Abstract 2525: Modulation of src and STAT3 pathways with dasatinib in patients with metastatic pancreatic cancer

Abstract

Abstract BACKGROUND: Cancer of the pancreas is the fourth leading cause of cancer-related death in the United States with less than 5% living for more than 5 years. These dismal statistics reflect the early metastasis of cancer cells. Overexpression or activation of Src and STAT3 are commonly detected in pancreas cancer leading to increased cell proliferation and migration. Dasatinib is a broad spectrum ATP competitive inhibitor of protein tyrosine kinases including the SRC family of kinases. We conducted a pilot trial of single agent dasatinib in patients with metastatic pancreas cancer. METHODS: Patients with metastatic pancreatic cancer were enrolled and treated with dasatinib 70 mg twice per day. Due to the difficulty of obtaining serial biopsies on pancreas cancer patients correlative studies were performed on peripheral blood mononuclear cells as a surrogate. Peripheral blood mononuclear cells were collected at baseline, 6 hours after the first dose and at the beginning of the next cycle. Western blots were performed to evaluate Src and STAT3 protein levels. RESULTS: Seven patients were enrolled in the trial with two patients completing two cycles of chemotherapy. Two patients withdrew for toxicity with one patient having grade 4 diarrhea and grade 3 vomiting. The second patient withdraw for grade 3 fatigue and grade 2 diarrhea. Two patients completed 2 cycles and had minor grade 1-2 toxicities attributable to dasatinib but had progressive disease upon restaging. Three patients did not want to continue on study and were removed in the first cycle. Western blots performed on peripheral blood mononuclear cells showed a rapid decrease of phosphorylated STAT3 (p-STAT3) six hours after treatment in three patients but only one patient had a corresponding decrease in phosphorylated Src (p-Src). For two patients the p-STAT3 levels remained low after completion of the first cycle. These patients had an overall survival of 50 weeks and 61 weeks. The overall survival for the other patients ranged from 8-12 weeks. CONCLUSION: Because pancreatic cancer remains resistant to current therapies despite recent advances in the development of molecular targeted therapies, there is an urgency to understand these pathways. Our patient with a rapid decrease in p-STAT3 and p-Src six hours after treatment had an overall survival of 61 weeks which reflects the biology of the tumor but also suggests the importance of simultaneously inhibiting these pathways. Since STAT is a target of Janus kinase, additional studies evaluating JAK activity are being done. Future clinical trials combining molecular targeted therapies in addition to traditional cytotoxics are warranted as we strive to improve the survival of our patients with this deadly disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2525.