Project Term: July 1, 2021 - June 30, 2026
I am a physician scientist with a clinical and a scientific focus on one type of T cell lymphoma, cutaneous T cell lymphoma or CTCL. CTCL is a cancer of the skin-homing T cell. As such, patients initially present with skin lesions. However, as disease progresses, patients develop widespread disease, bulky tumors, and eventual spread to the blood, the lymph nodes, and the visceral organs. Median survival for patients with advanced CTCL is less than 5 years. Nonetheless, disease course is highly variable, even for patients with Stage IV disease. Disease-specific survival can vary from less than 3 months to over 15 years. Because we do not know what mediates this patient-to-patient heterogeneity, we treat patients with the same standard-of-care therapies. Improving our ability to treat skin lymphomas requires an understanding of who has a poor prognosis and therefore require appropriately aggressive therapies. Moreover, we need to understand what makes aggressive CTCLs so deadly so we can develop novel therapeutic strategies specifically tailored for this dangerous subtype. To bridge this gap in knowledge, my lab has performed whole genome sequencing on a large clinically heterogeneous cohort of patient samples. Our genomic studies have identified multiple genetic biomarkers that predict disease outcomes. For example, patients with biomarker-positive Stage IV disease have a median survival of less than one year. In patients with biomarker-negative Stage IV disease, median survival is ~7 years. In this proposal, we propose to identify why these biomarkers define aggressive disease. To that end, we will use cutting edge approaches to systematically dissect the circuitry of biomarker-positive CTCLs. We will determine how these mutations affect the ability of the T cell lymphoma cells to acquire the building blocks required to divide and to grow. Secondly, we will identify how these mutations affect the T cells’ ability to make immune proteins that can affect the tumor microenvironment. Lastly, we will then determine how these molecular defects in biomarker-positive CTCLs can be potentially targeted by drugs. In summary, over the next five years, our goal is to functionally validate novel biomarkers that can be deployed immediately. Moreover, these studies will provide information critical for us to overcome the most critical unmet need in CTCL. These studies will provide the foundation for novel therapeutic strategies specifically for the patients who need it most, i.e., the patients who do the worst with standard-of-care therapies.