Medulloblastoma (MB) is the most common malignant pediatric brain tumor. These tumors are made up of four different molecular subgroups: Wingless (Wnt), Sonic hedgehog (Shh), group 3 and group 4.
The prognosis is poor for children with group 3 MB due to the lack of combination therapies to target the amplification of proto-oncogene MYC in these tumors, which is involved in cellular growth and proliferation. There’s a greater risk for metastatic dissemination (the tumor cell spreading into the leptomeningeal structures of the brain and spine), with 39% of children experiencing tumor metastasis and less than 45% achieving a 5-year overall survival rate. Most of these tumors recur metastatically, continuing or gaining MYC amplification at recurrence, and there’s a lack of second-line treatment options.
In this multi-center, international study, researchers investigated epigenetic inhibitors to identify potential treatments for children with therapy-resistant malignant tumors. Researchers from the Center for Cancer and Blood Disorders and the Neuro-Oncology Program at Children’s Hospital Colorado, including Siddhartha Mitra, PhD, Rajeev Vibhakar, MD, PhD, and Sujatha Venkatraman, PhD, worked in collaboration with the German Cancer Consortium (DKTK) University Hospital Dusseldorf.
Epigenic changes have been at the center of previous large studies because, unlike genes, they can be reversed and do not alter DNA. Past studies found that mutations and structural changes of chromatin modifiers, abnormal DNA methylation and histone modification signatures cause abnormal cancer epigenomes. These findings sparked growing interest in targeting epigenetic modifiers for cancer treatment, and several epigenetic modulators have undergone rigorous clinical trials.
Methods: Drug screenings seek to identify active medulloblastoma tumor inhibitors
In this study, investigators performed a primary screen to compare antitumoral activity of 78 epigenetic inhibitors in:
- 11 atypical teratoid/rhabdoid tumors (AT/RT)
- 14 MB
- 14 glioblastoma
To remove bias when evaluating selective activity emerging from biological differences, a secondary screen of 20 commercially available preclinical and clinically approved histone deacetylase inhibitors (HDACi) was performed using an in-house semi-automated platform.
In the secondary screening, the `study authors compared the median response (IC50 value) in one entity against the median of the other tested entities together to identify the inhibitors selectively active in one entity or subgroup.
Of the 78 inhibitors screened:
- 48 had median IC50 greater than 25 µM (negligible activity)
- 17 had significantly lower IC50 values in MB compared with glioblastoma and AT/RT in vitro
In those 17, 11 (65%) of the selective compounds were HDACi, demonstrating over-representation. After subdividing MB models by MYC status, the 11 inhibitors had significantly decreased IC50 values compared to MYC-driven MB with non-MYC-driven MB.
Study authors then analyzed epigenetic inhibitors exhibiting preferential sensitivity in MYC-driven MB, identifying:
- 32 with higher median activity in MYC-driven MB
- 13 significantly more active compared to other tested entities
- 40 with no preferential activity (group 2)
- 4 less active in MYC-driven MB when compared with the median response in the other tested entities (group 3)