Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα-Driven Leukemia.

Abstract

PURPOSE:

Retinoic acid-arsenic trioxide (ATRA-ATO) combination therapy is the current standard of care for patients with acute promyelocytic leukemia (APL) carrying the oncogenic fusion protein PML-RARα. Despite the high cure rates obtained with this drug combination, resistance to arsenic is recently emerging. Moreover, patients with APL carrying the PLZF-RARα fusion protein are partially resistant to ATRA treatment. Hypoxia-inducible factor-1α (HIF-1α) activation has been recently reported in APL, and EZN-2208 (PEG-SN38) is a compound with HIF-1α inhibitory function currently tested in clinical trials. This study investigates the effect of EZN-2208 in different preclinical APL models, either alone or in combination with ATRA.

EXPERIMENTAL DESIGN:

Efficacy of EZN-2208 in APL was measured in vitro by assessing expression of HIF-1α target genes, cell migration, clonogenicity, and differentiation, vis a vis the cytotoxic and cytostatic effects of this compound. In vivo, EZN-2208 was used in mouse models of APL driven by PML-RARα or PLZF-RARα, either alone or in combination with ATRA.

RESULTS:

Treatment of APL cell lines with noncytotoxic doses of EZN-2208 causes dose-dependent downregulation of HIF-1α bona fide target genes and affects cell migration and clonogenicity in methylcellulose. In vivo, EZN-2208 impairs leukemia progression and prolongs mice survival in APL mouse models. More importantly, when used in combination with ATRA, EZN-2208 synergizes in debulking leukemia and eradicating leukemia-initiating cells.

CONCLUSIONS:

Our preclinical data suggest that the combination ATRA-EZN-2208 may be tested to treat patients with APL who develop resistance to ATO or patients carrying the PLZF-RARα fusion protein.

• Authors: Nadia Coltella, Roberta Valsecchi, Manfredi Ponente, Maurilio Ponzoni, Rosa Bernardi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 16 Pg. 3685-94 (Aug 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25931453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Arsenicals
• EZN-2208
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Neoplasm Proteins
• Oncogene Proteins, Fusion
• Oxides
• PLZF-RARalpha fusion protein, human
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• Polyethylene Glycols
• Tretinoin
• Arsenic Trioxide
• Camptothecin

Topics

• Animals
• Arsenic Trioxide
• Arsenicals (administration & dosage)
• Camptothecin (administration & dosage, analogs & derivatives)
• Cell Differentiation (drug effects)
• Cell Movement (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis, genetics)
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, pathology)
• Mice
• Mutation
• Neoplasm Proteins (biosynthesis)
• Oncogene Proteins, Fusion (genetics)
• Oxides (administration & dosage)
• Polyethylene Glycols (administration & dosage)
• Tretinoin (administration & dosage)