Novel Role of Ref-1 in Pancreatic Cancer Etiology and Progression

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DESCRIPTION (provided by applicant): The vast majority of people diagnosed with pancreatic cancer will undergo treatment that will ultimately fail or at best only extend their livs by ~6 - 10 weeks. Current standard-of-care consists of Gemcitabine with erlotinib, or surgery and radiation. Pancreatic tumors are especially resistant to therapy which is due at least in part to their hypoxic nature and fibrotic phenotype. Several molecular targets have been identified, however, investigation of the signaling pathways and molecular mechanisms that are major contributors to pancreatic tumor progression and its resistance to traditional therapies is lacking Thus, there is a critical need to identify novel targets in pancreatic cancer that offer the most promise for clinical utility against this dreaded disease. The long-term goal of this work is to understand the critical pathways for survival and metastasis of pancreatic ductal adenocarcinoma (PDAC) and develop a therapy that improves patient outcome by therapeutically modulating these critical pathways. The novel target, redox factor-1 (Ref-1), is a reduction-oxidation (redox) factor involved in the transcriptional regulation of gene expression. Transcriptional factors, HIF-1α, NFκB, and AP-1 are regulated by Ref-1 and are implicated in pancreatic tumor growth and the response to hypoxia. The objective of this work is to determine the outcome of inhibiting the function of Ref-1 in PDAC as well as in the tumor microenvironment. Our data indicates that inhibition of Ref-1 in an orthotopic model reduces the number of metastatic lesions and growth of patient-derived ectopic xenografts. Furthermore, blocking the redox activity of Ref-1, using a selective inhibitor or a redox-dead Ref-1 mutant, inhibits the proliferation, migration, & adhesion of PDAC cell lines, decreases the transcriptional activation of HIF-1, NFκB, and AP-1, and interferes with stromal-induced tumor proliferation. Based on these results, the central hypothesis is that the redox function of Ref-1 is a critical regulator of pancreatic tumor growth and metastasis; therefore, inhibiting its function will interfere with hypoxia signaling pathways and markedly block pancreatic cancer progression. To address this hypothesis, three aims are proposed. Aim 1:determine the biological effects of modulating Ref-1's redox activity in tumor cells and in stromal fibroblasts; Aims 2 & 3: utilize an orthotopic mouse model of pancreatic cancer (Aim 2) and a genetic mouse model of pancreatic cancer (Aim 3) to determine the efficacy of blocking the redox function of Ref-1 alone and in combination with Gemcitabine. Upon successful completion of this project, we will establish the effects of Ref-1 inhibition on the pancreatic tumor growth and metastasis as well as how Ref-1 modulation affects hypoxia signaling pathways and pancreatic cancer progression. This new knowledge is expected to result in a fresh strategy to knock out multiple survival mechanisms within the heterogeneous milieu of pancreatic tumors. Moreover, evaluation of the effects of Ref-1 inhibition on tumor growth and proliferation, apoptosis, metastasis, and response to hypoxia will comprise a thorough assessment of the potential for Ref-1 inhibition to yield new approaches to treat PDAC.