Targeting heat shock response pathways to treat pancreatic cancer

Pancreatic cancer belongs to the group of extremely aggressive human cancers; conventional cancer treatments have little impact. Increasing understanding of the pathways associated with pancreatic cancer progression has enabled the development of targeted therapy on this cancer. Heat shock proteins (HSPs) and related heat shock response (HSR) pathways control multiple important oncogenic pathways for pancreatic cancer development. Consequently, they represent promising novel targets for pancreatic cancer therapy. Various strategies have been proposed and elaborated to target HSPs/HSR in pancreatic cancer with the corresponding modulators, the details of which are highlighted in this review.

Introduction

Pancreatic cancer belongs to the most lethal and devastating human cancers owing to its poor diagnosis, lack of effective therapies and rapid development of drug resistance [1]. Although pancreatic cancer accounts for only 3% of all cancers, it is the leading cause of cancer death in Western countries. Conventional treatments have little impact on this disease. Surgical resection followed by adjuvant treatment with both chemotherapy and radiation offers the best possibility of curing pancreatic cancer for a small percentage of patients at early-stage disease, whereas chemotherapy based on gemcitabine remains the standard of care for the majority of patients with advanced pancreatic cancer that precludes surgery [1].

Gemcitabine is a nucleoside drug, which exerts its anticancer activity mainly by inhibiting DNA synthesis alongside other possible modes of action [2]. However, gemcitabine is only moderately effective for pancreatic cancer, yielding a mere 12% response rate, a median survival period of five months and a five-year survival rate as low as 3%. Attempts to increase the efficacy of gemcitabine by modulating pharmacokinetic parameters or using combined treatments with a second cytotoxic agent, such as cisplatin, oxaliplatin, 5-fluorouracil (5-FU) or capecitabine, have been largely unsuccessful [3]. Consequently, there is an urgent need to explore new drug candidates with novel modes of action to combat pancreatic cancer.

Over the past few decades, considerable research has focused on understanding the mechanisms behind pancreatic cancer pathogenesis and the related molecular cascades 4, 5. Targeted therapies aimed at the regulation of molecules in pancreatic carcinogenesis, the activation of tumor suppressor genes and the inactivation of oncogenes have been exploited for pancreatic cancer treatment and have brought about several therapeutic advances 4, 6. Several drugs have been elaborated to target these pathways, some of which have been advanced to clinical trials. However, the clinical results have been rather disappointing. Although gemcitabine combined with erlotinib resulted in a small but significant improvement, the outcome in patients was not related to the expected targeted pathway and requires further detailed clarification [7]. Therefore, the discovery of novel molecular targets and the development of multitarget strategies constitutes an emerging and challenging issue for pancreatic cancer treatment.

It is well known that the intrinsic resistance to cytotoxic and therapeutic agents contributes to the extremely aggressive nature of pancreatic cancer 1, 4, 8. Therefore, therapies targeting cellular pathways essential for drug resistance are considered to hold great promise for pancreatic cancer treatment. Research on different cancer forms over the past decade has revealed that heat shock proteins (HSPs), molecular chaperones with strong cytoprotective and antiapoptotic properties, have crucial roles in tumor progression and drug resistance 9, 10, 11, 12. However, the direct targeting of HSPs for pancreatic cancer treatment is still at the exploratory stage. Meanwhile, an ever increasing amount of evidence shows the enormous potential of targeting HSPs in pancreatic cancer treatment, the details of which will be highlighted below.