Molecular targeted therapies for pancreatic cancer

Abstract

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.

Figure 1. EGFR and VEGFR activation

After EGF binds to its receptor, conformational changes induce the activity of the Tyrosine Kinase domain (TK). This signal is amplified through the PI3K and RAS pathways leading to proliferation of cancer cells and the transcription of signals that favor the aggressiveness, survival and invasiveness. Cetuximab and Matuzumab prevent the binding of EGFR to their ligands. Gefitinib and Erlotinib inhibit the activity of the Tyrosine Kinase Domain. When VEGF binds to its receptor it also induces the formation of a dimer that triggers the activity of the Tyrosine Kinase domain. Through the RAS pathway VEGF increases the proliferation of endothelial cells. Bevacizumab prevents the binding of VEGF to its receptor. Valatinib and Sorafenib are inhibitors of the TK domain of the VEGF receptor. Vandetanib inhibits the TK domain in both VEGF and EGF receptors.

Figure 2. Apoptosis induced by TRAIL

When TRAIL binds to Death Receptor 4 (DR4) or Death Receptor 5 (DR5), the Death Inducing Signal Complex is formed. This leads to apoptosis through the extrinsic or intrinsic pathway. Mapatumumab is an agonistic antibody that triggers apoptosis through DR4. TRA-8 and Lexatumumab are two agonistic anti-DR5 antibodies that also induce apoptosis in cancer cells.