Researchers have used radioactive monoclonal antibodies to discover and eliminate a particularly deadly form of pancreatic cancer, combining diagnosis and treatment. This new approach kills two birds with one stone and could pave the way for earlier detection and more effective treatment of the disease. With an average five-year survival rate of less than 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. It is also difficult to detect with traditional imaging methods, including positron emission tomography (PET).

Now, researchers at Japan's Osaka University have developed a strategy that combines therapeutics and diagnostics - "therapeutics" - into a single integrated process to fight this deadly cancer.

The method developed by the researchers uses radioactive monoclonal antibodies (mAbs) to target the protein glypican-1 (GPC1), which is highly expressed in PDAC tumors. GPC1 is related to cancer cell proliferation, invasion and metastasis, and high expression of this protein is a poor prognostic factor for some cancers, including pancreatic cancer.

"We decided to target GPC1 because it is overexpressed in PDAC but only present at low levels in normal tissue," said Tadashi Watabe, first author of the study.

The researchers injected human pancreatic cancer cells into mice and allowed them to develop into a full-blown tumor. GPC1mAb labeled with radioactive zirconium (89Zr) was intravenously injected into xenograft mice, and its anti-tumor effect was observed.

"We monitored the internalization of 89Zr-GPC1 mAb by PET scans over 7 days," said Kazuya Kabayama, second author of the study. "The uptake of the mAb by the tumors was strong, suggesting that this method facilitates tumor visualization. We confirmed that this was mediated by its binding to GPC1, as xenograft models in which GPC1 expression was knocked out showed significantly less uptake."

With the tumor visualized, the researchers then administered GPC1mAb labeled with radioactive astatine (211At) as a targeted alpha therapy. Alpha therapies utilize mAbs or peptides to selectively deliver radioisotopes directly into cells. Radioactive isotopes undergo alpha decay, producing kinetic energy and causing irreparable damage to cells.

Delivery of 211At-GPC1mAb causes double-strand breaks in cancer cell DNA and significantly reduces tumor growth. The researchers observed that these antitumor effects disappeared when mAb internalization was blocked, whereas non-radiolabeled GPC1 mAb did not induce these effects.

"Both radiolabeled GPC1mAbs we studied showed good results in PDAC," Watabe said. "The 89Zr-GPC1mAb showed a high tumor uptake rate, while the 211At-GPC1mAb can be used for targeted alpha therapy to support the inhibition of PDAC tumor growth."

The researchers say their findings demonstrate the potential of using therapeutic approaches to treat PDAC, which may lead to earlier detection and more effective treatment in the future.

The study was published in the Journal of Nuclear Medicine.