Molecular targeted therapies for pancreatic cancer.

BACKGROUND: Pancreatic cancer cells express different mutations that increase the aggressiveness and confer resistance to conventional chemotherapy and radiotherapy. Molecules that selectively bind and inhibit these mutations are effective in other solid tumors and are now emerging as a complementary therapy in pancreatic cancer. The objective of this review is to describe the effect of drugs that inhibit specific mutations present in pancreatic cancer with special emphasis on clinical trials. DATA SOURCES: We reviewed the English-language literature (MedLine) addressing the role of drugs that target mutations present in pancreatic cancer. Both preclinical and clinical studies were included. CONCLUSIONS: Preclinical evidence supports the combination of conventional approved therapies plus drugs that block epidermal growth factor receptor and vascular growth endothelial factor or induce apoptosis. However, most of the current clinical evidence is limited to small phase I trials evaluating the toxicity and safety of these regimens. The results of additional randomized trials that are still undergoing will clarify the role of these drugs in pancreatic cancer.

Brief overview of preclinical and clinical studies in the development of intraperitoneal radioimmunotherapy for ovarian cancer.

Due to the generally slow and incomplete transit of i.p. infused agents into the circulation, treating disease confined to the peritoneal cavity with chemotherapy, biologics, and/or radionuclides provides a pharmacologic advantage. A higher i.p. concentration can be achieved than could be tolerated by systemic administration. An advantage of i.p. versus i.v. administration for localization of radiolabeled antibodies to small peritoneal surface disease has been shown in animal model and human biopsy studies (1, 2). A recent phase III Gynecologic Oncology Group chemotherapy trial has confirmed a survival advantage for i.p. delivery among women undergoing initial therapy for advanced ovarian cancer (3). Although the therapy was more difficult to tolerate such that 60% of patients randomized to the i.p. arm did not complete the entire regimen, there was a 16-month survival advantage. I.p. radionuclide therapy has been used in treatment of ovarian cancer for more than three decades, but side effects have been problematic in non-tumor-targeted 32P therapy (4). Efforts to improve specificity have used a number of antigens expressed on ovarian cancer cells as targets for selective delivery of radionuclide-conjugates. Mouse models and cell culture have been prominent for preclinical study of agents and strategies in the development of i.p. targeted radionuclide therapy for ovarian cancer. Animal studies, which have directed clinical trials, have shown clear improvement in survival with various modifications including combination chemotherapy, pretargeting, and combination of antibodies over simply delivery of a radiolabeled antibody via i.p. route.