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Cutaneous T-Cell Lymphoma PDX Drug Screening Platform Identifies Cooperation between Inhibitions of PI3Kα/δ and HDAC
Chi-Heng Wu1, Chen-Yen Yang1, Linlin Wang2
1Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Abstract:
Cutaneous T-cell lymphoma is a form of non-Hodgkin lymphoma that manifests initially in the skin and disseminates systemically as the disease progresses. Mycosis fungoides and Sézary syndrome are the most common subtypes of cutaneous T-cell lymphoma. Advanced mycosis fungoides and Sézary syndrome 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 mouse models that recapitulated the cardinal features of mycosis fungoides and Sézary syndrome 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 patient-derived xenograft model leading to disease attenuation and prolonged survival. Isoform-specific small interfering RNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as required for tumor proliferation. Additional studies showed a synergistic combination of PI3K-α/δ inhibitors with histone deacetylase inhibitors. The strong preclinical efficacy of this potent combination against multiple patient-derived xenograft models makes it an excellent candidate for further clinical development.
Insights
New research identifies PI3K-δ as a key target for advanced cutaneous T-cell lymphoma. Combination therapies targeting PI3K and HDACs show strong preclinical efficacy, offering hope for improved treatment options.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides and Sézary syndrome, is a life-threatening non-Hodgkin lymphoma with limited treatment options for advanced stages.
- Identifying novel therapeutic targets is crucial for improving outcomes in advanced CTCL.
Purpose of the Study:
- To identify novel therapeutic targets for advanced cutaneous T-cell lymphoma (CTCL).
- To validate potential drug candidates using patient-derived xenograft (PDX) mouse models.
- To establish a blood-based biomarker assay for monitoring systemic tumor burden.
Main Methods:
- High-throughput screening identified phosphatidylinositol 3-kinase (PI3K) and cyclin-dependent kinases as potential targets.
- Patient-derived xenograft (PDX) mouse models were developed to mimic CTCL features.
- Tumor cell-free DNA was used to create a blood-based biomarker assay for longitudinal monitoring.
- PI3K inhibitors (BKM120) and isoform-specific PI3K inhibitors were tested in PDX models.
- Synergistic effects of PI3K inhibitors combined with histone deacetylase (HDAC) inhibitors were evaluated.
Main Results:
- PI3K-δ was identified as essential for tumor cell proliferation in CTCL models.
- Treatment with a PI3K inhibitor (BKM120) attenuated disease and prolonged survival in PDX models.
- A combination of PI3K-α/δ inhibitors with HDAC inhibitors demonstrated synergistic efficacy.
- The developed blood-based biomarker assay effectively measured systemic tumor burden in mice.
Conclusions:
- Targeting PI3K, particularly PI3K-δ, represents a promising therapeutic strategy for advanced CTCL.
- Combination therapy with PI3K and HDAC inhibitors shows significant preclinical efficacy.
- The PDX models and biomarker assay are valuable tools for future drug development in CTCL.
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