Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL.

Abstract

T-ALL patients treated with intensive chemotherapy achieve high rates of remission. However, frequent long-term toxicities and relapses into chemotherapy-refractory tumors constitute major clinical challenges which could be met by targeted therapies. c-MYC is a central oncogene in T-ALL, prompting the exploration of the efficacy of MYC inhibitors such as JQ1 (BET-bromodomain inhibitor), and SAHA (HDAC inhibitor). Using a standardized ex vivo drug screening assay, we show here that JQ1 and SAHA show competitive efficiency compared to inhibitors of proteasome, PI3K/AKT/mTOR and NOTCH pathways, and synergize in combination with Vincristine. We also compared for the first time the in vivo relevance of such associations in mice xenografted with human primary T-ALLs. Our data indicate that although treatments combining JQ1 or SAHA with chemotherapeutic regimens might represent promising developments in T-ALL, combinations will need to be tailored to specific subgroups of responsive patients, the profiles of which still remain to be precisely defined.

• Authors: Marie Loosveld, Rémy Castellano, Stéphanie Gon, Armelle Goubard, Thomas Crouzet, Laurent Pouyet, Thomas Prebet, Norbert Vey, Bertrand Nadel, Yves Collette, Dominique Payet-Bornet
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 10 Pg. 3168-72 (May 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24930440 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (+)-JQ1 compound
• Azepines
• Histone Deacetylase Inhibitors
• MYC protein, human
• Nylons
• Proto-Oncogene Proteins c-myc
• Pyrroles
• SAHA-PIP-delta
• Triazoles

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Azepines (administration & dosage)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Mice
• Nylons
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (metabolism)
• Proto-Oncogene Proteins c-myc (antagonists & inhibitors)
• Pyrroles (administration & dosage)
• Triazoles (administration & dosage)
• Xenograft Model Antitumor Assays