65IN - mTOR inhibitors and beyond: Targeting a critical pathway

Date 30 September 2012
Event ESMO Congress 2012
Session Molecular targets in malignant lymphomas: From basic science to clinical practice
Topics Anti-Cancer Agents & Biologic Therapy
Lymphomas
Presenter Martin Dreyling
Authors M.H. Dreyling
  • Dept. Of Medicine Iii, University of Munich, 81377 - Munich/DE

Abstract

Upregulation of the PI3K/AKT/mTOR signal pathway has been detected in numerous lymphoma subtypes including mantle cell lymphoma (MCL). Accordingly, the mTOR inhibitor Temsirolimus has been registered in EU based on a prospective randomized trial in 162 patients with relapsed MCL. In comparison to monochemotherapy, Temsirolimus achieved significantly higher response rates (22% vs 2%) and longer progression-free survival (4.8 vs. 1.9 months). Moreover, the efficacy of the mTOR inhibitor was confirmed not only in MCL, but also follicular and diffuse large B-cell lymphoma in numerous phase II studies. Based on in vitro studies current trials investigate the combination with chemotherapy. Thus, all 12 initial patients with relapsed MCL responded to a Bendamustin-Rituximab-Temsirolimus combination (BeRT). Recent research has confirmed the critical role of the B-cell receptor pathway upstream of mTOR in the molecular pathogenesis of malignant lymphoma. This pathway represents the physiological survival signal for maturating lymphocytes in the germinal center. Accordingly, small molecules attacking this pathway displayed high efficacy in various lymphoma subtypes even in monotherapy. Thus, a SYK inhibitor has been shown to be effective in patients with relapsed diffuse large cell lymphoma. Especially both, an inhibitor of the PI3K delta isoform (GS-1101, formally Cal-101) only expressed in lymphoid cells and the BTK inhibitor ibrutinib showed high efficacy in relapsed mantle cell lymphoma (response rate about 70%) as well as CLL (response rate between 70–90% in relapsed or previously untreated disease). In contrast, response rates were lower in follicular lymphoma presumely indicating the different survival signal of the constitutive BCL-2 overexpression in this lymphoma subtype. These data also confirm the crucial role of the micromilieu in lymphoid diseases which are hampered by the inhibition of the B-cell receptor pathway. Finally, recent in vitro data suggest some synergism of different members of the B-cell receptor pathway in combination with mTOR inhibition. Such molecular targeted strategies have therefore the potential to become part of the new treatment strategies in a broad spectrum of lymphoid neoplasias.

Disclosure

M.H. Dreyling: Pfizer (Temsirolimus): scientific advisory board, speaker's honoraria Janssen (Ibrutinib): scientific advisory board, support of IITs, speaker's honoraria