Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

Abstract

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

“Sandwich” protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study

“…According to various studies, STAT3 mutations are the most commonly observed genetic alterations, followed by activating mutations in JAK3. In the treatment of ENKTL, there are multiple inhibitors available that target the JAK/STAT pathway [ 15 ]. The selective JAK3 inhibitor has recently been demonstrated to have a potent anti-tumor activity in pre-clinical study.…”

“…The positive rate of PD-L1 was reported to be 39–100% in ENKTL tissues [ 16 ]. Anti-PD-1 antibodies (pembrolizumab, nivolumab, sintilimab, tislelizumab, and avelumab) have been studied in small cohorts of relapsed or refractory ENKTL, and have shown promising results [ 15 , 45 – 47 ]. The 2018 National Comprehensive Cancer Network (NCCN) guidelines recommend pembrolizumab and nivolumab for relapsed/refractory ENKTL [ 17 , 48 , 49 ].…”

“…The 5-year overall survival (OS) rate for patients treated with these modalities has been approximately 50%. ENKTL patients with relapsed or refractory disease have dismal outcomes, with median survival of less than 12 months [ 14 , 15 ]. Currently, there is a lack of established standard first-line treatment for ENKTL, particularly in children, despite the conduct of numerous prospective studies exploring novel drugs and showing improved patient outcomes [ 16 , 17 ].…”

Epstein–Barr virus‐associated lymphomas decoded

“…Cell survival/proliferation pathways are frequently upregulated, including the JAK/STAT, NF-κB, RAS/MAPK and PDGFRa pathways. 118 As a rare entity, there are no prospective randomised trials to guide optimal management. Traditionally, treatment is intensive multiagent chemotherapy for advanced-stage disease and/or local radiation for limited-stage disease.…”

“…BIM , TET2 , ASNS , PRDM1 , MLL2/MLL3 and BCOR ) and altered gene expression ( EZH2 overexpression), have been identified in significant minorities of cases, with epigenetic modification being the most common pathogenic mechanism of disease, suggesting potential roles for hypomethylating agents and novel miRNA inhibitors. Cell survival/proliferation pathways are frequently upregulated, including the JAK/STAT , NF‐κB , RAS/MAPK and PDGFRa pathways 118 …”