Androgen receptor expression in mantle cell lymphoma: Potential novel therapeutic implications

Mantle cell lymphoma (MCL) affects approximately 4500 patients/year in the US and demonstrates a male to female ratio of approximately 4:1. While the pathobiology underlying this ratio is unknown, the hematopoietic system is characterized by sex-related differences in androgen receptor (AR) expression, leading us to hypothesize that the male-biased incidence of MCL may reflect sex-related differences in AR signaling during MCL lymphomagenesis. To explore the AR axis in MCL, we evaluated AR expression in MCL cell lines and human tumors, and tested the impact of androgen pathway inhibition on MCL proliferation. AR transcript levels ranged up to ~2⁶ fold higher in MCL lines vs non-MCL NHL lines (p = 0.006) and were correlated with expression of the canonical AR-regulated gene, prostate-specific antigen (PSA; r = 0.715, p = 0.001), consistent with functional AR activity. Patient-derived MCL samples demonstrated a range of AR expression. Treatment of four different MCL lines with the potent AR antagonist enzalutamide demonstrated suppression of proliferation across both male and female-derived cell lines. These data suggest androgen-axis blockade may represent a novel therapeutic modality in MCL. This novel treatment approach is currently under investigation in a phase II clinical trial of AR inhibition in patients with relapsed/refractory MCL.