Researchers have combined diagnostics and therapeutics, using radioactive monoclonal antibodies to find and destroy a particularly lethal form of pancreatic cancer. The one-two punch provided by the novel approach 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 most lethal forms of cancer. It’s also difficult to detect using conventional imaging methods, including positron emission tomography (PET) scans.
Now, researchers at Osaka University in Japan have developed a strategy for combatting this deadly cancer by combining therapeutics and diagnostics – ‘theranostics’ – into a single, integrated process.
The process developed by the researchers uses radioactive monoclonal antibodies (mAb) to target glypican-1 (GPC1), a protein highly expressed in PDAC tumors. GPC1 has been implicated in cancer cell proliferation, invasion, and metastasis, and high expression of the protein is a poor prognostic factor in some cancers, including pancreatic cancer.
“We decided to target GPC1 because it is overexpressed in PDAC but is only present in low levels in normal tissues,” said Tadashi Watabe, the study’s lead author.
The researchers injected human pancreatic cancer cells into mice, allowing them to develop into a full tumor. The xenograft mice were administered intravenous GPC1 mAb labeled with radioactive zirconium (89Zr) and observed for antitumor effects.
“We monitored 89Zr-GPC1 mAb internalization over seven days with PET scanning,” said Kazuya Kabayama, the study’s second author. “There was strong uptake of the mAb into the tumors, suggesting that this method could support tumor visualization. We confirmed that this was mediated by its binding to GPC1, as the xenograft model that had GPC1 expression knocked out showed significantly less uptake.”
With the tumor visualized, the researchers then administered GPC1 mAb labeled with radioactive astatine (211At) as a targeted alpha therapy. Alpha therapy uses mAb or peptides to selectively deliver radioisotopes directly to cells. The radioisotope undergoes alpha decay, delivering kinetic energy that causes irreparable cellular damage.
The delivery of 211At-GPC1 mAb caused DNA double-strand breaks in the cancer cells and significantly reduced tumor growth. The researchers observed that these antitumor effects were absent when mAb internalization was blocked and that non-radiolabeled GPC1 mAb did not induce these effects.
“Both radiolabeled versions of the GPC1 mAb we examined showed promising results in PDAC,” Watabe said. “89Zr-GPC1 mAb showed high tumoral uptake, while 211At-GPC1 mAb could be used for targeted alpha therapy to support suppression of PDAC tumor growth.”
The researchers say their findings demonstrate the potential for using a theranostics approach to treat PDAC which, in future, may lead to earlier detection and more effective treatment.
The study was published in The Journal of Nuclear Medicine.
Source: Osaka University
