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Immunohistochemistry of pancreas

Frederick National Laboratory (FNL) scientists, led by Stephan Stern, Ph.D., and their colleagues have created a novel imaging agent that, with further development, might detect deadly pancreatic cancer at its earliest, most-treatable stages and thereby improve the prognosis for patients.

Pancreatic cancer has a high mortality rate because it is usually diagnosed late, with few treatment options. The five-year survival rate is just 10 just percent. 

Immunohistochemistry of pancreas
Immunohistochemistry with anti-PEG antibodies in pancreas of 10-month-old KRAS mouse treated with targeted polyplex NPs shows PEG staining in the PanINs. Magnification 10X.

Stern’s collaborator, Jill Smith, M.D., of Georgetown University’s Department of Medicine, discovered a membrane receptor (abbreviated CCK-BR) that is rare in the normal human pancreas but over-expressed in pancreatic cancer cells and in microscopic precancerous lesions called pancreatic intraepithelial neoplasia (PanINs). PanINs are undetected  by computerized tomography (CT) scans, magnetic resonance imaging (MRI) and other standard methods of detection. 

Together, Stern, Smith, and their collaborators developed a florescent nanoparticle that attaches to the CCK-BR on PanIN, resulting in cellular accumulation of the fluorescent signal, thereby revealing precancerous PanINs. The scientists tested the nanoparticle in mice genetically engineered to develop pancreatic cancer and a control group of normal mice. Results were published in November in the journal Biomolecules.

The scientists used mice at ages ranging from four months, when PanIN lesions begin to develop, to 10 months, when PanIN lesions have typically become grade 3 or cancer. With imaging, the florescent nanoparticles were visible only in the genetically engineered mice with PanIN lesions, and not in the normal group. In addition, the fluorescent signal was present only in mice treated with the CCK-BR target-specific nanoparticles, and not the untargeted control nanoparticles. The targeted nanoparticles accumulated only in the pancreas and not in other organs. These results demonstrate a proof-of-principle for the technology.

“The long-term goal would be to develop this imaging tool for screening human subjects at high risk for pancreatic cancer to enable early cancer detection,” the scientists reported.

Screening for pancreatic cancer typically involves high-risk individuals with a family history of the disease. Doctors use endoscopic ultrasound and MRI to monitor pancreatic cysts. But Stern’s group notes that most pancreatic cancers develop not from cysts but from PanIN cells that ultrasound and MRI cannot detect.

The experimental nanoparticles have another benefit. They can also carry anti-cancer agents, such as oligonucleotide therapeutics. So, in addition to imaging the precancerous cells, the nanoparticles could also target PanIN lesions for destruction. The researchers likened this to colon cancer screening, which looks for precancerous polyps that can be removed to stop the cancer before it starts.

Other members of the research group include Siva Sai Krishna Dasa, Ph.D. of FNL’s Nanotechnology Characterization Laboratory, Hong Cao, Ph.D. of Georgetown University Department of Medicine, and Elijah Edmondson, D.V.M., Ph.D. of FNL’s Molecular Histopathology Laboratory

Georgetown University has filed a patent application for the technology, jointly owned with the National Institutes of Health, naming Jill Smith and Stephan Stern as co-inventors.