JAK/STAT inhibition as a therapeutic strategy in T-cell lymphoma
Alison Moskowitz
MDMemorial Sloan Kettering Cancer Center
Project Term: July 1, 2019 - June 30, 2024
Given the high rate of JAK/STAT pathway dysregulation in T-cell lymphomas, we aim to develop new personalized therapies with JAK inhibitors for T-cell lymphoma. Our recent study with ruxolitinib (a JAK inhibitor) showed that activation of a parallel oncogenic pathway, PI3-kinase, predicts for poor response to ruxolitinib in T-cell lymphoma. Building upon this observation, we are assessing whether dual inhibition of JAK and PI3-Kinase will lead to higher efficacy in T-cell lymphoma.
This project aims to develop new personalized therapies to work in combination with ruxolitinib for the treatment of T-cell lymphomas. The T-cell lymphomas are rare diseases that are typically associated with poor prognosis. Developing new agents for T-cell lymphomas is particularly challenging due to the marked heterogeneity among these diseases. Despite their heterogeneity, we currently use the same treatment approach for the most common entities; however the treatment should be as varied as the diseases themselves. There are limited numbers of effective treatment options for patients with T-cell lymphoma, and the selection of treatment has been largely based on observation rather than driven by biomarkers or disease biology. Recent studies have revealed new insight into the biology of T-cell lymphomas, leading to identification of potential therapeutic targets in these diseases. One such target is the JAK and STAT pathway, which is activated in a significant subset of T-cell lymphomas. Ruxolitinib is a JAK inhibitor that is FDA-approved for the treatment of other blood disorders. Based on the biological characteristics of T-cell lymphomas, I am leading a phase II clinical trial to evaluate the efficacy of ruxolitinib in patients with various T-cell lymphoma subtypes, with particular focus on identifying biomarkers that predict sensitivity and resistance to this agent. Identification of biomarkers may be useful in the future to identify patients who are most likely to respond to this therapy as well the earlier identification of patients who are bound to develop resistance. Enrollment in this study is about 80% complete, and we have observed efficacy, particularly in patients with T-cell lymphoma characterized by JAK/STAT pathway activation. Most responses to ruxolitinib are partial and transient, indicating that T-cell lymphomas treated with ruxolitinib eventually acquire resistance to JAK inhibition. It is likely that activation of alternative pathways are at least in part responsible for acquired resistance. Targeting JAK and one or more such alternative pathways could improve the patient’s response. Through biomarker analyses of tissue and blood samples from patients treated with ruxolitinib, we are working to identify pathways that become activated following exposure to JAK inhibition. These analyses will inform the design of the next studies evaluating ruxolitinib in combination with alternative pathway inhibitors and ultimately lead to the development of promising treatment strategies for these diseases.