Understanding Drug Interactions in Diffuse Midline Gliomas

In recent years, studies have shown that diffuse intrinsic pontine glioma (DIPG) subtypes are driven by common genetic mutations, particularly in genes encoding histones, which are associated with epigenetic modifications. In search of novel therapies, the team examined multiple DIPG cultures with “combination” studies, including testing thousands of approved and investigational drug pairs.

“In the epigenetics community, we are still trying to define what the major driver alterations in DIPG are doing to the chromatin landscape, with the hopes that we will be able to better understand this disease,” says Benjamin Stanton, PhD, Principal Investigator in the Center for Childhood Cancer and Blood Diseases at Nationwide Children’s Hospital, “Even with decades of studies, median survival for DIPG patients remains less than one year post-diagnosis.”

The initial screens yielded 19,936 single-agent dose responses. Based upon those results, the researchers initiated a series of drug-drug combination assessments comprising 9,195 combinations. Those studies revealed that the histone deacetylase (HDAC) inhibitor panobinstat had broad synergistic interaction with several drug classes, particularly with the proteasome inhibitor marizomib, which possessed strong DIPG cell cytotoxicity as a single agent.

“While the HDAC inhibitor panobinostat is already in clinical trials, these studies provide motivation to understand how CNS-penetrant proteasome inhibitors may be useful in the clinic for its potentiation,” says Dr. Stanton.

Next, the most promising combinations were tested in patient-derived cell cultures representing the major DMG genotypes and in vivo in patient-derived xenograft models from both pontine and nonpontine gliomas. The efficacy of panobinostat and marizomib in combination was consistently validated in these experiments.

Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response following treatment with panobinostat and marizomib. Rescue experiments confirmed that the drug-induced cytotoxicity of the combination appears to act through downregulation of cellular metabolism and respiration, which leads to metabolic collapse. Thus, concomitant HDAC and proteasome inhibition appears to be a promising therapeutic strategy that targets metabolic vulnerabilities in DIPG.

“Even though the community has made fundamental advances in understanding DIPG tumor biology, in terms of transcriptional circuitry, we still have not defined a cell of origin or a differentiation model for DIPG. My hope is that revealing new vulnerabilities in this disease will catalyze new basic advances in understanding the etiology of DIPG,” says Dr. Stanton.

Reference

Lin GL, Wilson KM, Ceribelli M, et al. Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science Translational Medicine. 2019 Nov 20;11(519). pii: eaaw0064.

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