Monoclonal antibodies in the treatment of pancreatic cancer

Abstract

Human pancreatic cancer is a malignant disease with almost equal incidence and mortality. Effective diagnostic and therapeutic strategies are still urgently needed to improve its survival rate. With advances in structural and functional genomics, recent work has focused on targeted molecular therapy using monoclonal antibodies. This review summarizes the target molecules on the tumor cell surface and normal tissue stroma, which are related to pancreatic cancer oncogenesis, tumor growth or resistance to chemotherapy, as well as molecules involved in regulating inflammation and host immunoresponses. Targeted molecules include cell-surface receptors, such as the EGF receptor, HER2, death receptor 5 and IGF-1 receptor. Effects of monoclonal antibodies against these target molecules alone or in combination with chemotherapy, small-molecule signal transduction inhibitors, or radiation therapy are also discussed. Also discussed are the use of toxin or radioisotope conjugates, and information relating to the use of these targeting agents in pancreatic cancer clinical trials. Although targeted molecular therapy with monoclonal antibodies has made some progress in pancreatic cancer treatment, especially in preclinical studies, its clinical application to improve the survival rate of pancreatic cancer patients requires further investigation.

Keywords: cancer therapy; immunotherapy; monoclonal antibody; pancreatic cancer.

Figure 1. Death receptor 5 activation pathway

Death receptor 5 is a member of the TNF-receptor superfamily. When the TRAIL (or TRA-8) binds to receptor, the receptor forms a homotrimer, which subsequently induces the death-inducing signaling complex formation. DISC includes FADD, caspase 8 and cIAP or FLIP. Apoptosis is induced by the activation of caspase 8/caspase 3 as well as activation of the intrinsic mitochondrial pathway. FADD: Fas-associated death domain protein; TRAIL: TNF-related apoptosis-inducing ligand.

Figure 2. T-cell activation in immunosurveillance

Tumor antigens may be recognized and expressed by antigen-presenting cells (APCs). (A) T cells are activated by the binding of expressed tumor antigen to T-cell receptor. This activation also requires the binding of CD80 or CD86 from APCs to CD28 on T cells. (B) CTLA-4, a homolog of CD28 expressed on T cells, can bind to CD80 or CD86 with a higher affinity. This binding prevents the activation of T cells despite the binding of tumor antigen to T-cell receptor. Blocking the binding between CTLA-4 with CD80 or CD86 with antibodies against CTLA-4 may promote T-cell activation and enhance immunosurveillance. CTLA: Cytotoxic T-lymphocyte antigen.