Cutaneous T-cell lymphoma (CTCL) is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as disease progresses. Mycosis fungoides and Sézary syndrome (MF/SS) are the most common subtypes of CTCL. Advanced MF/SS are life-threatening with few treatment options. We searched for new agents by high-throughput screening of selected targeted compounds and identified high value targets including phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases. To validate these hits from the screen, we developed patient-derived xenograft (PDX) mouse models that recapitulated the cardinal features of MF/SS and maintained histologic and molecular characteristics of their clinical counterparts. Importantly, we established a blood-based biomarker assay using tumor cell-free DNA to measure systemic tumor burden longitudinally in living mice during drug therapy. A PI3K inhibitor, BKM120, was tested in our PDX model leading to disease attenuation and prolonged survival. Isoform-specific siRNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed synergistic combination of PI3K-α/δ inhibitors with histone deacetylase (HDAC) inhibitors. The strong preclinical efficacy of this potent combination against multiple PDX models makes it an excellent candidate for further clinical development.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.