MEPED as salvage therapy for relapsed/refractory Hodgkin's lymphoma incorporating edited non-oncogene addiction: mTOR as a bottleneck

Abstract

Rescue therapies of relapsed/refractory (r/r) Hodgkin's lymphoma (HL) in the third to sixth-line provide major, yet unresolved problems. The MEPED regimen includes nuclear receptor agonists such as pioglitazone and dexamethasone, which counterbalance HL homeostasis, HL stress response inhibitors, everolimus and COX-2 inhibitor, and a stress response inducer, low-dose metronomic treosulfan. CR (six of seven patients) and long-term cCR in patients receiving no consolidating allogeneic stem cell transplantation highlight MEPED as a potent salvage therapy in advanced refractory HL. MEPED edits everolimus activities in such a way that mTORC1 becomes a non-oncogene addiction bottleneck, hence determining long-term therapy outcome. The implications of the therapeutic paradigm shift toward editing of HL tissue, and particularly mTOR addiction, could prove to be profound for clinical practice, both in terms of outcome and treatment tolerability. The long-term results of MEPED treatment indicate the urgent evaluation of the schedule in a multicenter trial for r/r HL.

Keywords: Hodgkin’s lymphoma tissue editing; M-CRAC; anakoinosis; dexamethasone; mTOR; non-oncogene addiction; pioglitazone; relapsed/refractory Hodgkin’s lymphoma.

FIGURE 1

Hodgkin’s lymphoma (HL) tissue editing with MEPED: impact of target selection on patient performance status.

FIGURE 2

Communicatively integrating, counterregulating, and inhibiting non-oncogene addiction targets, while instigating HL stress response enables durable long-term responses in relapsed/refractory Hodgkin’s lymphoma (r/r HL).

FIGURE 3

Multiple cues of HL stress response modulate and activate mTOR, followed by mTOR-dependent regulation and activation of specific transcription factors, as well as receptor-triggered transcription factors targeted with the MEPED schedule.