Due to a perfect storm of contributing factors, pancreatic cancer is probably the most notoriously intractable of all cancer types, with a dismal prognosis and a dearth of effective treatment options. The history of drug development for this disease is littered with failures. There is an urgent need for new approaches, particularly since pancreatic cancer is expected to become the second leading cause of cancer-related mortality by 2030.1
A better understanding of the barriers to effective treatment of patients with pancreatic cancer is providing new inroads for discovery, and many experimental regimens have entered clinical testing (Table). The most advanced novel strategies include a drug that targets the unique microenvironment, agents aimed at aberrant DNA repair pathways, and approaches for attacking cancer stem cells.
Table. Selected Clinical Trials in Pancreatic Cancer
Meanwhile, researchers believe that identifying effective combinations that can be used to overcome the immunosuppressive nature of pancreatic cancers could be the key to unleashing the power of immunotherapy against this tumor type.
The prognosis for patients with pancreatic cancer, which presents as pancreatic ductal adenocarcinoma (PDA) in the majority of cases, has remained stubbornly dismal over the past several decades, with 5-year survival rates in the single digits.2,3
Due to a lack of early symptoms and no effective screening methods, more than half of all patients are diagnosed at an advanced stage of disease; their median survival is less than a year. Even among the minority of patients who are diagnosed at an early stage, and with resectable disease, median survival averages only about 2 years.4
Beyond the development of novel chemotherapies, which have had only a modest impact on survival, there have been few advancements in the past several decades. The lack of new drugs is not for want of trying. Although myriad targets have been tested, despite many successful phase II clinical trials, most have faltered at the phase III stage. The success rate of phase III clinical trials in pancreatic cancer is slightly more than 10%—and at least 6 were declared negative in the past year alone.5
Part of the challenge stems from the substantial molecular heterogeneity of this tumor type. The key driver mutations and core signaling pathways that have been identified through genome sequencing efforts are not readily druggable yet.6-8
A case in point is the KRAS
oncogene in which activating mutations are found in 75% to 95% of PDA tumor samples, driving constitutive activation of the protein and oncogenic activity through the RAS/RAF/MAPK pathway.9
Decades of efforts to target the KRAS protein in a variety of ways have proved fruitless, including attempts to block its association with the cell membrane through the use of farnesyltransferase inhibitors, which progressed as far as phase II trials. Nevertheless, aberrant KRAS
activity continues to present a tempting target, and the National Cancer Institute is spearheading a major effort to systematically explore RAS
The epidermal growth factor receptor (EGFR) inhibitor erlotinib (Tarceva) remains the only FDA-approved molecularly targeted therapy for PDA. The overexpression of EGFR in 40% to 70% of cases served as the rationale behind this high-profile target. Other EGFR inhibitors did not prove effective, and even erlotinib is not widely used.9
Another significant hurdle is the unique tumor microenvironment—the surrounding cells, tissues, and vasculature that can establish an oncogenic niche—of pancreatic cancers. The tumor cells are often surrounded by a massive growth of dense fibrous tissue known as the desmoplastic reaction. It is highly inflammatory in nature and characterized by changes in stromal cell proliferation and deposition of extracellular matrix (ECM) components.12,13
These features are thought to contribute to a highly chemoresistant microenvironment. In addition, they can present a physical barrier to anticancer drugs by creating high interstitial fluid pressure (IFP) in the tissues and preventing perfusion, diffusion, or convection of small molecules from the blood vessels.14
Hacking the Pressure
Although elevated fluid pressure in the tumor microenvironment was first described more than 60 years ago,15 researchers have just recently begun to unravel some of the molecular mechanisms responsible. In pancreatic cancer, there is one component in particular that seems to play a central role, and its discovery has yielded one of the most promising new treatment strategies.