Project Term
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University of Virginia
Charlottesvile, VA
United States
Project Summary
Large granular lymphocyte leukemia (LGLL) is a rare blood cancer that causes low blood counts and autoimmune disease, which currently lacks FDA-approved treatments. Our research has shown that drugs that change the epigenetic “on/off switches” in DNA, such as azacitidine and cladribine, turn off abnormal growth signals and kill LGLL cells. We have also developed a new nanotechnology version of cladribine, called Nano-Cladribine, which exhibits increased in vitro potency and is designed to reduce side effects. This project will define the efficacy and mechanisms of epigenetic drugs, test new combinations, and advance Nano-Cladribine toward clinical use, with the goal of developing safer, more effective therapies for patients with aggressive or refractory LGLL.
Lay Abstract
Large granular lymphocyte leukemia (LGLL) is a rare and chronic blood cancer that affects white blood cells called T cells or NK cells. In healthy people, these cells help fight infections, but in LGLL they expand uncontrollably and do not die when they should. As a result, patients develop serious health problems including low blood cell counts and autoimmune diseases such as rheumatoid arthritis. Current treatments use low doses of chemotherapy-like drugs that suppress the immune system. These nonspecific drugs often work slowly, help only about half of patients, and frequently result in relapse. Importantly, there are no therapies approved by the FDA specifically for LGLL.
Research has shown that a key growth signal called the STAT3 pathway is “turned on” in all LGLL patients. Our studies and others have also found that changes to the way DNA is chemically marked (called epigenetic changes) are common in LGLL and frequently co-occur with STAT3 activation. These changes act like faulty “switches” that turn off important tumor-fighting genes and allow leukemia cells to survive. Because epigenetic switches are reversible, they provide an important target to develop new therapies.
We tested two drugs that are FDA-approved for other blood cancers, azacitidine and cladribine, which act on these epigenetic switches. Both reprogram abnormal DNA, reduce STAT3 activity, lower production of harmful inflammatory signals, and kill LGLL cells in laboratory models. Importantly, we confirmed similar effects in patient-derived LGLL samples, demonstrating strong translational relevance. To support therapeutic testing and development, we created a new mouse model that closely mimics the human disease, with abnormal cells infiltrating blood, bone marrow, and spleen. Finally, we engineered Nano-Cladribine, a nanotechnology-based version of the drug for greater potency, improved safety and enhanced delivery.
Our hypothesis is that survival of leukemic LGLs depends on abnormal STAT3 signaling and epigenetic dysregulation, and that these vulnerabilities can be targeted with existing drugs and our new Nano-Cladribine. Aim 1 will compare the effects of individual epigenetic therapies in patient samples and laboratory models. Aim 2 will test whether combining cladribine with other epigenetic drugs produces stronger effects than single agents. Aim 3 will advance Nano-Cladribine as a next-generation therapy by defining its safety, drug distribution, and anti-leukemia activity.
The successful completion of these studies will: (1) identify new vulnerabilities in LGLL, (2) define drug combinations to move into clinical trials, and (3) develop Nano-Cladribine as a safer, more powerful treatment. Together, this project addresses the urgent need for new LGLL therapies and aligns directly with the LLS mission to accelerate the development of novel therapies for rare blood cancers.
Program