Extensive preclinical data supports the relevance of the MAP kinase RAS/RAF/MEK/ERKsignaling pathway in cancer biology and its potential as a therapeutic target in human cancers. Weshowed previously that inhibition of tumor MEK and ERK1/2 phosphorylation by 1st generationMEK and ERK pharmacologic inhibitors (or related shRNA knockouts) result in significant cell deathin diffuse large B-cell lymphoma (DLBCL) tumor models. MCT-1, an oncogene, immediatelydownstream 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 survivalpathways, while previous work from our group and others has shown that the MCT-1 oncogenethrough its association with density-regulated protein interacts with the cap complex and modulatesthe translation of critical cancer-related mRNAs. We have strong preliminary data showing that the novel 2nd generation MEK small moleculeinhibitor, 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-dependentapoptosis 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 thatAZD6244 downregulates pERK and induces significant cell death in T-cell lymphoma cells. Severalstrategies 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, theyhave never been clinically studied in non-Hodgkin lymphoma (NHL). Over the period of nearly 18months, CTEP reviewed, vetted, and ultimately approved/activated (December 2010) a clinical trialproposal using the novel small-molecule MEK inhibitor, AZD6244, for relapsed DLBCL. The central hypothesis of this multi-PI 'team science' translational proposal is thatinterruption of the MAP kinase signaling pathway with novel MEK inhibitors alone, and moreovercombined together rationally with other novel targeted agents, will effectively repress the NHLphenotype pre-clinically (in B-cell and T-cell NHL cells, in vivo NHL SCID xenografts, and tumorgraft models) and result in a new therapeutic paradigm and efficacious therapy for NHL patients.Furthermore, the proposed research will investigate the molecular characterization of geneticnetworks including 'translational profiles' which will fundamentally advance our understanding of thebiology of B-cell and T-cell lymphomagenesis.

Public Health Relevance

The proposed work is innovative because it capitalizes on a novel and targeted means oftreating non-Hodgkin's lymphoma and it is our expectation that the resultant translational research willidentify a new therapeutic paradigm for patients with non-Hodgkin's lymphoma. These results will besignificant; because they are expected to provide a new; efficacious treatment for lymphoma. Inaddition; it is expected that the pre-clinical results generated from this project wil also fundamentallyadvance our understanding of the biology of B-cell and T-cell lymphomagenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Merritt, William D
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Tufts University
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Landon, Ari L; Muniandy, Parameswary A; Shetty, Amol C et al. (2014) MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL. Nat Commun 5:5413
Mazan-Mamczarz, Krystyna; Zhao, X Frank; Dai, Bojie et al. (2014) Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development. PLoS Genet 10:e1004105
Ravi, Dashnamoorthy; Bhalla, Savita; Gartenhaus, Ronald B et al. (2014) The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models. Clin Cancer Res 20:6023-33
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Mazan-Mamczarz, Krystyna; Gartenhaus, Ronald B (2013) Role of microRNA deregulation in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). Leuk Res 37:1420-8