“… the Fifth of November! “, so the old rhyme goes. And as every British schoolchild knows, this day marks the day that Guy Fawkes attempted to blow up the Houses of Parliament in 1605. For families of pancreatic cancer patients, November is the Pancreatic Cancer Awareness month, — a month filled with fundraising and awareness raising activities.
For my family, today marks my father’s birthday, and the day when my mother was diagnosed with pancreatic cancer 21 years ago. For me, it’s a time to reflect on how far we’ve come in our understanding of the disease, and how far we have to go.
The advent of the genomic era brought with it a slew of technologies that fundamentally changed our understanding of pancreatic cancer. Affymetrix GeneChips that let us identify genes that were differentially expressed in pancreatic cancer; Next Generation Sequencing, Whole Genome Sequencing, Whole Exome Sequencing and RNASeq that helped us see the mutational landscape of pancreatic cancer, and much more.
The first of these discoveries was the PanIN (Pancreatic Intraepithelial Neoplasia) model that describes the early neoplastic changes that occur in pancreatic cancer. These early lesions had been nearly 100 years earlier, and had been known by various names including ductal hyperplasia, hypertrophy, metaplasia and dysplasia, but a progressive model that described the underlying genetic changes had heretofore never been attempted. In 2000, Ralph Hruban of Johns Hopkins, outlined the histopathologic changes and identified mutations in KRAS, CDKN2A, TP53, and SMAD4 as drivers in this process in his paper entitled “Progression Model for Pancreatic Cancer”.
In a follow-up paper entitled “Update to Pancreatic Intraepithelial Neoplasia”, Hruban described how the progression model had been used to create genetically engineered mouse models, which are essential to helping researchers create and test new drugs. He also described how the model could be used for improved early diagnostics.
In 2002, Christine Iacobuzio-Donahue used Affymetrix GeneChips to identify differentially expressed genes in pancreatic cancer that might be used to help diagnose the disease. This paper, entitled “Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression Technology”, identified 97 differentially expressed genes that could potentially be used as biomarkers in future diagnostic tests.
This early research gave us some clues about the early progression of the disease and potential diagnostics, but we still didn’t have an appreciation for the genetic complexity of pancreatic cancer, until 2008, when Sian Jones of Johns Hopkins published a paper entitled “Core signaling pathways in human pancreatic cancers revealed by global genomic analyses” [Jones, et al]. The paper used a limited number of tumor samples (n=24) to identify an average of 63 modifications that occur during pancreatic cancer.
The genes identified in the paper fell into the following categories/pathways: KRAS signalling, TGFB signalling, JNK signalling, integrin signalling, Wnt/Notch signalling, hedgehog signalling, control of G1/S Phase transition, apoptosis, DNA damage control, small GTP-ase signalling, invasion, and cell-cell adhesion.
A subsequent paper, “Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer” [Yachida & Jones, et al] published in 2010, established a timeline for the progression of pancreatic cancer of over 20 years, thus providing us with a longer potential window of opportunity to diagnose and treat this disease.
And a follow-on paper, also by Yachida further established how alterations in KRAS, CDKN2A, TP53, and SMAD4 (the most commonly mutated genes in pancreatic cancer) can directly influence the patient outcomes. “Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors.” [Yachida et al]
Additional tools began to make their way into the lab and helped us gain a better understanding of the importance of epigenetic changes in driving pancreatic cancer. We were beginning to understand how a gene like CDKN2A could become inactivated in pancreatic cancer due to promoter hypermethylation. “Hypermethylation of multiple genes in pancreatic adenocarcinoma” [Ueki et al]
And beyond epigenetics, we were beginning to see the roles that microRNAs play in pancreatic cancer, acting sometimes as tumor suppressors, and inhibiting invasion and migration. These new potential drug targets also brought with them a whole new potential therapeutic class: oligonucleotides, stretches of man-made RNA that could bond to the microRNA and interfere with them in ways that small molecules could not. In addition, researchers began exploring how circulating microRNAs could be used as diagnostic tools in pancreatic cancer.
These new tools brought with them the promise of new diagnostics, and new therapies, and a deeper understanding of the disease necessary to begin to make progress. In the posts that follow, we’ll take a look at some of the new pathways that were discovered, the role of familial genetics and smoking in pancreatic cancer, and the promise of precision medicine and pancreatic subtypes. We’ll also take a closer look at the pipelines of drug companies both large and small, and what promises they hold for the pancreatic cancer patients of tomorrow.