Molecular-Based and Alternative Therapies for Pancreatic Cancer Looking Out of the Box

The current treatment options for pancreatic ductal adenocarcinoma fall exceedingly short of a cure, providing a sobering 5-year survival rate of only 5% for all patients, and the disease will be responsible for more than 37,000 deaths in the United States alone this year. These numbers continue to grow, and it was recently predicted that, within decades, pancreatic ductal adenocarcinoma will become the second most lethal cancer in this country. Beyond conventional oncologic-based therapies, researchers are working hard, albeit with increasingly limited federal support, to develop multiple novel therapeutic options focusing primarily on targeting specific, disrupted core signaling pathways within pancreatic cancer cells. In line with the history of medical oncology and medical paradigms, many pharmaceutical companies and large academic institutions have been focused on searching for compounds (biologic and chemicals) in an effort to find that unique magic bullet that will extend pancreatic cancer patients' lives (e.g., K-ras inhibitors). This magic bullet has been difficult to find in a haystack full of molecular pathways and mutated genes because the challenge is defined by identifying a therapeutic window that kills the tumor, yet spares the host. This therapeutic window has been hard to discover in the backdrop of the heterogeneous cell populations that make up a pancreatic tumor together with a heterogeneous patient population that has multiple, undefined tumor subtypes. Thus, to date, efforts have had limited success. Perhaps the best recent example of limited success is the discovery of the classic combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), extending life by only 4 months when compared with gemcitabine (note that this drug combination does not directly target one single pathway or pancreatic cancer subtype).