Developing Novel Therapeutics for Aggressive Variants of CTCL

T cell lymphomas are a heterogeneous collection of incurable cancers. Progress in this important field has been limited by a lack of understanding about the molecular basis of how the cancer starts and progresses. To overcome this gap in knowledge, we have used next generation sequencing to identify clinically relevant mutations that promote lymphomagenesis. As a physician-scientist, I have focused on cutaneous T cell lymphoma (CTCL). CTCL is one type of T cell lymphoma that arises from the skin-homing T cell. Initially, patients present with thin skin lesions. As the disease progresses, patients develop widespread disease, bulky tumors, and eventually involvement of the blood, lymph nodes, visceral organs. Median survival for patients with advanced CTCL is less than 5 years. Nonetheless, disease course is highly variable. Disease-specific survival can vary widely from less than 3 months to over 15 years. Because we do not know what mediates this heterogeneity, we treat all patients with the same standard of care therapies. To improve patient care, we have to understand what makes aggressive CTCLs so deadly. Our genomic studies have revealed a putative genetic biomarkers that predict disease prognosis. Patients with Stage IV biomarker-positive disease have a median survival of less than one year. In patients with biomarker-negative disease, median survival is ~7 years. In this proposal, we propose to functionally validate why biomarker-positive disease is so aggressive. We will use cutting edge approaches to dissect the circuitry of biomarker-positive CTCLs. Our preliminary data suggests that this information will lead to the identification of novel targetable signaling nodes. These studies will provide information critical for us to overcome the most critical unmet need in CTCL. We will develop novel therapeutic strategies specifically for the patients who need it most, i.e., the patients who do the worst with standard-of-care therapies.