Pancreatic cancer is the fifth most common cause of cancer death in the U.S. The majority of patients present with incurable disease, and of those that are candidates for surgical resection by pancreaticoduodenectomy, few survive five-years. The broad objective of this proposal is to foster interactions between basic science laboratories and clinicians at the Johns Hopkins Hospital, focusing upon adenocarcinoma of the pancreas. Specifically this proposal plans to 1) enroll patients with pancreatic cancer in new therapeutic trials, stratifying for successful tumor resection versus unresectable disease, and 2) perform correlative laboratory studies relevant to future clinical trials, using patient tumor specimens, and assessing the tumors for karyotypic analysis, DNA content, allelic deletion and ras mutation analysis. The new clinical trials will involve resectable and unresectable patients. Patients with resectable pancreatic cancer will be enrolled in a phase II study combining with 5-FU and leucovorin. Patients with unresectable pancreatic cancer will be enrolled in a phase II study using systemic chemotherapy with the new anti-tumor drug 773U82, which has just completed phase I testing. The objectives of these clinical studies will be to a) compare survival data in these to a recent historical control group (1987- 1990) at our institution, b) study the patterns of failure and causes of death, c) investigate the toxicities of these regimens, and d) correlate patient survival and patterns of failure with data obtained from preoperative tumor staging (CT, angiogram), pathologic tumor staging, and tumor genetics. The correlative laboratory studies will use tumor specimens obtained at surgical exploration. We plan to initiate an investigation of the genetics of pancreatic cancer, performing studies including a) tumor DNA content by absorption and flow cytometry, b) allelic loss patterns by allelic deletion analysis, c) ras mutations by PCR amplification and d) karyotyping. Correlations between the genetic data and the clinical outcome will be analyzed to determine if genetic alterations have prognostic implications in pancreatic cancer, as they appear to have in other tumors. Further, it is anticipated that information about the genetics of pancreatic cancer, such as types of mutations, possible carcinogenic mechanisms, and types of genetically altered metabolic pathways may lead to future therapeutic strategies.
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