A large, international collaboration led by researchers from the Johns Hopkins Kimmel Cancer Center has identified promising new targets for pancreatic cancer treatment and early diagnosis after examining various aspects of these tumours’ genes and proteins.
“Right now, patients with pancreatic cancer have very few options, and the wealth of data produced by this study could lead to new ways to fight this disease,” said study leader Hui Zhang, Director of the Mass Spectrometry Core Facility and Professor of Pathology at the Johns Hopkins University School of Medicine.
Despite decades of study, find a treatment for pancreatic cancer has remained unsuccessful, explains study co-author Ralph Hruban, Director of the Sol Goldman Pancreatic Cancer Research Center and Professor of Pathology at the Johns Hopkins University School of Medicine. Because of its lack of symptoms and lack of reliable and effective methods for screening and early detection, the vast majority of patients are diagnosed at a late stage when surgery isn’t possible, leading to an extremely poor prognosis. The five-year overall survival rate is less than 10%, says Hruban, and the median survival in patients with metastatic disease is less than 12 months.
Zhang adds that although numerous studies have examined the genes of pancreatic tumours and identified several mutations linked to this disease, these mutations cannot be targeted with drug therapies. In addition, these tumours don’t attract a significant response from the immune system, so immunotherapies have not been broadly effective.
Searching for new ways to fight pancreatic cancer, researchers and collaborators from Johns Hopkins as well as other institutions around the globe took a new look at pancreatic tumours from several different angles. They compared 140 tumour samples with 67 samples of normal adjacent pancreatic tissue from the same patients, and with nine samples of pancreatic tissue from patients who did not have cancer.
The team looked at the whole genome, DNA coding sequences, modifications to DNA that turn certain genes on or off, messenger RNA molecules to which the information in the DNA is transferred, and micro RNAs that regulate gene expression. They took an accounting of proteins produced in pancreatic cancer cells, including various modifications to these proteins, such as adding phosphate groups or sugar molecules that can change their function.
The team confirmed that pancreatic tumours are more likely to have mutations in several genes identified in previous studies, including KRAS, TP53, CDKN2A and SMAD4. In addition, they identified 222 proteins with at least a two-fold increase in abundance between pancreatic cancerous cells and normal cells; nearly 5,000 sites in these proteins with increased phosphorylation abundance patterns; and more than 1,700 sites with an increase in attached carbohydrates, or glycosylation.
Several of these glycosylated proteins are secreted from pancreatic cancer cells, Zhang says, suggesting they could potentially be captured in the blood for early diagnosis. In addition, PAK1 and PAK2 — two specialised proteins, called kinases, that place phosphate groups onto other proteins — that are dysregulated in pancreatic cancer could offer previously unrecognized targets to treat this disease. There are several small molecule inhibitors targeting PAK1, offering a potential path toward treating pancreatic tumours, which are still under investigation. Other protein differences between the cancer cells and normal tissue appear to be roadblocks that stymie immune system attack, adds Zhang, suggesting new ways to improve immune response to these tumours.
Other Johns Hopkins researchers who contributed to this study include: Yingwei Hu, T. Mamie Lih, David J. Clark, Michael Schnaubelt, Lijun Chen, Rodrigo Vargas Eguez, Weiming Yang, Jianbo Pan, Hariharan Easwaran, Ludmila Danilova and Qing Kay Li.
Image credit: National Cancer Institute