Pancreatic Cancer: a Challenge to Cure

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a challenging disease, as overall survival has not improved over the last several decades. The disease is characterized by late diagnosis, difficult major surgery in resectable patients, and a biologically chemoresistant tumor. Intense research in the field is ongoing to develop biomarkers for early detection and prognostication. Surgery is presently the crux of the management of PDA and has been standardized over the years with high-volume centers reporting <5 % operative mortality. The biggest problem is to overcome the inherent chemoresistance of the tumor that is densely fibrotic and hypoxic and has a tendency to invade surrounding neuronal plexuses. This review attempts to summarize in brief the reasons why PDA is difficult to treat, and provides a glimpse of the ongoing research in the field.

Keywords: Chemoresistance; Diagnosis; Pancreatic ductal adenocarcinoma; Surgery; Survival.

Fig. 1

Schema of the genetic evolution of pancreatic cancer. Tumorigenesis begins with an initiating mutation in a normal cell that confers a selective growth advantage. Successive waves of clonal expansion occur in association with the acquisition of additional mutations, corresponding to the progression model of pancreatic intraepithelial neoplasia (PanIN) and time T1. One founder cell within a PanIN lesion will seed the parental clone and hence initiate an infiltrating carcinoma (end of T1 and beginning of T2). Eventually, the cell that will give rise to the index lesion will appear (end of T2 and beginning of T3). Unfortunately, most patients are not diagnosed until well into time interval T3 when cells of these metastatic subclones have already escaped the pancreas and started to grow within distant organs. The average time for intervals T1, T2, and T3 for all seven patients is indicated in the parentheses at the left (reproduced with permission from [8])

Fig. 2

Diagrammatic representation of tumor microenvironment in PDA with new therapeutic targets. Ab antibody, CAF cancer-associated fibroblast, CTGF connective tissue growth factor, ECM extracellular matrix, GM-CSF granulocyte-macrophage colony-stimulating factor, PDA pancreatic ductal adenocarcinoma, PSC pancreatic stellate cell, SHH sonic hedgehog, nab-paclitaxel albumin-bound paclitaxel, ARB angiotensin II type 1 receptor blocker. Red arrows indicate the site of action. 1. PSC and CAF can be targeted by inhibition of SHH, CTGF, and ARBs. 2. ECM components lead to desmoplasia, creating barriers for drug delivery that can be circumvented by drug alteration and conjugation such as nab-paclitaxel and human recombinant PEGylated hyaluronidase (PEGPH20). 3. Tumor vessels are compressed by dense tumor stroma, resulting in a hypoxic environment; tumor vasculature can be targeted by SHH and gamma-secretase inhibitors. 4. Suppressor immune cells can be targeted by agonist CD40 antibodies or anti-GM-CSF antibodies. 5. Host immune response can be strengthened by cancer vaccines such as GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines [67]. 6. Selected ongoing and recently completed clinical trials are mentioned by National Clinical Trial (NCT) number, and details can be obtained online at http://clinicaltrials.gov/