Project Title: In vivo evaluation of Src kinase inhibition as adjuvant therapy following pancreatic cancer resection.
Research Aims: The aim of this proposal is to use a genetically engineered mouse model of human pancreatic cancer to determine if a new class of potential anti-cancer agents, inhibitors of Src kinase, can inhibit the development of metastases and improve survival following surgical removal of the primary tumour. In the clinic, the majority of patients who present with small localised tumours that can be removed surgically invariably develop recurrent disease, presumably due to the presence of micro-metastases at the time of diagnosis. Although chemotherapy can improve outcome in this situation, overall survival remains disappointing.
We have recently demonstrated that levels of Src kinase expression and activity are of prognostic relevance following resection of human pancreatic cancers and that dasatinib, an inhibitor of Src kinase, can inhibit pancreatic cancer cell invasion and migration. We have also shown, using a mouse model of invasive and metastatic pancreatic cancer that closely mimics the human disease, that Src activity is up-regulated during progression to an invasive pancreatic cancer, and that dasatinib inhibits the development of metastases, although mice succumb to the continued growth of the primary tumour.
In this proposal we will perform potentially curative surgical re-section of the primary tumour in mice, and determine if administration of dasatinib alone, or in combination with gemcitabine, can inhibit the development of metastases, and therefore reduce disease recurrence and improve relapse-free and overall survival. We anticipate that the results of these experiments could influence the design of the next Phase III clinical trial of adjuvant therapy in human patients who have undergone resection of primary pancreatic cancer.