BCL2 Inhibitors: What’s the Latest Research?

BCL2 inhibitors are drugs that prompt cancer cells to die by altering the interactions among key proteins within the cells. They were clinically developed, in large part, by researchers at Dana-Farber and have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in adults. They’re also being studied in clinical trials for treatment of a range of cancers including diffuse large B-cell lymphoma and mantle cell lymphoma. 

How do BCL2 inhibitors work? 

As their name suggests, BCL2 inhibitors work by targeting a family of proteins known as BCL2, which are especially abundant in certain types of cancer cells. Members of the BCL2 family capture and stifle “pro-apoptotic” proteins that would otherwise nudge the cancer cells to self-destruct. BCL-2 inhibitors cause these pro-apoptotic proteins to be released, allowing the self-destruct process to move forward.

In 2016, venetoclax became the first BCL2 inhibitor to receive FDA approval as standard therapy. It is used in combination with chemotherapy or other agents to treat AML and CLL. Other BCL2 family inhibitors are currently in development or being tested in clinical trials. 

At Dana-Farber, researchers are engaged in a wide range of studies involving BCL2 inhibitors. They’re leading clinical trials of the drugs in patients with specific types of cancer, are working to identify patients most likely to be helped by the drugs, and tackling the problem of resistance, in which the drugs lose effectiveness over time. Here is a look at some of these efforts. 

Clinical trials 

Active trials 

• A trial of the safety and effectiveness of the BCL2 inhibitor BGB-11417 in patients with relapsed or resistant Waldenström’s Macroglobulinemia. 
• A trial evaluating venetoclax and the targeted drug pirtobrutinib in patients previously treated for Waldenström’s Macroglobulinemia. 
• A trial of the addition of venetoclax to standard chemotherapy for patients with Richter’s transformation of CLL. 
• A trial of the addition of venetoclax to standard intensive chemotherapy (“7+3”) in younger patients with AML that arises as a new condition. 
• A trial of the addition of venetoclax to low doses of chemotherapy (mini-hyperCVD) in older patients with acute lymphoblastic leukemia (ALL). 

Planned trials

• A planned trial of the safety and activity of the BCL2 inhibitor navitoclax and targeted drug trametinib in patients with solid tumors harboring mutations in the genes KRAS or NRAS. 
• A trial of a new BCL2 inhibitor, lisaftoclax (APG-2575), in combination with the targeted drug acalabrutinib for relapsed/refractory CLL. 
• A global, randomized phase 3 trial comparing venetoclax in combination with either obinutuzumab or acalabrutinib as initial therapy for CLL.  

Other recent BCL2 research by Dana-Farber investigators 

Dana-Farber researchers led by Jun Qi, PhD, discovered one way that B-cell lymphomas such as mantle cell lymphoma and double-hit lymphoma become resistant to venetoclax. In addition to acquiring new genetic mutations, certain regions of the lymphoma cells’ DNA can become under- or overactive, enabling the cells to skirt the effects of venetoclax and stay alive. The findings suggest that combining venetoclax with an agent that targets a protein involved in gene activity could prevent venetoclax resistance. 

Researchers led by Matthew Davids, MD, MMSc, recently uncovered another mechanism of venetoclax resistance — a finding that suggests a way of putting resistance into reverse. In examining cell lines of diffuse large B-cell lymphoma, which is often resistant to venetoclax, they found a pattern of “hyperphosphorylation” in several members of the BCL2 protein family. Phosphorylation is a process in which chemical clusters known as phosphate groups are attached to proteins, increasing or decreasing the proteins’ activity. Extreme, or “hyper,” phosphorylation can make those changes extreme. In CLL patient samples, too, they found heavy phosphorylation of BCL2 proteins in venetoclax-resistant cells. When they tested fingolimod, a drug that removes phosphate groups from BCL2 proteins, in venetoclax-resistant cells, the cells again became vulnerable to venetoclax. 

Davids and Charles Herbaux, MD, MSc, have also shown that a combination of venetoclax and a drug targeting a cell-signaling pathway known as JAK/STAT could be effective in patients with a rare disease called T-cell prolymphocytic leukemia. The finding came when researchers discovered that the leukemia cells depended not just on BCL-2 for their survival but a second protein as well. 

Learn more about how Dana-Farber’s research in BCL2 inhibitors has benefited patients.