Elucidating the Biology of Aggressive Kinase Fusion-Driven Cutaneous T-Cell Lymphomas
Abstract
Focus Area: This proposal will address two Focus Areas. We found that the vast majority of Primary Cutaneous Aggressive Epidermotropic T Cell Lymphomas (PCAETCLs) express a JAK2 mutation. We hypothesize that this mutation drives lymphoma formation. Thus, we propose a series of experiments in this proposal to identify and functionally characterize the molecular pathways by which this mutation contributes to this devastating disease. We will then investigate a novel therapeutic strategy, i.e., how a JAK2 inhibitor developed for other cancer types can be repurposed for this disease. Thus, it will address Biology and Etiology as well as Therapy. What types of patients will it help and how will it help them? This proposal will help patients with primary cutaneous aggressive epidermotropic T cell lymphomas. Currently, there are no effective treatments for this aggressive disease. Median survival is only 11 months! Since we do not understand the biology of this rare cancer, it is difficult, if not impossible, to improve the ways we treat and care for these patients. We have recently identified a novel, potential therapeutic vulnerability specifically for this disease. The vast majority of PCAETCLs express a cancer-promoting mutation, a JAK2 fusion gene. Importantly, this mutation appears to be potentially targetable with JAK inhibitors that were originally developed for other cancer types. Because the drug is already Food and Drug Administration-approved for other blood cancers, it is possible that these drugs can be used almost immediately for patients who otherwise do not have other options. Thus, this award will help patients. It will help us to understand how this mutant JAK2 protein supports lymphoma development, why JAK2 inhibitors are efficacious (if they are), and why some patients are resistant to this therapy. In other words, this proposal will help patients with this devastating disease by elucidating the biology of these cancers and by studying a novel therapeutic strategy that can help patients immediately. What are the potential clinical applications, benefits, and risk? This proposal is clinically applicable with important clinical benefits to patients. It will help us understand how to improve the way we treat this disease. We found disease-defining JAK2 mutations in approximately 90% of PCAETCLs. Our preliminary data suggest that these mutations are targetable by drugs originally designed for other cancer types, i.e., JAK1/2 inhibitors. Based on these data, we have launched a clinical trial to test this concept in patients. If the drug is effective, the experiments outlined in this grant proposal will help explain why. This is important to determine who should be treated, how long they should be treated, and why they should be treated. Moreover, if the drug is not effective or if patients develop resistance, our proposal will help explain why. Collectively, we can leverage these scientific and translational data together to determine how we can design next-generation effective treatments tailor-made for this aggressive lymphoma. We do not foresee clinical risks from the experiments outlined in the proposal. The clinical trial, which has risks, is associated with but not funded or sponsored by this proposal. What is the projected time anticipated to achieve a clinically relevant outcome? We project that we will have a clinically relevant outcome by the end of this funding mechanism. Within three years, we will understand the biology of these PCAETCL-specific mutations, how they can be targeted, and mechanisms of drug resistance (if any) to the JAK1/2 inhibitor ruxolitinib. What are the likely contributions of this study to advancing rare cancers research? We have an uncommon opportunity to apply a precision medicine approach to treating/curing this devastating rare cancer. In a stroke of serendipity, we discovered that the vast majority of these rare cancers, PCAETC
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210763
Entities
People
- Jaehyuk Choi
Organizations
- Northwestern University
- United States Army