Unique Aspects of Pancreatic Cancer Proteins Could Lead to Early Detection and New Treatments

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Newswise – A large international collaboration led by researchers from Johns Hopkins Kimmel Cancer Center identified promising new targets for pancreatic cancer treatment and early diagnosis after examining various aspects of the genes and proteins of these tumors.

Their findings, published online September 16 in Cell, may offer hope to patients with this deadly disease.

“At present, 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,” says the head of the ‘study. Hui Zhang, Ph.D., director of the Mass Spectrometry Core Facility and professor of pathology at the Johns Hopkins University School of Medicine.

Despite decades of studies, pancreatic cancer has remained a grim diagnosis, says study co-author Ralph Hruban, MD, director of the Sol Goldman Pancreatic Cancer Research Center and professor of pathology in the Johns Hopkins University School of Medicine. Due to the absence of symptoms and the lack of reliable and effective screening and early detection methods, the vast majority of patients are diagnosed at a late stage when surgery is not possible, resulting in an extremely poor prognosis. . The five-year overall survival rate is less than 10%, Hruban says, and the median survival in patients with metastatic disease is less than 12 months.

Although many studies have examined the genes of pancreatic tumors and identified several mutations linked to this disease, adds Zhang, these mutations cannot be targeted by drug therapies. In addition, these tumors do not elicit a significant response from the immune system, so immunotherapies have not been widely effective.

In Search of New Ways to Fight Pancreatic Cancer, Hui Zhang, Ralph Hruban, Daniel W. Chan, Ph.D., Director of the Division of Clinical Chemistry and Professor of Pathology, Postdoctoral Fellow Liwei Cao, Ph.D. ., and collaborators from Johns Hopkins and other institutions around the world have taken a fresh look at pancreatic tumors from several different angles. They compared 140 tumor samples with 67 samples of normal adjacent pancreatic tissue from the same patients, and with nine pancreatic tissue samples from patients who did not have cancer. The team looked at the entire genome, DNA coding sequences, DNA modifications that turn certain genes on or off, messenger RNA molecules to which information in DNA is transferred, and micro-RNAs that regulate gene expression. They took into account the proteins produced in pancreatic cancer cells, including various modifications made to these proteins, such as the addition of phosphate groups or sugar molecules that can alter their function.

The team confirmed that pancreatic tumors 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 doubling of the abundance between pancreatic cancer cells and normal cells; nearly 5,000 sites in these proteins with increased phosphorylation abundance patterns; and over 1700 sites with an increase in attached carbohydrate, or glycosylation.

Several of these glycosylated proteins are secreted by pancreatic cancer cells, says Zhang, suggesting that they could potentially be captured in the blood for early diagnosis. Additionally, PAK1 and PAK2 – two specialized proteins, called kinases, which place phosphate groups on other proteins – which are deregulated in pancreatic cancer may offer previously unknown targets for treating this disease. There are several small molecule inhibitors targeting PAK1, offering a potential route to the treatment of pancreatic tumors, which are still under investigation. Other protein differences between cancer cells and normal tissue appear to be barriers that block the immune system from attacking, Zhang adds, suggesting new ways to improve the immune response to these tumors.

The abundance of data produced in this study could help find new ways to improve detection and treatment of pancreatic cancer in the distant future, adds Hruban. “This study is a starting point to answer research questions that could revolutionize pancreatic cancer care,” he says.

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.

This work was supported by grants U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA210986, and U01CA214 Protein Analysis of the National Cancer Institute Clinical Cancer Institute. Part of this research was funded by NIH grants P30CA008748 and P30ES017885, and by the Troper Wojcicki Foundation, the Rolfe Pancreatic Cancer Foundation, and the Evelyn Grollman Glick Scholar Award.


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