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.

Identification of TAX2 peptide as a new unpredicted anti-cancer agent

“…Indeed, the relevance of targeting VEGFR signaling in pancreatic cancer has also been demonstrated [ 53 ]. An obvious approach for VEGF inhibition is to decrease the availability of ligand (VEGF), as demonstrated by bevacizumab, a humanized murine anti-human VEGF-A monoclonal antibody that has been used in the treatment of pancreatic cancer together with other chemotherapy agents [ 54 , 55 ]. In the MIA PaCa-2 xenograft model, our results show that TAX2 administrations led to higher inhibition rates compared to 5 mg/kg bevacizumab intraperitoneally injected twice weekly [ 56 ], suggesting that TAX2 peptide may be useful upon development of tumor resistance against bevacizumab and other conventional anti-angiogenic therapies.…”

Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma

“…This failure emphasizes likely heterogeneity in drug resistance mechanisms in PDAC and that these mechanisms are not of key importance in driving growth or drug sensitivity. An alternative explanation is that the extensive cross talk between redundant oncogenic pathways in this cancer allows pathway blockade to be easily circumvented [12] . Of these, cross talk between the mitogen-activated protein kinase pathway (MAPK) and the PI3K/Akt/mTOR (PAM) pathway appears particularly important clinically.…”

Curcumin Induces Pancreatic Adenocarcinoma Cell Death Via Reduction of the Inhibitors of Apoptosis

“…However, early diagnosis, a prerequisite for the surgery, is made difficult by the absence of early signs or symptoms (1-3). As a result, most patients are ineligible for the surgery at the time of diagnosis and are offered chemotherapy (2-4). The gold standard chemotherapeutic for pancreatic cancer is Gemcitabine, which has shown significant clinical benefits, with survival rates ranging from six to fifteen months when resection is not an option and the patients exhibit either non-metastatic or metastatic disease (5-8).…”