MAP Kinase Signaling in Lymphoma: A Novel Therapeutic Paradigm

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ABSTRACT Extensive preclinical data supports the relevance of the MAP kinase RAS/RAF/MEK/ERK signaling pathway in cancer biology and its potential as a therapeutic target in human cancers. We showed previously that inhibition of tumor MEK and ERK1/2 phosphorylation by 1st generation MEK and ERK pharmacologic inhibitors (or related shRNA knockouts) result in significant cell death in diffuse large B-cell lymphoma (DLBCL) tumor models. MCT-1, an oncogene, immediately downstream of MEK/ERK, is constitutively over expressed in the majority of primary DLBCLs (>95%) (by immunohistochemistry), as well as in all peripheral T-cell lymphoma cases (100%). Furthermore, MCT-1 has ben shown to induce cel proliferation and activate cell survival pathways, while previous work from our group and others has shown that the MCT-1 oncogene through its association with density-regulated protein interacts with the cap complex and modulates the translation of critical cancer-related mRNAs. We have strong preliminary data showing that the novel 2nd generation MEK small molecule inhibitor, AZD6244, downregulates pERK and key substrates such as MCT-1, c-MYC and MCL-1. Further, AZD6244 inhibited proliferation, decreased colony formation, and induced dose-dependent apoptosis at nanomolar (and clinically achievable) concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model. We have additional exciting new data showing that AZD6244 downregulates pERK and induces significant cell death in T-cell lymphoma cells. Several strategies have been developed to suppress MEK/ERK activity for the treatment of cancer; however, few small-molecule MEK/ERK inhibitors have become clinically available. Moreover, they have never been clinically studied in non-Hodgkin lymphoma (NHL). Over the period of nearly 18 months, CTEP reviewed, vetted, and ultimately approved/activated (December 2010) a clinical trial proposal using the novel small-molecule MEK inhibitor, AZD6244, for relapsed DLBCL. The central hypothesis of this multi-PI "team science" translational proposal is that interruption of the MAP kinase signaling pathway with novel MEK inhibitors alone, and moreover combined together rationally with other novel targeted agents, will effectively repress the NHL phenotype pre-clinically (in B-cell and T-cell NHL cells, in vivo NHL SCID xenografts, and tumor graft models) and result in a new therapeutic paradigm and efficacious therapy for NHL patients. Furthermore, the proposed research will investigate the molecular characterization of genetic networks including 'translational profiles' which will fundamentally advance our understanding of the biology of B-cell and T-cell lymphomagenesis.