Translation initiation is known to be a common downstream target of signal transduction pathways deregulated in cancer and initiated by mutated/overexpressed oncogenes and tumor suppressors. There is a growing body of evidence linking deregulated translation on the causal pathway to cancer. Therefore, it is reasonable to assume that the downstream translation step provides a major contribution to tumorgenesis induced by activated oncogenic pathways and that this oncogenic addiction may serve as an """"""""Achilles heel"""""""" in the treatment of malignancies. MCT-1, an oncogene involved in translational regulation has recently been shown by the Gartenhaus laboratory to be overexpressed in the vast majority of primary diffuse large B-cell lymphomas (DLBCL). Knocking down MCT-1 protein levels in DLBCL significantly reduced cell viability through an apoptotic mechanism, providing the first direct genetic evidence that interfering with MCT-1 function was able to induce apoptosis in lymphoma cells with high endogenous levels of MCT-1 protein. MCT-1 protein interacts with the cap complex, which recruits Density Regulated Protein (DENR) protein, containing an SUI1 domain. The recruitment of DENR has been shown to increase the translation initiation of a subset of mRNAs (translatome), containing a long and highly structured 5'UTR, typically found in cancer related messages. While there are no specific small molecule inhibitors that can directly inhibit MCT-1 at present, its activity has been shown to be regulated by MEK/ERK kinases. Previous work from our group has shown that MCT-1 physically associates with ERK and that disruption of this protein-protein interaction provides a novel targeted approach to treat DLBCL. Furthermore, inhibition of MEK/ERK blocks the phosphorylation and biological activity of MCT-1, further establishing the functional interaction between MCT-1 and the MEK/ERK pathway. Several strategies have been developed to suppress MEK/ERK, however few small-molecule MEK inhibitors have become clinically available. Moreover, this strategy has never been extensively evaluated in lymphoma. We currently have full access to a selective and potent 2nd generation small-molecule MEK inhibitor, AZD-6244. This presents a unique opportunity to target a translational regulatory protein critical to lymphomagenesis. The objective of this application is to investigate the importance of the MEK/ERK pathway and the associated interaction(s) with MCT-1 towards B-cell lymphomagenesis in vitro and in vivo tumor models. The central hypothesis of this proposal is that the MEK/ERK signaling plays a critical role in regulating the stability and activity of the MCT-1 protein in DLBCL and that interruption of MEK/ERK/MCT-1 function with a novel targeted MEK inhibitor will effectively repress the lymphoma phenotype. Furthermore, the molecular characterization of the genetic networks of DLBCL will help us to understand how perturbation of MEK/ERK/MCT-1 regulated genes contributes to lymphomagenesis. The rationale for the proposed research is that MCT-1 and the MEK/ERK pathway have been shown to be important survival pathways in lymphoma and that newer more potent small-molecule MEK inhibitors are now available. We have shown in preliminary experiments that the selective MEK inhibitor, AZD-6244, inhibited proliferation and induced dose-dependent apoptosis at nanomolar concentrations in DLBCL cell lines, primary cells, and in a human lymphoma xenograft model.
The American Cancer Society estimates that 66,120 persons were diagnosed with NHL in 2008, and 19,160 died from lymphoma. Lymphomas are increasing in incidence especially in the elderly, a major segment of our current VA population. Unfortunately, despite aggressive chemotherapy mortality is greater than 50% and is associated with significant toxicity. Our understanding of the fundamental processes for this malignancy is limited at present and impedes the rational development of targeted therapies, which can improve response rates while reducing toxicities. The MCT-1 oncogene was recently shown to be overexpressed in the vast majority of the most common lymphoma in adults, DLBCL. Identifying and targeting the kinases that specifically regulate MCT-1 function offers the hope of fewer side effects while improving clinical outcomes in our aging veteran population.