ReviewPancreatic cancer: Pathogenesis, prevention and treatment
Introduction
Pancreatic cancer is the fourth leading cause of cancer death in the United States with a median survival of < 6 months and a dismal 5-year survival rate of 4.6% (Jemal et al., 2006). Even for those patients diagnosed with local disease, the 5-year survival rate is only 16%. Approximately, 33,730 people are expected to develop pancreatic cancer, and 32,300 people will die from the disease in 2006 (Jemal et al., 2006). The lethal nature of pancreatic cancer stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. The presence of occult or clinical metastases at the time of diagnosis together with the lack of effective chemotherapies contributes to the high mortality in patients with pancreatic cancer. Pancreatic cancer is one of the most intrinsically drug-resistant tumors and the cancer cell resistance to chemotherapeutic agents is a major cause of treatment failure in pancreatic cancer. Therefore, there is a dire need for designing new and targeted therapeutic strategies that can overcome the drug-resistance and improve the clinical outcome for patients diagnosed with pancreatic cancer. For this purpose, the knowledge on the molecular pathogenesis of pancreatic cancer is very important and is likely to be helpful in the design of newer drugs and the molecular selection of existing drugs for targeted therapy against pancreatic cancer. The following sections will summarize what we know regarding the molecular pathogenesis of pancreatic cancer and how some of these molecular pathways could be exploited for the prevention and/or treatment of pancreatic cancer.
Section snippets
Molecular pathogenesis of pancreatic cancer
Intensive investigation of molecular pathogenesis will aid in identifying useful molecules for diagnosis, treatment, and prognosis of pancreatic cancer. In the past several years, considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological status. It has been found that multiple subsets of genes undergo genetic changes, either activation or inactivation, during the development and progression of pancreatic cancer
Prevention of pancreatic cancer progression by dietary chemopreventive agents
It has been estimated that more than two-thirds of human cancers could be prevented by modification of lifestyle including dietary modification. The dietary factors which are associated with increased risk of pancreatic cancer are meat, red meat in particular, and energy. Protection is mainly provided by fruit, vegetables, and vitamins. In recent years, more dietary compounds have been recognized as cancer chemopreventive agents because of their anti-carcinogenic activity. Therefore, early
Targeting EGFR pathway for enhancing cancer therapeutic efficacy
Two classes of EGFR inhibitors, monoclonal antibodies and small molecule tyrosine kinase inhibitors have been considered for the treatment of pancreatic cancer. Cetuximab, a monoclonal antibody targeting EGFR, binds to EGFR competitively with high affinity, preventing activation of EGFR by its ligands. By binding to EGFR, cetuximab inhibits cell proliferation, enhances apoptosis, and reduces angiogenesis and invasion (Marshall, 2006). Cetuximab is currently under investigation in pancreatic
Conclusion
The development and progression of pancreatic cancer are closely associated with the activation of oncogenes, the inactivation of tumor suppressor genes, the deregulation of EGFR, Akt, NF-κB, and their downstream signaling pathways. Therefore, novel and newer strategies targeting EGFR, NF-κB, COX-2, and Akt signaling pathways to interrupt their molecular cross talk (Fig. 1) could be promising for the prevention and/or treatment of pancreatic cancer.
Acknowledgments
The authors' work cited in this review was funded by grants from the National Cancer Institute, NIH (5R01CA083695, 5R01CA101870, and 5R01CA108535 awarded to FHS), a sub-contract award to FHS from the University of Texas MD Anderson Cancer Center through a SPORE grant (5P20-CA101936) on pancreatic cancer awarded to James Abbruzzese, and a grant from the Department of Defense (DOD Prostate Cancer Research Program DAMD17-03-1-0042 awarded to FHS).
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