇgan, Eroldoˇgan, Ezra, Fazi, FitzGerald, Gargan, Gaudêncio, Gligora Udoviˇc, Ivoševi´c DeNardis, Jónsdóttir, Kataržyt˙e, Klun, Kotta, Ktari, Ljubeši´c, Luki´c Bilela, Mandalakis, Massa-Gallucci, Matijošyt˙e, Mazur-Marzec, Mehiri, Nielsen, Novoveská, Overling˙e, Perale, Ramasamy, Rebours, Reinsch, Reyes, Rinkevich, Robbens, Röttinger, Rudovica, Sabotiˇc, Safarik, Talve, Tasdemir, Theodotou Schneider, Thomas, Toru´nska-Sitarz, Varese and Vasquez.. This article was first published in Frontiers in Marine Science on 16.03.2021. This document was downloaded from https://openair.rgu.ac.uk fmars-08-629629 March 10, 2021 Time: 14:8 # 1 REVIEW published: 16 March 2021 doi: 10.3389/fmars.2021.629629 The Essentials of Marine Biotechnology Ana Rotter1*, Michéle Barbier2, Francesco Bertoni3,4, Atle M. Bones5, M. Leonor Cancela6,7, Jens Carlsson8, Maria F. Carvalho9, Marta Cegłowska10, Jerónimo Chirivella-Martorell11, Meltem Conk Dalay12, Mercedes Cueto13, 14 15 16 17 Edited by: Thanos Dailianis , Irem Deniz , Ana R. Díaz-Marrero , Dragana Drakulovic , 18 19
    [Show full text]
  • Marine Vibrionaceae As a Reservoir for Bioprospecting and Ecology Studies
    Downloaded from orbit.dtu.dk on: Oct 09, 2021 Marine Vibrionaceae as a reservoir for bioprospecting and ecology studies Giubergia, Sonia Publication date: 2016 Document Version Publisher's PDF, also known as Version of record Link back to DTU Orbit Citation (APA): Giubergia, S. (2016). Marine Vibrionaceae as a reservoir for bioprospecting and ecology studies. Novo Nordisk Foundation Center for Biosustainability. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Marine Vibrionaceae as a reservoir for bioprospecting and ecology studies. Sonia Giubergia PhD thesis April 2016 Copyright: Sonia Giubergia 2016 Novo Nordisk Foundation Center for Biosustainability Technical University of Denmark Kogle Allè 6 – 2970 Horshølm Denmark Cover: the Mediterranean Sea at Hyères, France (Sonia Giubergia) ii PREFACE The present PhD study has been conducted at the Department of Systems Biology and at the Novo Nordisk Foundation Centre for Biosustainability at the Technical University of Denmark from May 2013 to April 2016 under the supervision of Professor Lone Gram.
    [Show full text]
  • Cancer Control Potential of Marine Natural Product Scaffolds Through
    Drug Discovery Today Volume 21, Number 11 November 2016 REVIEWS Teaser Greater emphasis on marine natural products research could selectively cure multiple human ailments with fewer hazardous effects. Cancer control potential of marine natural product scaffolds through FOUNDATION REVIEW inhibition of tumor cell migration and invasion Reviews 1 2 Mudit Mudit BS Mudit Mudit and Khalid A. El Sayed Pharmacy, PhD, is an assistant professor in the 1 Department of Pharmaceutical, Social and Administrative Sciences, D’Youville College School of Pharmacy, Department of Pharmaceutical, Social and Buffalo, NY 14201, USA 2 Administrative Sciences at Department of Basic Pharmaceutical Sciences, School of Pharmacy, The University of Louisiana at Monroe, the D’Youville College Monroe, LA 71201, USA School of Pharmacy. He is an active member of several professional organizations, including the The marine environment is a reliable source for the discovery of novel American Association of Colleges of Pharmacy, American Association of Pharmaceutical Scientists treatment options for numerous diseases. Past research efforts toward the (AAPS), American Chemical Society, and Rho Chi discovery of marine-derived anticancer agents have resulted in several Pharmacy Honor Society. He has given numerous research presentations both at regional and national commercially available marine-based drugs. The pharmaceutical value of meetings, and has been recognized by the AAPS for excellence in graduate education in the fields of Drug anticancer drugs from marine natural products (MNPs) ranges from Design and Discovery. He has also been a reviewer for US$563 billion to US$5.69 trillion. In this review, we highlight several many scientific manuscripts, research and educational grants, and annual professional meeting abstracts and marine-derived entities with the potential for cancer control and posters.
    [Show full text]
  • Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells
    Published OnlineFirst September 14, 2016; DOI: 10.1158/1535-7163.MCT-16-0172 Small Molecule Therapeutics Molecular Cancer Therapeutics Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells Gema Santamaría Nunez~ 1, Carlos Mario Genes Robles2, Christophe Giraudon2, Juan Fernando Martínez-Leal1, Emmanuel Compe2,Fred eric Coin2, Pablo Aviles1, Carlos María Galmarini1, and Jean-Marc Egly2 Abstract We have defined the mechanism of action of lurbinectedin, a ubiquitin/proteasome machinery; and (iii) the generation of marine-derived drug exhibiting a potent antitumor activity DNA breaks and subsequent apoptosis. The finding that inhi- across several cancer cell lines and tumor xenografts. This drug, bition of Pol II phosphorylation prevents its degradation and currently undergoing clinical evaluation in ovarian, breast, and the formation of DNA breaks after drug treatment underscores smallcelllungcancerpatients,inhibits the transcription pro- the connection between transcription elongation and DNA cess through (i) its binding to CG-rich sequences, mainly repair. Our results not only help to better understand the high located around promoters of protein-coding genes; (ii) the specificity of this drug in cancer therapy but also improve our irreversible stalling of elongating RNA polymerase II (Pol II) understanding of an important transcription regulation mech- on the DNA template and its specific degradation by the anism. Mol Cancer Ther; 15(10); 1–14. Ó2016 AACR. Introduction derivatives, anthracyclines, etc.; ref. 10). Currently, several laboratories are developing inhibitors of cyclin-dependent Cancer cells aberrantly deregulate specific gene expression kinases (CDK) that have a critical role in regulating transcrip- programs with critical functions in cell differentiation, prolifer- tion initiation, pause release, and elongation (e.g., CDK7, ation, and survival (1).
    [Show full text]
  • The Antitumor Drugs Trabectedin and Lurbinectedin Induce
    1 The antitumor drugs trabectedin and lurbinectedin induce 2 transcription-dependent replication stress and genome 3 instability 4 5 Emanuela Tumini 1, Emilia Herrera-Moyano 1, Marta San Martín-Alonso 1, 6 Sonia Barroso 1, Carlos M. Galmarini 2 and Andrés Aguilera 1 * 7 8 1 Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, 9 CSIC-Universidad Pablo de Olavide-Universidad de Sevilla, Av. Américo 10 Vespucio 24, 41092 SEVILLE, Spain; 2 PharmaMar, Av. de los Reyes 1, 11 28770 Colmenar Viejo, Spain 12 13 *Corresponding author: Andrés Aguilera, Centro Andaluz de Biología 14 Molecular y Medicina Regenerativa-CABIMER; Av. Américo Vespucio 24, 15 41092 SEVILLE, Spain. Phone: +34 954468372. E-mail: [email protected] 16 17 Running title: ET743 and PM01183 and RNA-dependent DNA damage 18 19 Keywords 20 Trabectedin, lurbinectedin, R-loops, genome instability, cancer 21 22 Conflict of interests statement 23 Dr C.M. Galmarini is an employee and shareholder of PharmaMar. The 24 remaining authors declare no conflict of interest. 25 1 26 ABSTRACT 27 28 R-loops are a major source of replication stress, DNA damage and genome 29 instability, which are major hallmarks of cancer cells. Accordingly, growing 30 evidence suggests that R-loops may also be related to cancer. Here we 31 show that R-loops play an important role in the cellular response to 32 trabectedin (ET743), an anticancer drug from marine origin and its derivative 33 lurbinectedin (PM01183). Trabectedin and lurbinectedin induced RNA-DNA 34 hybrid-dependent DNA damage in HeLa cells, causing replication 35 impairment and genome instability.
    [Show full text]
  • The Essentials of Marine Biotechnology
    Roskilde University The essentials of marine biotechnology Rotter, Ana; Barbier, Michèle; Bertoni, Francesco; Bones, Atle; Cancela, Leonor; Carlsson, Jens; Carvalho, Maria; Ceglowska, Marta; Chirivella-Martorell, Jeronimo; Dalay, Meltem; Cueto, Mercedes; Dailianis, Thanos; Deniz, Irem; Diaz-Marrero, Ana; Drakulovic, Dragana; Dubnika, Arita; Edwards, Christine; Einarsson, Hjörleifur; Erdogan, Aysegül; Eroldogan, Tufan; Ezra, David; Fazi, Stefano; FitzGerald, Richard; Gargan, Laura; Gaudencio, Susana; Udovic, Marija; DeNardis, Nadica; Jonsdottir, Rosa; Katarzyte, Marija; Klun, Katja; Kotta, Jonne; Ktari, Leila; Ljubesic, Zrinka; Bilela, Lada; Mandalakis, Manolis; Massa-Gallucci, Alexia; Matijosyte, Inga; Mazur-Marzec, Hanna; Mehiri, Mohamed; Nielsen, Søren Laurentius; Novoveská, Lucie; Overlinge, Donata; Perale, Giuseppe; Praveenkumar, Ramasamy; Rebours, Céline; Reinsch, Thorsten; Reyes, Fernando; Rinkevich, Baruch; Robbens, Johan; Röttinger, Eric; Rudovica, Vita; Sabotic, Jerica; Safarik, Ivo; Talve, Siret; Tasdemir, Deniz; Schneider, Xenia; Thomas, Olivier; Torunska-Sitarz, Anna; Varese, Giovanna; Vasquez, Marlen Published in: Frontiers in Marine Science DOI: 10.3389/fmars.2021.629629 Publication date: 2021 Document Version Publisher's PDF, also known as Version of record Citation for published version (APA): Rotter, A., Barbier, M., Bertoni, F., Bones, A., Cancela, L., Carlsson, J., Carvalho, M., Ceglowska, M., Chirivella- Martorell, J., Dalay, M., Cueto, M., Dailianis, T., Deniz, I., Diaz-Marrero, A., Drakulovic, D., Dubnika, A., Edwards, C., Einarsson, H., Erdogan, A., ... Vasquez, M. (2021). The essentials of marine biotechnology. Frontiers in Marine Science, 8(8), [629629]. https://doi.org/10.3389/fmars.2021.629629 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.
    [Show full text]
  • And Yondelis® (Trabectedin) at ESMO 2020
    PharmaMar will present data for ZepzelcaTM (lurbinectedin) and Yondelis® (trabectedin) at ESMO 2020 Results of lurbinectedin monotherapy will be presented in patients with Small Cell Lung Cancer (SCLC) that relapsed 90 and 180 days after completion of first-line chemotherapy. Results of trabectedin in combination with immunotherapy (durvalumab) in pre-treated patients with advanced Soft-Tissue Sarcomas, will be presented in an oral session. Results of trabectedin in combination with immunotherapy (nivolumab) in patients with metastatic or inoperable Soft-Tissue Sarcomas after treatment with an anthracycline, will also be presented. Madrid, 14th September, 2020. At the European Society of Medical Oncology (ESMO) Congress, which will be held virtually from 17th to 19th of September, PharmaMar (MSE:PHM) will present data on lurbinectedin in second-line SCLC patients who had received previous platinum-based chemotherapy and relapsed 90 and 180 days after its completion and therefore, being candidates for platinum re- challenge. Phase I results for lurbinectedin in Japanese patients with previously treated advanced Solid Tumours, will also be presented. Results of trabectedin in combination with immunotherapy (durvalumab) in pre- treated patients with advanced Soft-Tissue Sarcomas, will be presented at an oral session. In addition, results of Yondelis® (trabectedin) in combination with immunotherapy (nivolumab) for the treatment of Soft-Tissue Sarcoma, as well as results of trabectedin in combination with doxorubicin (PLD) for the treatment of Recurrent Ovarian Cancer, will be presented. ZepzelcaTM (lurbinectedin) The poster, titled "Activity of Lurbinectedin in Second-line SCLC Patients Candidates for Platinum Re-challenge" will present the evaluation of a subset of patients from the Phase II basket trial, conducted both in the United States and in Europe, in which 5 105 patients with SCLC who had progressed after previous platinum-based chemotherapy, participated.
    [Show full text]
  • Lurbinectedin (PM01183): Under the Spotlight on the Treatment of Relapsed Small Cell Lung Cancer (SCLC)”
    ARISTOTLE UNIVERSITY OF THESSALONIKI SCHOOL OF MEDICINE POSTGRADUATE STUDIES PROGRAMME “Clinical and Industrial Pharmacology - Clinical Toxicology” Master Thesis “Lurbinectedin (PM01183): Under the spotlight on the treatment of relapsed small cell lung cancer (SCLC)” By Theodora Theodoropoulou Regional Medical Liaison Supervisor: Chrysoula Pourzitaki Assistant Professor Laboratory of Clinical Pharmacology at Aristotle University of Thessaloniki Advisory Committee: Demitrios Kouvelas: Professor and Head of Clinical Pharmacology at Aristotle University of Thessaloniki Georgios Papazisis: Associate Professor of Basic and Clinical Pharmacology at Aristotle University of Thessaloniki NOVEMBER 2020 0 ARISTOTLE UNIVERSITY OF THESSALONIKI SCHOOL OF MEDICINE POSTGRADUATE STUDIES PROGRAMME “Clinical and Industrial Pharmacology - Clinical Toxicology” Master Thesis “Lurbinectedin (PM01183): Under the spotlight on the treatment of relapsed small cell lung cancer (SCLC)” By Theodora Theodoropoulou Regional Medical Liaison Supervisor: Chrysoula Pourzitaki Assistant Professor Laboratory of Clinical Pharmacology at Aristotle University of Thessaloniki Advisory Committee: Demitrios Kouvelas: Professor and Head of Clinical Pharmacology at Aristotle University of Thessaloniki Georgios Papazisis: Associate Professor of Basic and Clinical Pharmacology at Aristotle University of Thessaloniki NOVEMBER 2020 1 Acknowledgements I would like to acknowledge my supervisor Chrysoula Pourzitaki, for her support and the learning opportunities provided by her throughout
    [Show full text]
  • Activity of Lurbinectedin As Single Agent and in Combination in Patients with Advanced Small Cell Lung Cancer (Sclc)
    ACTIVITY OF LURBINECTEDIN AS SINGLE AGENT AND IN COMBINATION IN PATIENTS WITH ADVANCED SMALL CELL LUNG CANCER (SCLC) Mª Eugenia Olmedo1, Martin Forster2, Emiliano Calvo3, Víctor Moreno4, Mª Pilar López Criado5, José Antonio López-Vilariño6, Carmen Kahatt6, Pilar Lardelli6, Erik Luepke6 Arturo Soto6. Hospital Universitario Ramón y Cajal, Madrid, Spain1; University College of London Hospital, London, United Kingdom2; Centro Integral Oncológico Clara Campal – Hospital Madrid-Norte Sanchinarro, Madrid, Spain3; Fundación Jiménez Díaz-START, Madrid, Spain4; MD Anderson Cancer Center, Madrid, Spain5; PharmaMar SA, Colmenar Viejo, Spain6 BACKGROUND • Lurbinectedin (PM01183, L) is a novel anticancer drug that inhibits activated transcription, induces DNA double- strand breaks generating apoptosis, and modulates tumor microenvironment. Inhibition of active transcription Generation of DNA breaks I- Binding of PM1183 to the DNA VII- Induction of apoptosis (Cytosine Guanine-rich motifs) Tumor Microenvironment Effect II- Phosphorylation of Pol II Inhibition of Tumor Associated Macrophages (TAM) III- Stalling of elongating Pol II IV- Recruitment of the ubiquitin- proteasome machinery V- RNA Pol II degradation VI- Recruitment of XPF and 2 METHODS • Safety and efficacy of three different clinical trials were reviewed A.- (Lurbinectedin +DOX) B.- (Lurbinectedin +TAX) C.- (Lurbinectedin single-agent) Phase Ib dose escalation followed by dose expansion at RD in selected diseases, Phase I dose escalation followed by dose Phase II Multicenter, open-label, exploratory, Basket including SCLC. expansion at RD in selected diseases trial Less than 3 prior chemotherapy lines for including SCLC. Less than 2 prior chemotherapy lines for advanced advanced disease disease Less than 3 prior chemotherapy lines for Treatment Schedule advanced disease Primary objective: Response rate Cohort A: doxorubicin 50 mg/m2 + L 3-5 mg Treatment Schedule Sample size: initially 15 patients to be recruited flat dose (FD) Day 1 q3w and cont.
    [Show full text]
  • LURBINECTEDIN INVESTOR UPDATE JANUARY 10, 2020 Forward-Looking Statements "Safe Harbor" Statement Under the Private Securities Litigation Reform Act of 1995
    LURBINECTEDIN INVESTOR UPDATE JANUARY 10, 2020 Forward-Looking Statements "Safe Harbor" Statement Under the Private Securities Litigation Reform Act of 1995 This presentation contains forward-looking statements, including, but not limited to, statements related to the potential benefits to Jazz Pharmaceuticals plc from the exclusive license agreement with PharmaMar for lurbinectedin in the U.S., including potential meaningful near-term revenue opportunity; potential accelerated FDA approval and launch of lurbinectedin in the U.S. in 2020; potential regulatory, sales and development milestones under the licensing agreement between Jazz Pharmaceuticals and PharmaMar and related potential future payments by Jazz Pharmaceuticals to PharmaMar; and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals’ current plans, objectives, estimates, expectations and intentions and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward- looking statements as a result of these risks and uncertainties, which include, without limitation, risks and uncertainties associated with: the closing of the licensing agreement between Jazz Pharmaceuticals and PharmaMar upon expiration or termination of HSR waiting period; Jazz Pharmaceuticals' ability to achieve the expected benefits (commercial or otherwise) from the license agreement; pharmaceutical product development and clinical success thereof; the regulatory approval process; effectively commercializing any product candidates; and other risks and uncertainties affecting Jazz Pharmaceuticals, including those described from time to time under the caption "Risk Factors" and elsewhere in Jazz Pharmaceuticals plc's Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and future filings and reports by the company.
    [Show full text]