Background: preventing radioresistance
Diffuse midline gliomas (DMGs) are highly aggressive and fatal brain tumors in children usually located in the brainstem. More than 85% of patients with DMGs have the H3K27M-mutation, which is associated with aggressive tumor behavior and an 11-month average survival.
There are multiple challenges in treating DMGs:
- Tumors are not surgically resectable due to their location
- Only standard treatment is radiation therapy (RT) over 6 weeks
- Systemic treatments combined with RT are unsuccessful
- RT shows benefit yet tumors return and can then resist other therapy
RT-induced stress increases association of the BCL2 family of proteins with BH3 pro-apoptotic activators and prevents cell death. Medications that mimic the action of BH3 proteins, such as venetoclax, can inhibit BCL2-BH3 protein binding, reducing radioresistance and promoting tumor cell death. Venetoclax, which crosses the blood-brain barrier, is well-tolerated and has been approved by the FDA, and it’s currently being investigated in many cancer clinical trials.
Neuro-oncology researchers in the Center for Cancer and Blood Disorders at Children's Hospital Colorado, including Rajeev Vibhakar, MD, and Sujatha Venkataraman, PhD, an assistant research professor at the University of Colorado Anschutz Medical Campus, hypothesized that inhibition of RT-induced BCL2 venetoclax would block BCL2 activity leading to increased cell death in DMG tumor cells. This study is the first time BCL2 has been implicated in DMG as a RT-induced resistant mechanism.
Methods: testing venetoclax and radiation therapy combination efficacy
Researchers performed an integrated genomic analysis to determine the genes responsible for radioresistance and a targeted drug screen to identify drugs that synergize with radiation in DMG. This included:
- After screening short hairpin (sh)RNA-targeting DNA repair and non-targeting controls, nine genes with FDA-approved drug inhibitors were selected and then narrowed to four drugs that crossed the blood-brain barrier.
- After a simultaneous oncology drug screen, drugs that induced at least a 25% decrease in cell viability enhanced by RT were selected.
- An immunohistochemistry (IHC) was performed to identify tumor regions.
Study authors evaluated the effect of venetoclax on radiation-naïve and 6Gy radiation on cells by studying cell death, changes in BCL2 phosphorylation, reactive oxygen species (ROS), and apoptosis, as well as BCL2 association with BH3 apoptosis initiators.
They also evaluated the efficacy of combining venetoclax with radiation in vivo using orthotopic xenograft models.
Results: When combined with radiation, Venetoclax increases radiosensitivity in DIPG
Discussion: Venetoclax radiation combination promotes DMG tumor cell death
Tumor relapse is a major challenge in treating H3K27M-mutant or H3.3 WT DMGs since the only available standard of care is RT. There is a desperate need for new combination therapies that can enhance the efficacy of RT.
This study identified that RT induces overexpression of the anti-cell death protein BCL2 due to cellular stress, contributing to radioresistance in DMG cells. Venetoclax, an FDA-approved medication that passes through the blood-brain barrier, inhibits BCL2 upregulation, promoting DMG tumor cell death after exposure to 6Gy radiation. Radiation alone does not lead to prolonged tumor regression, and venetoclax alone has little to no anti-tumor effect.
The mechanism of action of venetoclax is p53-independent. However, the p21 tumor suppressor gene may be involved. These results support a phase 1b clinical trial to assess the safety and efficacy of venetoclax given concurrently with fractionated RT (54-60Gy over 6 weeks) as a first-line treatment in newly diagnosed patients with DMG.
Conclusion: Venetoclax and radiation therapy to treat DMG is ready for phase 1b clinical trial
Venetoclax with 6Gy RT suppresses BCL2 overexpression and promotes DMG tumor cell death. Pre-clinical study results demonstrate the potential use of venetoclax combined with RT for pediatric DMG and warrants a phase 1b clinical trial.