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

Nadia Coltella, Roberta Valsecchi, Manfredi Ponente, Maurilio Ponzoni, Rosa Bernardi

Research output: Contribution to journalArticle

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 PLZFRARα, 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 maybe tested to treat patients with APL who develop resistance to ATO or patients carrying the PLZF-RARα fusion protein.

Original languageEnglish
Pages (from-to)3685-3694
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
Publication statusPublished - Aug 15 2015

    Fingerprint

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this