Targeted therapies against Acute Myeloid Leukemia - PowerPoint Presentation

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Targeted therapies against Acute Myeloid Leukemia

Hiba El Hajj, Ph.D.Assistant Professor, Departments of Internal MedicineAND Experimental Pathology, Immunology and MicrobiologyFaculty of MedicineAmerican University of Beirut

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Although arsenic is known to be poisonous, it has been used therapeutically for more than

2,400 years. In the 15th 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

Arsenic: A Reviving Weapon Against Leukemias

Salvarsan

, an organic arsenical for treating syphilis and trypanosomiasis, was developed in 1910 by Paul Ehrlich. The History of Arsenic Trioxide as Therapeutic Agent

Tryponema

pallidum

(Syphilis)

Trypanosoma

The History of Arsenic Trioxide in Cancer Therapy

In the 18th century (1878),Thomas Fowler compounded a potassium bicarbonate-based solution of arsenic trioxide (As2O3) 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 1880s 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.

In the 1930s, arsenic was reported to be effective in

chronic myelogenous leukemia (CML). Mid-20th 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

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

Cytoplasm

Nucleus

Nucleolus

NPM wt

NPMc

+

SUMO-1

Normal Cell

NPM-1

mutant AML Cell

PML NB

NPM-1c

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-1c

Arsenic/RA restores wt NPM-1 localization to the nucleolus

Confocal microscopy on THP-1 and OCI-AML3 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 (%)

Blasts in PB (%)

Blasts in BM (%)

Blasts in PB (%)

Blasts in BM (%)

Blasts in PB (%)

20

38

5 ND

ND

6 ND

ND

33

ND

ND

ND

ND 7 2

2 4

6

ND

0

0

27 3

27 2

0

0

0

9

55 ND 14 79

ND

ND 7

0

Patient 4

Patient 5

Patient 6

(days) 0 8 15 21 28 32 39 41 56

(days) 0 15 30 45

(days) 0 7 15 28

Conclusions

Cytoplasm

Nucleus

Nucleolus

NPM wt

NPMc

+

SUMO-1

Normal Cell

NPM-1

mutant AML Cell

Arsenic/RA

PML NB

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, PhD, 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 NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-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….

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. These promising results support further exploration of the mechanism of action of this combination in vitro and in vivo.A broader evaluation of therapeutic regimen comprising the arsenic/RA combination, particularly, in elderly patients should be performed.

Perspectives

Acknowledgments

: Lab members and Research team, Collaborators, AUB research C

ores

and

Facilities All the Funding Agencies (AUB MPP, LNCSR, CEDRE)

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L’Oréal-UNESCO For Women in Science Levant and Egypt fellowships program

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L’Oreal Unesco For Women in Science: Rising talents 2016