INNOVATIVE TREATMENTS FOR PANCREATIC CANCER

Abstract

Pancreatic cancer is the fifth leading cause of cancer-related death in the United States.⁴⁶ The prognosis for pancreatic cancer patients is consistently poor because of inadequate methods for early detection. At diagnosis, nearly 50% of patients have metastatic disease with less than 10% presenting with resectable, local disease.¹³³ The overall 5-year survival for all stages combined is less than 4%. The overall median survival is less than 20 months and may be less than 10 months in patients with locally advanced disease and less than 6 months when metastatic disease is present.¹¹⁵ Despite continued efforts to optimize conventional treatment regimens, most patients with pancreatic cancer experience local recurrence or metastatic spread. Thus, new therapeutic approaches are needed to improve the outcome of patients with pancreatic cancer.

Progress in basic immunology and molecular biology has led to significant advances in our understanding of the mechanisms involved in tumor growth and progression. These advances have resulted in the development of several novel strategies for treating pancreatic cancer. This article focuses on three areas of active investigation: (1) immunotherapy, (2) gene therapy, and (3) antiangiogenesis treatment of pancreatic cancer.

The identification of tumor antigens expressed by pancreatic carcinoma cells has renewed interest in the development of immunotherapy as a treatment modality. The goal of most immunotherapeutic approaches is to generate systemic antitumor immune responses against viable pancreatic tumor cells. This has been achieved using both nonspecific techniques, such as powerful cytokines that promote general immune responses and tumor-specific methods, best exemplified by vaccines designed to target specific tumor antigens.

Gene therapy is the transfer of genetic material into host cells, generally performed to correct existing genetic mutations. Because multiple genes have been found harboring mutations in pancreatic tumor cells, gene replacement and correction has been suggested. Another way that gene therapy can be used is to confer increased susceptibility to chemotherapy agents by direct gene transfer into tumor cells. The recognition that tumor growth depends on developing a new blood supply has provided another system for therapeutic intervention in pancreatic cancer. The formation of new blood vessels feeding a tumor site is known as angiogenesis and is a necessary step in tumor growth and metastasis. The identification of the molecules involved in the regulation of this process has come under scrutiny as targets for preventing tumor growth and metastasis.

The sequencing of the human genome through the Human Genome Project^28a of the National Institutes of Health and the Department of Energy is one of the most important accomplishments in modern biology and will profoundly affect the diagnosis and treatment of human disease. Knowledge of the DNA sequence of all human genes coupled with improvements in genetic technology and bioinformatics will lead to an increasing number of molecular targets for cancer therapy. Although basic research is providing insights into new targets and strategies for cancer treatment, the application of these approaches depends on the conduct of well-controlled and well-designed clinical trials. The rapid translation of new treatment strategies into patients with pancreatic cancer is already under way and will be reviewed.