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All B cells, including chronic lymphocytic leukemia cells, are dependent on the B-cell receptor signaling pathway. One of the enzymes in this pathway is Bruton’s tyrosine kinase (BTK), which is the target of BTK inhibitors such as ibrutinib and acalabrutinib. In CLL cells, the B-cell receptor pathway is always turned on, which leads to cells continuously growing and dividing in an uncontrolled manner. BTK inhibitors turn off BTK, which shuts down the B-cell receptor (BCR) signaling pathway and leads to the death of CLL cells.
At the annual meeting of the American Society of Hematology (ASH) 2020 our own Dr. Brian Koffman interviewed Dr. Jennifer Woyach, a professor of medicine and hematologist at the James Cancer Center of the Ohio State University. They discussed an ongoing Phase 1 clinical trial testing the safety of protein kinase C-beta inhibitor MS-553 in patients with relapsed/refractory CLL. Updated data presented at European Hematology Association (EHA) 2021 are also in the results below.
- The B-cell receptor signaling pathway is extremely important to the growth of CLL cells, so researchers want to know if there are proteins (other than BTK) in the pathway that can be targeted to turn it off.
- BTK inhibitors have been extremely helpful for treating CLL, but there are some patients that don’t respond to them or develop resistance to them.
- Preclinical studies in the laboratory have shown that protein kinase C-beta (PKCβ) is an important enzyme in the B-cell receptor pathway.
- PKCβ is located downstream of BTK. So even if BTK is mutated, PKCβ can still be targeted to turn off the pathway.
- MS-553 is the first PKCβ inhibitor that has been tested in patients with CLL.
- Thus far, 11 patients with relapsed/refractory CLL have been treated with various doses of MS-553.
- Preliminarily, researchers have observed lymph node shrinkage in 73% of patients and was dose-dependent.
- MS-553 is administered orally, and so far, it has been well tolerated.
- Common drug-related side effects thus far have included nausea, diarrhea, and fatigue.
- This drug should also be effective for patients with a mutation in phospholipase Cγ2 (PLCƔ2), which is in between BTK and PKCβ in the B-cell receptor pathway.
Protein kinase C inhibitors are a new class of drugs being investigated for the treatment of CLL. While they are still early on in development, their mechanism of action suggests they could potentially help patients with mutations in the BTK binding site such as C481 or “gain of function” PLCƔ2 mutations. The gain of function defined here is the ability of PLCƔ2 to turn back on the BTK pathway even when it’s blocked by a BTK inhibitor. These types of mutations usually lead to the BTK inhibitor no longer working. Since MS-553 blocks PKCβ which is “downstream” from BTK and PLCƔ2, it should work in blocking the BCR signaling pathway, leading to cell death even in the presence of these mutations.
We look forward to seeing more results as this research continues.
Please enjoy this brief interview with Dr. Woyach from the virtual ASH meeting which was held in December 2020.
You can read the more recent EHA abstract here: Initial Results of a Phase 1 Dose Escalation Study Evaluation of MS-553, a Novel, Selective Inhibitor of PKC-beta, in Patients with Relapsed or Refractory CLL/SLL.
The early ASH abstract that Dr. Woyach describes in the video can be found here: Early Results from a Phase 1 Dose Escalation Study Evaluating MS-553, a Novel, Selective Pkcβ Inhibitor, in Relapsed or Refractory CLL/SLL Patients.
Take care of yourself first.
Ann Liu, PhD
Ann Liu is a medical writer who lives in southern California. In a former life as a scientist, she conducted research on diet and chronic diseases such as cancer and obesity. She enjoys learning new things about science and health, and she also loves beagles and trips to the beach.
Originally published in The CLL Society Tribune Q3 2021.