Page 74 - 2019_06-Haematologica-web

Ferrata Storti Foundation
Haematologica 2018 Volume 104(6):1156-1167
Acute Myeloid Leukemia
Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes
Kimberly N. Smitheman,1 Tesa M. Severson,2 Satyajit R. Rajapurkar,1
Michael T. McCabe,1 Natalie Karpinich,1 James Foley,1 Melissa B. Pappalardi,1 Ashley Hughes,3 Wendy Halsey,3 Elizabeth Thomas,3 Christopher Traini,3
1124 Kelly E. Federowicz, Jenny Laraio, Fredrick Mobegi, Geraldine Ferron-Brady,
Rabinder K. Prinjha,1 Christopher L. Carpenter,1 Ryan G. Kruger,1 Lodewyk Wessels2,5 and Helai P. Mohammad1
1Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA; 2Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands; 3Target Sciences, GlaxoSmithKline, Collegeville, PA, USA; 4Clinical Pharmacology and Modeling Sciences, GlaxoSmithKline, Collegeville, PA, USA and 5Faculty of EEMCS, Delft University of Technology, the Netherlands
ABSTRACT
Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all-trans retinoic acid was explored. All-trans retinoic acid is currently approved for use in acute promyelocytic leukemia in which it pro- motes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all-trans retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.
Introduction
Acute myelocytic leukemia (AML) is characterized by excessive growth of hematopoietic progenitor cells that reach varying stages of differentiation depend- ing on the subtype. With the exception of acute promyelocytic leukemia (APL) few patients with AML are cured, despite treatment that includes high-dose induction and consolidation therapy and even, for some, bone marrow transplant.1 The disease is classified using the French-American-British (FAB) classification that divides AML into eight subtypes (M0 to M7) based on the differentiation status of the tumor cells as well as the cell type from which the cancer arises. The World Health Organization (WHO) further distinguishes AML types by also considering somatic genetic alterations.2 For most subtypes, first-line treatment consists of chemotherapy followed, in some instances, with hematopoietic stem cell trans- plant (HSCT).3 Due to the intensity of HSCT treatment, this approach is often only recommended for younger patients or those deemed fit enough to tolerate it. Even among the younger patient population, the 5-year overall survival is only approximately 40%.3 For patients over the age of 60, only approximately 20% sur- vive;4 therefore, more effective second-line treatment options are needed.
Lysine specific demethylase 1 (LSD1) is a histone-modifying enzyme that is a member of the monoamine oxidase family.5 LSD1 has been shown to suppress
Correspondence:
HELAI P.MOHAMMAD
helai.x.mohammad@gsk.com
Received: June 4, 2018. Accepted: November 30, 2018. Pre-published: December 4, 2018.
doi:10.3324/haematol.2018.199190
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1156
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1156
haematologica | 2019; 104(6)
ARTICLE