DOCSLIB.ORG

Cancer Control Potential of Marine Natural Product Scaffolds Through

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read 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. prevention through the inhibition of crucial tumor cell motility and/or Khalid El Sayed, BS Pharmacy, MSc, PhD, is a migration steps involved in subsequent cancer metastases. This report also tenured professor, covers the major hurdles typically faced by the MNPs research scientific Department of Basic community. Pharmaceutical Sciences, School of Pharmacy, University of Louisiana- Monroe. Dr El Sayed is an active member in the Introduction American Society of Pharmacognosy, American Chemical Society and American Association for Cancer is one of the deadliest diseases worldwide and is the second most common cause of death Cancer Research. Dr El Sayed has more than 125 in the USA after cardiovascular diseases. It is defined as ‘a group of diseases characterized by the research publications, including nearly 50 papers on marine natural products and their use as scaffolds for uncontrolled growth and spread of abnormal cells’, according to Cancer Facts and Figures of 2016, a design of anticancer analogs, eight patents and five publication distributed by the American Cancer Society (www.cancer.org/acs/groups/content/@ book chapters. He is currently funded by the National Cancer Institute and has secured more than US$1.6 research/documents/document/acspc-047079.pdf). Approximately 1.7 million new cancer cases million in research funds during his Louisiana career. are expected to be diagnosed in 2016, with nearly 600 000 Americans projected to die from cancers. Within the next two decades, annual worldwide cancer cases are expected to rise from 14 million in 2012 to 22 million, according to the World Health Organization (www.who.int/ mediacentre/factsheets/fs297/en/). In the USA, the probability of developing invasive cancer during the lifetime of an individual is slightly less than 1 in 2 for men and slightly more than 1 in 3 for women (www.cancer.org). Prostate cancer is the most frequently diagnosed cancer in men, with an estimated 221 000 new cases in the USA expected during 2016. Similarly, more than 230 000 new cases of breast cancer are expected to be diagnosed in women in the USA. Both prostate and breast malignancies constitute the second-leading cause of cancer-related death (prostate: estimated more than 27 000 deaths; breast: estimated 40 000 deaths in 2016) in men and women in the USA, respectively. Corresponding author: Mudit, M. ([email protected]) 1359-6446/ß 2016 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2016.06.032 www.drugdiscoverytoday.com 1745 REVIEWS Drug Discovery Today Volume 21, Number 11 November 2016 1 1 Natural products have proven to be an unparalleled source of mesylate (Halaven ), brentuximab vedotin (Adcetris ), and io- 1 molecular diversity for the discovery and development of new ta-carrageenan (Carragelose ) were approved in the USA by the drugs. The screening of natural sources, such as microbial and Food and Drug Administration (FDA), while trabectedin, ET-743 1 plant extracts and MNPs, has led to the discovery of numerous new (Yondelis ) was approved in the European Union (EU). Ziconotide pharmacologically active agents. Some of these agents have is labeled for the management of severe chronic pain in patients Reviews proved to be clinically useful drugs for the treatment of human with AIDS or cancer. It was first isolated from the venom of the diseases [1]. Aside from those drugs, which can be classified as fish-hunting marine snail Conus magus and collected in the ‘original natural products’, more drugs in clinical use or develop- Philippines under the name v-conotoxin MVIIA [13]. Ziconotide FOUNDATION REVIEW ment can be characterized as ‘semisynthetically derived from is an extremely effective analgesic with 1000-fold more potency natural products’, or ‘synthetic products based on natural product than morphine [10,14]. Omega-3 acid ethyl esters can be obtained models’ [2]. From January 1981 to December 2014, 73% (1142 out from fish oils and have been approved for reducing serum triglyc- of 1562) of the new chemical entities (NCEs) approved worldwide eride levels. These fish oils are formulated as 1-g soft-gelatin and captured across all disease states were ‘other than formal capsules comprising at least 900 mg of the ethyl esters of ome- synthetics’, including natural products and natural product-in- ga-3 fatty acids (approximately 465 mg eicosapentaenoic acid and spired drugs [3]. Furthermore, an exhaustive survey by Newman 375 mg docosahexaenoic acid) [10]. Studies suggest that severe and Cragg compiled a list of 246 approved anticancer drugs from hypertriglyceridemia, which is often associated with the risk of the 1940s to 2014 [3] and, of these, 207 were small-molecule types, coronary heart disease, can be treated with omega-3 acid ethyl excluding high-molecular-weight biologics and vaccines. In addi- esters [10]. Halichondrin B has been isolated from Halichondria tion, 77.3% (160 out of 207) of those small molecule-based ap- sponges and is a cytotoxic macrolide. However, eribulin mesylate proved anticancer agents were naturally inspired molecules, is an optimized, and much simpler, analog of halichondrin B. This suggesting that nature is a major contributor to anticancer drug optimized analog is approved for the treatment of metastatic discovery [3]. breast cancer, especially for patients who have previously received Terrestrial plants have longstanding historical medical uses; taxane- and anthracycline-based chemotherapy regimens [14]. however, marine organisms have recently been given considerable Brentuximab vedotin is derived from dolastatins that were isolated attention because of their extreme biodiversity [4,5]. These marine from Dolabella auricularia, a small sea mollusk. It is approved for organisms are widespread in oceans that cover more than 70% of the treatment of systemic anaplastic large cell lymphoma and the surface of the Earth [6]. The most important advantage of Hodgkin’s lymphoma. Approval of brentuximab in 2011 by the MNPs as potential lead entities is that they are more likely to show US FDA constituted the first new treatment option for Hodgkin ‘drug-likeness and biological friendliness when compared to total- lymphoma since 1977 [14]. The sulfated galactose polymer iota- ly synthetic molecules’, because they have been elaborated within carrageenan was recently approved for ITs antiviral properties. living systems and created to exert pharmacological activity for This polymer is derived from the red seaweeds Eucheuma and purposes of survival, chemical defense, and competitive advantage Chondrus and is currently sold as a nasal spray for the prophylaxis in their ecosystems [4,7]. There are many unique structural fea- and therapy of respiratory infections against human rhinoviruses tures present in a variety of molecules in almost every class of [10]. Similarly, Yondelis (trabectedin) isolated from the tunicate marine organism [8]. This can be attributed to the extreme chemi- Ecteinascidia turbinate, which is found in the Caribbean and the cal and physical conditions in the marine environment [8]. The Mediterranean Sea, was approved for patients with soft tissue advancement and popularity of MNPs research is evident; there sarcoma (STS) and ovarian cancer [15,16]. were only four published papers on MNPs by 1963 and only one The current pipeline of MNPs in clinical trials comprises 20 paper stating new compounds [9]. Today, the isolation of 24 662 compounds (Fig. 1) either in Phase I, II, or III clinical trials [10,17]. new compounds has been reported in 9220 published papers [9]. Recently, cytotoxic marine-derived compounds were chemically In terms of bioactive compounds, more
Load more

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]
  • 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]
  • Efficacy and Safety of Lurbinectedin and Doxorubicin in Relapsed Small Cell Lung Cancer
    Investigational New Drugs https://doi.org/10.1007/s10637-020-01025-x PHASE I STUDIES Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. Results from an expansion cohort of a phase I study María Eugenia Olmedo1 & Martin Forster2 & Victor Moreno3 & María Pilar López-Criado4 & Irene Braña5 & Michael Flynn2 & Bernard Doger3 & María de Miguel6 & José Antonio López-Vilariño7 & Rafael Núñez7 & Carmen Kahatt7 & Martin Cullell-Young7 & Ali Zeaiter7 & Emiliano Calvo6 Received: 15 October 2020 /Accepted: 22 October 2020 # The Author(s) 2021 Summary Background A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; me- dian overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, de- creased appetite, vomiting, alopecia) were mostly mild or moderate.
    [Show full text]