Molecular targeted approaches for treatment of pancreatic cancer

Abstract

Human pancreatic cancer remains a highly malignant disease with almost similar incidence and mortality despite extensive research. Many targeted therapies are under development. However, clinical investigation showed that single targeted therapies and most combined therapies were not able to improve the prognosis of this disease, even though some of these therapies had excellent anti-tumor effects in pre-clinical models. Cross-talk between cell proliferation signaling pathways may be an important phenomenon in pancreatic cancer, which may result in cancer cell survival even though some pathways are blocked by targeted therapy. Pancreatic cancer may possess different characteristics and targets in different stages of pathogenesis, maintenance and metastasis. Sensitivity to therapy may also vary for cancer cells at different stages. The unique pancreatic cancer structure with abundant stroma creates a tumor microenvironment with hypoxia and low blood perfusion rate, which prevents drug delivery to cancer cells. In this review, the most commonly investigated targeted therapies in pancreatic cancer treatment are discussed. However, how to combine these targeted therapies and/or combine them with chemotherapy to improve the survival rate of pancreatic cancer is still a challenge. Genomic and proteomic studies using pancreatic cancer samples obtained from either biopsy or surgery are recommended to individualize tumor characters and to perform drug sensitivity study in order to design a tailored therapy with minimal side effects. These studies may help to further investigate tumor pathogenesis, maintenance and metastasis to create cellular expression profiles at different stages. Integration of the information obtained needs to be performed from multiple levels and dimensions in order to develop a successful targeted therapy.

Fig. 1. Hedgehog signaling pathway

Hedgehog ligand receptor (Ptc) is a transmembrane protein. (A) When there is no binding of Hh ligand to Ptc, Ptc represses the downstream protein Smo. Smo represses the downstream Gli family. (B)When Hh ligand binds to Ptc, Ptc activates Smo, which subsequently activates Gli family and induces transcription of Hh targeted genes.

Fig. 2. Delivery of nab-paclitaxel to cancer cells from blood stream

Injected nab-paclitaxel drug binds to albumin receptor, gp 60, through its albumin molecules which are transported into endothelial cells. The drugs are then transported across cells through formation of caveolae and released into extracellular space. The drugs selectively bind to SPARC, which are expressed on the stromal cells in pancreatic cancer tissue.

Fig. 3. Inhibition of HSP70 expression is highly effective as a therapeutic strategy in an animal model of pancreatic cancer

(A) Inhibition of HSP70 expression by triptolide markedly reduced the growth of MIA PaCa-2 tumors in an orthotopic model of pancreatic cancer in nude mice. Triptolide was administered at a dose of 0.2 mg/kg/day for 60 days. Animals were sacrificed at the 60^th day and the tumor volumes in the triptolide group were compared with the control group (treated with vehicle alone). n=8 in each group, *=p<0.05. (B) Representative pictures of tumor tissue in the control and triptolide treatment group. (C) Table demonstrating reduced loco-regional spread in the triptolide treatment group. (p < 0.001, n = 8, χ² analysis) [167].

Fig. 4. T cell activation in immunosurveillance

(A) Tumor antigens are expressed by antigen-presenting cells (APCs). T cells are activated by the binding of expressed tumor antigens to T cell receptors. The activation requires the binding of CD80/CD86 from APCs to CD28 which is expressed on T cell surface. (B) CTLA-4 is a homolog of CD28 expressed on T cells. CTLA-4 can bind to CD80/CD86 with a high affinity. This binding prevents the activation of T cells even in the presence of tumor antigen on APCs. Blocking the binding between CTLA-4 and CD80/CD86 may resume T cell activation and enhance immunosurveillance.