Targeted therapies against Acute Myeloid Leukemia Hiba El
Targeted therapies against Acute Myeloid Leukemia Hiba El Hajj, Ph. D. Assistant Professor, Departments of Internal Medicine AND Experimental Pathology, Immunology and Microbiology Faculty of Medicine American University of Beirut 1
L’OREAL-UNESCO FOR WOMEN IN SCIENCE PROGRAM
ABOUT THE L’OREAL-UNESCO FOR WOMEN IN SCIENCE PROGRAM − A program created 18 years ago by the L’Oréal Foundation that supports women scientists at different stages of their career. − Today, it is present in 50 countries. − Since 1998: − 92 Laureates have been honored for excellence in science (including two who went in to win the Nobel Prize) − 2438 talented young women 3
L’OREAL-UNESCO FOR WOMEN IN SCIENCE PROGRAM CONVICTION Science is a driving force of innovation and progress. The world needs Science, Science needs Women In Science have the power to change the world 4
MECHANICS OF THE PROGRAM Recognizing and supporting women throughout their scientific career INTERNATIONAL AWARDS “WORLD BEST FELLOWS” REGIONALS FELLOWSHIPS NATIONAL FELLOWSHIPS Renowned researchers Researchers at mid-career Researchers at Ph. D or post. Doctorat level 5
Arsenic: A Reviving Weapon Against Leukemias • Although arsenic is known to be poisonous, it has been used therapeutically for more than 2, 400 years. • In the 15 th century, William Withering, argued: “Poisons in small doses are the best medicines; and the best medicines in too large doses are poisonous”. Digitalis purpuria or Foxglove plant
The History of Arsenic Trioxide as Therapeutic Agent • Salvarsan, an organic arsenical for treating syphilis and trypanosomiasis, was developed in 1910 by Paul Ehrlich. Tryponema pallidum (Syphilis) Trypanosoma
The History of Arsenic Trioxide in Cancer Therapy • In the 18 th century (1878), Thomas Fowler compounded a potassium bicarbonatebased solution of arsenic trioxide (As 2 O 3) that would bear his name and used it to reduce white blood cell counts in two normal individuals and one with “leucocythemia. ” • Pharmacology texts of the 1880 s describe the use of arsenical pastes for cancers of the skin and breast, and arsenous acid was used to treat hypertension, bleeding gastric ulcers, heartburn, and chronic rheumatism.
The History of Arsenic Trioxide in Cancer Therapy • In the 1930 s, arsenic was reported to be effective in chronic myelogenous leukemia (CML). • Mid-20 th century, China: high proportion of hematologic responses in Acute Promyelocytic Leukemia (APL) treated with arsenic trioxide. • Arsenic trioxide (Trisenox™) FDA approved for APL in September 2000.
The History of Arsenic Trioxide in Cancer Therapy In APL, Arsenic is the most active single agent (Shen et al. , 1997; Zhu et al. , 2002; reviewed in Rice and De The 2014). The combination of ATRA and arsenic: most effective and the least toxic therapy for newly diagnosed APL patients (Lallemand 2009, Locco 2013). In CML mouse model, cytarabine and arsenic eliminates Leukemia Initiating Cells (LICs) (Ito et al. , 2008). In CML, Arsenic and Interferon prolonged survival of CML mice, and led to a dramatic decrease in CML LIC activity (El Eit et al. , 2013).
The History of Arsenic Trioxide in Cancer Therapy • In 2010, Dr Ali Bazarbachi ‘ s team showed that Arsenic combination with IFN cures murine ATL through LIC eradication and significantly improved long-term survival in patients with ATL. • In 2015, we showed that Arsenic combined to ATRA synergistically induce proteasomal degradation of mutant NPM-1, leading to differentiation and apoptosis of AML cells. Combined RA/arsenic treatment significantly reduced bone marrow blasts in NPM-1 mutant AML patients.
Acute Myeloid leukemia
Normal Cell Cytoplasm Nucleus NPM-1 mutant AML Cell Nucleolus PML NB NPM wt NPMc+ SUMO-1 NPM-1 c oligomerizes with wild type NPM-1 leading to ectopic accumulation of both proteins in the cytoplasm of leukemic cells Expression of NPM-1 mutant protein is associated with altered formation of PML nuclear bodies.
Arsenic/RA induced growth arrest is mediated by proteasomal degradation of NPM-1 c
Arsenic/RA restores wt NPM-1 localization to the nucleolus Confocal microscopy on THP-1 and OCI-AML 3 cell lines
Arsenic/RA clears AML blasts in bone marrow and peripheral blood of elderly AML patients with NPM-1 mutation Arsenic RA Off treatment Blasts in BM (%) 20 38 5 ND ND ND 6 ND Blasts in PB (%) ND 7 2 0 2 4 0 0 8 15 21 28 32 39 ND 33 ND 6 Patient 4 (days) 41 56 Blasts in BM (%) 27 3 0 9 Blasts in PB (%) 27 2 0 0 0 15 30 45 Patient 5 (days) Blasts in BM (%) 55 Blasts in PB (%) ND ND 14 79 7 0 ND 15 28 Patient 6 (days) 0 7
Normal Cell Cytoplasm Nucleus PML NB Conclusions NPM-1 mutant AML Cell Nucleolus Arsenic/RA NPM wt NPMc+ SUMO-1 §Arsenic/RA induces proteasomal degradation of mutant NPM-1, yielding AML differentiation, growth arrest and apoptosis and significantly reduced leukemic blasts in NPM-1 -mutant AML patients §Arsenic /RA combination restores both nucleolar localization of NPM-1 and PML nuclear bodies ex vivo and in vivo.
Volume 125, Issue 22 WASHINGTON, May 28, 2015 - Welcome to “This Week in Blood, ” a weekly snapshot of the hottest studies from each week’s issue of Blood, the official journal of the American Society of Hematology (ASH), hand-picked by Blood Editor-in-Chief Bob Löwenberg, MD, Ph. D, and Deputy Editor Nancy Berliner, MD. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM-1, resulting in apoptosis of AML cells Arsenic trioxide and all-trans-retinoic acid target NPM 1 mutant oncoprotein levels and induce apoptosis in NPM 1 -mutated AML cells The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) therapy in acute promyelocytic leukemia (APL) represents one of the greatest successes of targeted therapy in oncology. In two independent innovative articles in this week’s Blood, El Hajj et al. and Martelli et al. report that in non-APL acute myeloid leukemia (AML) the same ATRA-ATO combination may be therapeutically active….
Perspectives v These results provide a strong rationale for the use of the arsenic/RA combination as part of the treatment strategy of NPM-1 mutated AML patients. v These promising results support further exploration of the mechanism of action of this combination in vitro and in vivo. v A broader evaluation of therapeutic regimen comprising the arsenic/RA combination, particularly, in elderly patients should be performed.
Acknowledgments: Lab members and Research team, Collaborators, AUB research Cores and Facilities All the Funding Agencies (AUB MPP, LNCSR, CEDRE)
L’Oréal-UNESCO For Women in Science Levant and Egypt fellowships program 21
L’Oreal Unesco For Women in Science: Rising talents 20 22
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