Novel therapeutic targets for pancreatic cancer

Abstract

Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16^INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.

Keywords: Pancreatic cancer, CTHRC1, RAC1, RalGEF-RAl, Notch Signaling, Nodal/Activin Signaling, NDRG1, Hypoxic condition, DR5, PAR2, HER3, IAP, Non-coding RNA, HDAC, BMI1, EZH2, Pancreatic cancer stem cell, Tumour microenvironment

Core tip: Some of the targets discussed here have been discovered to enhance the effectiveness of gemcitabine upon co-administration of the corresponding agents, for instance, hyaluronidase can deplete hyaluronan in stromal region to enhance gemcitabine delivery. Besides, some signaling molecules, e.g., RalGEF-RAl, Rac1, and PAR2 are being targeted to suppress metastasis. Tumour proliferation is limited upon DR5 activated apoptosis and others promising therapeutic areas like epigenetic modifiers; IAP, miR, lncRNA, and cancer stem cells-tumour microenvironment will also be discussed.