Profiling Meningioma Sensitivity to Epigenetic Inhibition Using a High-Throughput Pharmacological Screen in Meningioma Cell Lines

Background: Epigenetic processes are major regulators of meningioma biology, and have great potential as a diagnostic tool to identify recurrent or treatment resistant tumors. Epigenetics may also present opportunities as direct therapeutic targets. In a broad drug screen of FDA-approved cancer therapies, we found that inhibiting epigenetic regulators has the potential to efficaciously treat meningiomas. However, the few FDA-approved drugs that inhibit epigenetic processes cover a narrow range of these processes. To determine the potential clinical utility of epigenetic inhibitors for the treatment of meningiomas, we screened a comprehensive epigenetic compound library in a large cohort of meningioma cell lines. Progressing our understanding of both the mechanisms of oncogenesis in meningiomas and their sensitivity to novel treatments will result in additional treatments for patients suffering from these tumors.

Methods: We have developed a high throughput cell viability assay that allows us to screen large compound libraries. We screened the Cayman Chemical Epigenetic Inhibitor library, containing over 140 compounds, in a large cohort of meningioma cell lines and expanded cells from patient tumors. Additionally, we are actively screening new tumors as they become available from our operating rooms. Each drug was screened at a single dose of 5 µm. Any drug that reduced cell viability by 50% or more was considered a positive hit.

Results: Each cell line had a very broad sensitivity to the compounds in the epigenetic library, covering all epigenetic processes. Collectively, most of the compounds in this library have the potential to inhibit growth of at least a single tumor. However, inhibitors of Histone Deacetylases (HDACs) were found to inhibit the growth of the majority of meningiomas. These compounds include: 2-hexyl-4-phentynoic acid, cay10603, kD 5170, rsc-133, sb939, and sodium butyrate. Additional common families of compounds found to frequently inhibit the viability of meningiomas are bet proteins inhibitors, lysine methyltransferases inhibitors, and histone trimethyl demethylases inhibitors. Notably, DNA methyltransferase inhibitors showed little to no effect on the viability of meningiomas.

Conclusion: High-throughput drug screening is a viable way to identify possible therapeutic targets in meningiomas. Using an epigenetic screen, we were able to generate a high-resolution profile of compound sensitivity for individual tumors, some of which could treat the majority of meningiomas. HDAC inhibitors provide a potential avenue for the broad treatment of meningiomas. As we continue to screen more tumors, we will be able to determine if the sensitivity to HDACs is broad in nature, or class dependent. These findings have immediate implications for the treatment of meningiomas due to the existence of FDA-approved HDAC inhibitors.