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
|