American Association for Cancer Research
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Supplementary Figure 2 from Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas

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journal contribution
posted on 2023-12-01, 07:44 authored by Anahid Ehteda, Aaminah Khan, Gayathiri Rajakumar, Anne S. Vanniasinghe, Anjana Gopalakrishnan, Jie Liu, Maria Tsoli, David S. Ziegler

Microtubule disruption.

Funding

Kids' Cancer Project (TKCP)

Cancer Institute NSW (Cancer Institute New South Wales)

National Health and Medical Research Council (NHMRC)

History

ARTICLE 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.