Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas.
Mol Cancer Ther
; 22(12): 1413-1421, 2023 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-37683275
ABSTRACT
Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009-1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal human astrocyte cells. TRX-E-009-1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, while also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009-1 and the histone deacetylase (HDAC) inhibitor SAHA extended survival in DIPG orthotopic animal models. This antitumor effect was further enhanced with irradiation. Our findings indicate that TRX-E-009-1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.
Full text:
1
Database:
MEDLINE
Main subject:
Brain Stem Neoplasms
/
Diffuse Intrinsic Pontine Glioma
/
Glioma
Type of study:
Prognostic_studies
Limits:
Animals
/
Child
/
Humans
Language:
En
Journal:
Mol Cancer Ther
Journal subject:
ANTINEOPLASICOS
Year:
2023
Type:
Article
Affiliation country:
Australia