Dissecting the Spatial Molecular Architecture of the Transformed Cutaneous T-Cell Lymphoma Tumor Microenvironment to Target Novel Therapeutic Vulnerabilities
Abstract
Cutaneous T cell lymphomas (CTCLs) are a group of rare, incurable cancers of skin-homing T cells. It affects males more often than females, and large-scale Surveillance, Epidemiology, and End Results (SEER) Program studies show that Black/African American (AA) patients have a higher incidence rate, younger age of onset, and inferior survival compared to Whites. The most common form of CTCLs, mycosis fungoides, is characterized by cutaneous patch/plaque lesions or tumors, whereas Sezary syndrome is the leukemic variant of CTCL in the peripheral blood. Large cell transformation occurs in a subset of CTCL patients when the lymphoma cells undergo morphologic transition to become an aggressive large cell lymphoma. It portends a rapid decline in survival and resistance to multiple forms of systemic therapies. Notably, Black/AA patients with transformed CTCL show inferior survival compared to White patients. Major advances have been made in the treatment of advanced CTCL with the U.S. Food and Drug Administration (FDA) approval of brentuximab vedotin (anti-CD30) and mogamulizumab (anti-CCR4), yet the reported median progression-free survival was 15.9 months and 7.7 months, respectively, and large cell transformation was one of the exclusion criteria in the mogamulizumab trial. At the present time, there is no cure for transformed CTCL, and the molecular determinants of large cell transformation and racial disparity in CTCL are poorly understood. As CTCL is a rare cancer, the paucity of tissue samples and patient-derived cell lines to identify the disease-defining molecular targets in the tumor microenvironment contribute to the complete lack of drug development for CTCL at its most lethal state. While CTCL is a rare cancer, the H. Lee Moffitt Cancer Center s Cutaneous Lymphoma Multidisciplinary Clinic is the largest CTCL referral center in the U.S. Southeast and treats approximately 10% to 15% of all new CTCL patients in the U.S. each year. In our preliminary genomics studies from a cohort of 56 patients with transformed CTCL, we uncovered the genomic landscape of transformed CTCL and identified potential therapeutic targets. However, it was evident that bulk genomic and dissociated single cell studies lacked the spatial context of the innate tumor microenvironment and the ability to probe the complex biological interplays between its diverse tumor and benign cell types. Recent advances in high resolution spatial -omics and multiplexed single cell imaging technologies have provided unprecedented opportunities to probe the functional states and cellular networks that can be quantitatively mapped to every cell s unique position in the tumor. In this highly translational study, we will leverage Moffitt s high-volume CTCL Multidisciplinary Clinic, with a diverse patient population, and deploy high-resolution spatial -omics platforms to interrogate the transformed CTCL tumor microenvironment for disease-defining pathways that govern transformation and racial disparities in outcomes (Focus Area: Biology and Etiology). We will also target novel therapeutic vulnerabilities in the transformed CTCL tumor microenvironment using Palbociclib, an FDA-approved cell cycle inhibitor, in patient-derived cell lines from diverse racial background (Focus Area: Therapy). The proposed spatial molecular and pharmacologic preclinical studies using an FDA-approved drug have the potential to make a significant impact in the field, with novel mechanistic understanding of the transformed CTCL tumor microenvironment and clinical trials that could transform the management of patients with a hitherto orphan disease. Our investigation using spatial -omics technologies to elucidate the architectural and molecular differences in the Black/AA versus White tumor microenvironment could open new avenues for additional preventive or therapeutic interventions in combating racial disparity in CTCL. Furthermore, the computation algorithms developed fo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310947
Entities
People
- Pei-ling Chen
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army