Identification of p38β as a Therapeutic Target for the Treatment of Sézary Syndrome

Abstract

Cutaneous T-Cell Lymphomas (CTCL) represent a group of hematopoietic malignancies that home to the skin and have no known molecular basis for disease pathogenesis. Sézary syndrome (SS) is the leukemic variant of CTCL. Currently, CTCL is incurable, highlighting the need for new therapeutic modalities. We have previously observed that combined smallmolecule inhibition of protein kinase C (PKC) β and glycogen synthase kinase 3 (GSK3) causes synergistic apoptosis in CTCL cell lines and patient cells. Through microarray analysis of a SS cell line, we surveyed global gene expression following combined PKCβ-GSK3 treatment to elucidate therapeutic targets responsible for cell death. Clinically relevant targets were defined as genes differentially expressed in SS patients that were modulated by combination-drug treatment of SS cells. Gene set enrichment analysis uncovered candidate genes enriched for an immune cell signature, specifically the T-cell receptor and MAPK signaling pathways. Further analysis identified p38 as a potential therapeutic target that is over-expressed in SS patients and decreased by synergistic-inhibitor treatment. This target was verified through small-molecule inhibition of p38 leading to cell death in both SS cell lines and patient cells. These data establish p38 as a SS biomarker and potential therapeutic target for the treatment of CTCL.

Multi-Kinase Inhibitor with Anti-p38γ Activity in Cutaneous T-Cell Lymphoma

“…Given that we previously described a role for p38b in CTCL (Bliss-Moreau et al, 2015), we evaluated the role of other p38 isoforms in CTCL. To examine expression of the p38 isoforms in CTCL, we first analyzed a publicly available RNA sequencing database [phs000725] for Sézary Syndrome (SS) (Wang et al, 2015) and microarray databases (GSE17601, n ¼ 32 for SS; GSE12902, n ¼ 22 for mycosis fungoides) (Iqbal et al, 2010).…”

“…We recently showed enrichment of transcripts involved in the T-cell receptor (TCR) and mitogen-activated protein kinase (MAPK) pathways in CTCL and identified the MAPK p38b isoform as a potential therapeutic target for CTCL (Bliss-Moreau et al, 2015). That study prompted us to characterize the potential of other isoforms of p38 to be therapeutic targets in CTCL.…”

The Expression of IL-21 Is Promoted by MEKK4 in Malignant T Cells and Associated with Increased Progression Risk in Cutaneous T-Cell Lymphoma

“…These results suggest that there might be an association between IL-21 expression/signaling and disease progression. Notably, p38 and STAT3 activity were also shown to correlate with disease progression (Bliss-Moreau et al, 2015), thereby further highlighting the clinical relevance of our in vitro findings in malignant T-cell lines.…”

“…Yet, a downstream MAP kinase, p38, is constitutive active in this malignancy and associated with disease progression (Bliss-Moreau et al, 2015).…”

Sézary‐Syndrom: von ungelösten Fragen zu neuen Therapieansätzen

“…Interessanterweise ist TGFβ, ein Zytokin, das von den Treg selbst produziert wird, in der Lage, Fut7 zu induzieren. Dies geschieht über p38 , eine MAPK, die in SC konstitutiv überexprimiert wird .…”