Date of Award
Medical Doctor (MD)
Cutaneous T cell lymphomas (CTCLs) are a group of primarily CD4+ skin-homing non-Hodgkin’s T cell lymphomas with a wide variety of clinical and histologic findings. Therapeutic options for advanced CTCL have expanded in recent decades beyond traditional chemotherapy with the advent of histone deacetylase inhibitors and biologic agents among other modalities; however, many patients do not respond to currently available treatments. Given the heterogeneity of genetic and epigenetic changes in CTCL, a broader range of agents may be necessary to control disease. Using recent advances in the understanding of CTCL genetics, we selected a range of small molecule inhibitors with genetically relevant mechanisms of action and developed an in vitro screen to test these drugs on malignant cells isolated from peripheral blood of patients, as well as CTCL cell lines. We tested drug effects on cell viability, apoptosis induction, and expression levels of relevant genes. This screen identified ABT-199 (venetoclax) as a potent inducer of caspase activity and cell death with viability EC50 for some patient cells ranging in the low nanomolar range for a 3-day assay. Bcl-2 expression, previously identified in non-CTCL cell lines as a biomarker predicting sensitivity to venetoclax, was explored; preliminary investigations suggest a similar relationship for patient cells and CTCL cell lines. Because of the extreme sensitivity demonstrated by some patients, we initiated design of a clinical trial for venetoclax in patients with leukemic CTCL. In parallel, to facilitate future selection of personalized therapy for CTCL, we also validated a FISH-based genetic diagnostic panel to detect common amplifications and deletions in sorted blood samples. This panel identified copy number alterations in recurrently affected genes at similar frequency to exome sequencing on a non-overlapping set of patients. With a new and convenient diagnostic modality, a personalized in vitro drug screen, and a biomarker-paired therapeutic option potentially on the horizon, we aim to bring genetically and functionally personalized therapy closer to its full potential in the management of CTCL.
Weed, Jason G., "Bcl-2 Inhibition For Leukemic Cutaneous T Cell Lymphoma: Targeted Molecular Screen, Biomarker Association, And Clinical Trial Design" (2017). Yale Medicine Thesis Digital Library. 2184.