Inhibition of PKCβ as a strategy for BTK inhibitor refractory CLL
Jennifer Woyach
MDThe Ohio State University
Project Term: July 1, 2023 - June 30, 2026
Patients with CLL that have progressed on BTK inhibitors have high risk disease with few clinical options. Here we propose a novel, selective inhibitor of PKCβ, MS-553, as a strategy for these patients. Our project will evaluate this drug alone and in combination with venetoclax preclinically and will perform correlative studies from an ongoing phase 1/2 trial of this drug alone and in combination with venetoclax.
Chronic lymphocytic leukemia (CLL) is treated with inhibitors of Bruton’s Tyrosine Kinase (BTKi) in many patients. BTK inhibitors inhibit the B cell receptor (BCR) signaling pathway, which is important in CLL cell survival. Patients whose disease progresses after BTKi need new treatment strategies, as current therapies do not often produce long-term remissions. Because disease progression with BTKi usually occurs through mutations in BTK, we hypothesize that continued targeting of the BCR pathway will be a successful strategy in these patients. In this application, we propose MS-553, an inhibitor of PKCb, as a novel treatment for CLL.
PKCb is a protein downstream of BTK in the BCR pathway. PKCb is expressed at a high level and is very active in CLL. Our preliminary data shows that MS-553 can inhibit signaling inside CLL cells and slows disease progression in a mouse model of CLL. We are currently leading the first clinical trial of MS-553 in CLL. In this trial the majority of patients had previously been treated with a BTKi, and we have seen early signs that the drug is effective. Despite these exciting data, we expect that combination treatment with MS-553 will be more effective than single agent treatment, and here we propose to study MS-553 alone as well as in combination with venetoclax. Venetoclax is chosen as a partner for MS-553 because our laboratory data shows that MS-553 causes CLL cells to be more dependent for survival on BCL2, which is the target of venetoclax.
Our experiments for this project will use multiple models of CLL including cell lines, primary patient samples, and mouse models. To evaluate how effective MS-553 is, we will be studying toxicity to CLL cells as well as the ability of the drug to inhibit cell signaling, both by itself and in combination with venetoclax. We will also perform studies on samples from patients participating in the MS-553 clinical trial. We expect that this project will justify continued development of MS-553 in CLL and identify an exciting combination strategy.