Mechanism of Transformation in T-Cell Lymphomas: Identification of Therapeutic Targets

Project Summary T-cell lymphomas (TCL) are a highly aggressive and heterogeneous group of non-Hodgkin lymphomas derived from post-thymic mature T- and NK-cells. Limited understanding of the genetics and pathogenesis of TCL have led to relatively few targeted therapeutic with none considered curative. Among them, histone deacetylase inhibitors (HDACi) have emerged as a class of epigenetic drugs with single-agent activity in patients with cutaneous and peripheral T-cell lymphoma, with overall response rates (ORR) of ~27-33% in relapsed TCL. However, even among patients that do initially respond, duration of response is short lived, and the patient eventually relapses. Here, I will formally explore the genetic mechanisms underlying resistance to HDACi in TCLs. The central hypothesis of this proposal is that the therapeutic effects of HDACi observed in T-cell lymphomas occurs due to alterations in critical oncogenic pathways implicated in the growth and progression of T-cell lymphomas. Additionally, I propose that genetic aberrations affecting epigenetic and signaling pathways can bypass or compensate for HDACi-mediated inhibition to drive resistance to HDACi treatment. To test this hypothesis, I will utilize a well-defined clinical series of cutaneous T-cell lymphoma (CTCL) primary patient samples treated with HDACi as well as established cell line models of CTCL. This series of primary patient samples will enable the longitudinal analysis of individual tumors along with grouped analysis of HDACi sensitive and resistant tumors. Using these models, I propose to address the central hypothesis in the following two Specific Aims: Aim 1, to identify mechanisms of response and resistance to HDACi in T-cell lymphoma cell lines and primary patient samples through bulk and single-cell sequencing techniques as well as genome wide CRISPR knockout screens; and Aim 2, to develop synergistic HDACi-based therapeutics using in vivo and in vitro models that overcome HDACi resistance. Experiments related to these two aims will be performed in close collaboration with groups within the Herbert Irving Comprehensive Cancer Center and the Columbia University Department of Systems Biology to ensure rigorous analysis and to leverage expertise in a wide range of fields relevant to the experiments proposed. The goal of this project is to uncover genetic mechanisms driving resistance to HDACi in T-cell lymphomas and leverage this knowledge to identify potential therapeutics that may reverse HDACi resistance. These results will not only further our understanding behind the treatment of T-cell lymphomas but also have powerful clinical applications to address the poor prognosis a T-cell lymphoma diagnosis carries.