Novel therapeutic inhibition of the Rac oncogene in pancreatic cancer

Mayo Clinic Rochester, Rochester MN

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Abstract

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a 5-year survival rate of only 5%. Current therapies have proven ineffective, making the identification of new drug targets essential. A recently identified cellular target is the oncogenic small GTPase Rac1, which is known to sustain cell growth and invasion. Interestingly, a guanine nucleotide exchange factor (GEF) and activator of the Rac oncogene, termed Vav1, is a member of a broad class of Rac GEFs that has recently been shown to be ectopically expressed in pancreatic cancers. Although Vav1 expression is normally restricted to hematopoietic cells, its expression in pancreatic cancer has been shown to correlate with increased mortality in patients and promote increased transformation in culture and tumorigenesis in mice. The drug azathioprine is a well-established anti-inflammatory agent that has recently been shown to inhibit Vav1-Rac activity in hematopoietic cells. Our preliminary data indicate that this drug also attenuates growth of pancreatic cancer cells and markedly prevents their invasive potential in culture. Therefore, the CENTRAL HYPOTHESIS of this proposal predicts that azathioprine targets ectopically expressed VAV1 in pancreatic cancers to reduce invasive properties in vitro and metastasis in vivo. The research proposed in this pilot study will define the drug-sensitive cellular processes in pancreatic cancer cells that support metastasis, such as cell proliferation, invasive matrix degradation, and cell migration, both in cell culture (SA#1) and in nude mouse models (SA#2). The ectopic expression of this protein in a majority of pancreatic tumors makes this therapeutic approach particularly attractive. The information gathered from this proposal will provide the basis of an exciting, important, and novel pre-clinical trial toward treating this lethal disease.