Identification of novel therapeutic strategies for aggressive subtypes of CTCL

Cutaneous T cell lymphoma or 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. Because we do not know what mediates this patient-to-patient heterogeneity, we treat all patients with the same standard-of-care therapies. Improving patient outcomes requires treating patients with proportionally aggressive therapies. To elucidate drivers of disease variability, my lab has performed whole genome sequencing on a large clinically heterogeneous cohort of patient samples. Our genomic studies have identified genetic biomarkers that predict disease outcomes. In this proposal, 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. Then, we will then determine how these molecular defects in biomarker-positive CTCLs can be potentially targeted by drugs. Collectively, 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.