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. 2024 Oct;41(3-4):117-131.
doi: 10.1007/s10014-024-00493-w. Epub 2024 Sep 24.

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma

Naohide Fujita  1   2   3 , Andrew Bondoc  1   2 , Sergio Simoes  1   2 , Joji Ishida  1   2   4 , Michael S Taccone  1   2   5   6 , Amanda Luck  1   2 , Dilakshan Srikanthan  1   2 , Robert Siddaway  1   2   7 , Adrian Levine  1   2   7 , Nesrin Sabha  1   2 , Stacey Krumholtz  1   2 , Akihide Kondo  3 , Hajime Arai  3 , Christian Smith  1   2 , Paul McDonald  8 , Cynthia Hawkins  1   2   7   5 , Shoukat Dedhar  8   9 , James Rutka  10   11   12   13
Affiliations

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma

Naohide Fujita et al. Brain Tumor Pathol. 2024 Oct.

Abstract

Diffuse intrinsic pontine glioma (DIPG) remains a significant therapeutic challenge due to the lack of effective and safe treatment options. This study explores the potential of combining histone deacetylase (HDAC) and carbonic anhydrase 9 (CA9) inhibitors in treating DIPG. Analysis of RNA sequencing data and tumor tissue from patient samples for the expression of the carbonic anhydrase family and hypoxia signaling pathway activity revealed clinical relevance for targeting CA9 in DIPG. A synergy screen was conducted using CA9 inhibitor SLC-0111 and HDAC inhibitors panobinostat, vorinostat, entinostat, and pyroxamide. The combination of SLC-0111 and pyroxamide demonstrated the highest synergy and was selected for further analysis. Combining SLC-0111 and pyroxamide effectively inhibited DIPG cell proliferation, reduced cell migration and invasion potential, and enhanced histone acetylation, leading to decreased cell population in S Phase. Additionally, the combination therapy induced a greater reduction in intracellular pH than either agent alone. Data from this study suggest that the combination of SLC-0111 and pyroxamide holds promise for treating experimental DIPG, and further investigation of this combination therapy in preclinical models is warranted to evaluate its potential as a viable treatment for DIPG.

Keywords: CA9; Combination therapy; DIPG; HDAC inhibitor; Pyroxamide; SLC-0111.

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