New Compound Takes Aim at CLL
- Sylvester Comprehensive Cancer Center researcher Justin Taylor, M.D., is conducting research to address chronic lymphocytic leukemia tumor resistance to BTK inhibitors.
- Whereas current BTK inhibitors inactivate the BTK molecule, Dr. Taylor is working with compounds that destroy the BTK molecule.
- Initial results are promising, with the compound NX-2127 showing the ability to destroy cancer cells in the lab and shrink tumors in some patients enrolled in an early-stage clinical study.
Patients with chronic lymphocytic leukemia (CLL) and related blood cancers are often prescribed targeted drugs called BTK (Bruton’s tyrosine kinase) inhibitors.
The drugs can shrink tumors, ease symptoms and extend lifespan. However, some patients develop resistance to the drugs, limiting their therapeutic options.
In a new study, researchers introduce a potential solution, a next-generation BTK-targeting therapy that acts in a unique way.
Approved BTK inhibitors like ibrutinib work by inactivating the BTK molecule. The new compound goes further, aiming at and destroying the same target.
Dr. Taylor and his colleagues assessed the new compound in laboratory studies and in a phase 1 clinical trial of patients whose tumors had become resistant to previous therapies or had failed to respond. The researchers report that the compound overcame resistance in cells grown in a petri dish and in cells from patients. A large percentage of CLL patients treated with the compound also experienced shrinkage of their tumors.
Science reported the findings. Dr. Taylor led the study with Memorial Sloan Kettering Cancer Center researchers and the biotechnology company Nurix Therapeutics. Skye Montoya, a graduate student in Dr. Taylor’s lab, is first author on the publication.
Designing a Leukemia Degrader
Most approved, targeted drugs don’t destroy their targets. Instead, they bind to the targets and modulate their activity.
Ibrutinib and other approved BTK inhibitors bind to BTK, an enzyme that keeps B cells alive. The drugs quell BTK activity, leading to the death of B cells in CLL and other malignancies that arise from B cells.
Biopharma companies are now developing next-generation drugs that not only inactivate drug targets but degrade and eliminate them. So-called “BTK degraders” are designed to eliminate BTK.
Nurix Therapeutics’ BTK degrader, NX-2127, is constructed with two modules. One module binds to BTK. The other module directs BTK to the cell’s trash heap, a molecular complex involved in degrading cellular proteins.
Destroying the BTK Target
Researchers showed that NX-2127 efficiently destroyed its target in cells in a petri dish and in patient cells. The compound also destroyed BTK in cells resistant to approved BTK inhibitors. And it shrank tumors in 11 of 14 CLL patients, including tumors resistant to approved BTK drugs.
One CLL patient had a particularly strong response to NX-2127. The elderly patient had been on pitoibrutinib for two years but developed resistance to it and other therapies.
“There were no conventional options left for him,” said Dr. Taylor.
The patient’s symptoms and quality of life improved on the trial and he stopped receiving blood transfusions for anemia, said Dr. Taylor.
“CLL is an incurable disease, but with treatments like BTK inhibitors and potentially these new BTK degraders, the goal is to alleviate the symptoms and get patients back to their normal, everyday routines,” said Dr. Taylor, a member of the Translational and Clinical Oncology Program at Sylvester and assistant professor of hematology at the Miller School.
The researchers continued the study past the Sept. 2022 data cutoff for the Science publication and provided an update in December. The elderly patient was still responding to NX-2127. Overall, 41% of CLL patients responded to the new compound.
CLL occurs in about 20,000 people in the U.S. each year and is one of the most common adult leukemias. Dr. Taylor said BTK degraders may also potentially treat other B-cell malignancies or even autoimmune conditions such as multiple sclerosis. He and his colleagues are now enrolling patients in a study testing a more potent BTK degrader developed by Nurix, NX-5948.
Looking for New Ways to Overcome Tumor Resistance
The new findings have their origins in Dr. Taylor’s long-running research exploring how tumors become resistant to BTK inhibition.
Previously, Taylor and his team had identified mutations in BTK that lead to resistance in patients’ CLL tumors in the clinic. Some of the mutations restored BTK’s enzymatic function, resulting in renewed B-cell growth and the return of tumors.
In the current study, Dr. Taylor and his team found that resistance can also develop when BTK acquires mutations that give it an entirely new function. Those mutations cause BTK to operate as a “scaffold” that recruits other cellular molecules to keep B cells alive.
The researchers went on to show that NX-2127 could overcome resistance to all of these different types of mutations.
“Each BTK mutant we study can cause resistance to multiple BTK inhibitors, which can really limit therapeutic options for patients harboring these mutations,” said Montoya. “We were all excited to see positive responses in both cell lines and patients, regardless of BTK mutational status.”
The current study went from clinical findings to laboratory research, and then back to the clinical setting, within two years.
“That’s record time,” said Dr. Taylor, who attributed the speed to the commitment of his team and the breadth of resources available at Sylvester.