The Bottom Line:
A novel PROTAC-based BCL-2/BCL-XL degrader was able to cause cell death in laboratory models of venetoclax-resistant chronic lymphocytic leukemia (CLL).
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Woyach from the Ohio State University and colleagues presented the results at the American Society for Hematology Annual Meeting in 2022. Dr. Deepa Sampath, an MD Anderson Cancer Center Associate Professor, primarily led this research.
Background:
Cancer is a smart disease that is constantly changing to try to escape from any therapy we might throw at it. Many patients treated with the BCL2 inhibitor venetoclax, especially those who have relapsed/refractory CLL or small lymphocytic lymphoma (SLL), will eventually develop resistance to the drug. Scientists are exploring new ways of targeting drug-resistant CLL / SLL.
In this interview, Dr. Brian Hill, Director of the Lymphoid Malignancies Program and a Staff Physician at the Cleveland Clinic Taussig Cancer Institute, interviewed Dr. Jennifer Woyach, co-director of the Leukemia Research Program at the James Cancer Center of the Ohio State University in Columbus, OH. They discussed new preclinical research looking at a novel drug belonging to a class known as proteolysis-targeting chimera (PROTAC) protein degraders. These PROTAC molecules have two parts; one binds to a target molecule of interest, and the other attaches to a protein known as an E3 ubiquitin ligase, which tags the target molecule for protein degradation.
Methods and Participants:
This was a preclinical study with CLL cells in a dish in a laboratory that was treated with a PROTAC-based BCL-2/BCL-XL degrader (PZ18753b).
Results:
- The PROTAC-based BCL-2/BCL-XL degrader caused cell death (apoptosis) in treatment-naïve CLL cells.
- Its efficacy was between venetoclax (a BCL2 inhibitor) and navitoclax (a BCL-XL/BCL-2 inhibitor).
- The researchers also introduced BCL2 mutations into CLL cells known to cause resistance to venetoclax.
- These mutant cells exhibited decreased sensitivity to venetoclax.
- When the mutant cells were treated with the PROTAC-based BCL-2/BCL-XL degrader, it caused rapid and potent BCL-XL degradation and partial BCL-2 degradation, resulting in cell death.
Conclusions:
This novel PROTAC-based BCL-2/BCL-XL degrader was able to cause cell death in laboratory models of venetoclax-resistant chronic lymphocytic leukemia (CLL). This research is still in its very early stages and provides proof that this new way of targeting venetoclax-resistance CLL / SLL could potentially work. At this time, it’s not quite ready for trials in humans, but in the future, we might be hearing more about PROTAC-based protein degraders.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Targeting Venetoclax Resistant CLL Using a Protac-Based BCL-2/BCL-XL Degrader
Take care of yourself first.
Ann Liu, PhD
