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Pancreatic cancer metastasis. More than 80% of pancreatic cancers have metastasized before they are found. Abdominal CT demonstrating pancreatic cancer (large red arrow) with metastasis to the liver (small red arrows). (Credit: JasonRobertYoungMD/Wikimedia)A new blood test identified pancreatic cancer with 100 percent accuracy in 250 of 250 patients, said a recent report in Nature.

The test found pancreatic exosomes in blood via the biomarker GPC1. It distinguished early-stage cancer from late-stage cancer—with zero false positives/negatives. It predicted survival. This matters. More than 80 percent of pancreatic cancers right now are diagnosed in stages too late for cure.

“This is an elegant, well-executed study that provides a ray of hope for early PDAC (pancreatic ductal adenocarcinoma) diagnosis, which is a holy grail for this treatment-recalcitrant cancer,” Murray Korc, M.D., told Drug Discovery & Development. Korc, head of the University of Indiana’s Pancreatic Cancer Signature Center, was uninvolved with the study. “It has been estimated that on the average it takes 20 years of tumor growth before PDAC can develop distant metastases. Therefore, a non-invasive, sensitive, and specific screening test for PDAC could be paradigm shifting…The study is of crucial importance.”

Andreas Friedl, M.D., chair of the University of Wisconsin Department of Pathology and Laboratory Medicine, told Drug Discovery & Development, “This study creates enthusiasm that early detection of pancreatic cancer, which is incurable unless removed during very early stages, might become a reality.” Friedl was also uninvolved with the study.

“Huge,” wrote Curie Institute exosome expert Clotilde Thery of the implications, if the results are repeated, in a Nature companion piece. She told Drug Discovery & Development hope may exist for breast cancer, as well.

Summarized senior author, and MD Anderson Cancer Center Cancer Biology Chair Kalluri, M.D., Ph.D., to Drug Discovery & Development: “We were quite surprised by the absoluteness of the results with pancreatic samples.”

The new biomarker

Exosomes are extracellular vesicles, containing nucleic acids and proteins, that are secreted by all cells into the blood, apparently as part of routine cellular housecleaning to shed excess proteins. It has not been possible to fish cancer-cell-specific exosomes out of blood.

But by using mass spectrometry, Kalluri’s team pulled it off. Finding that the cell surface proteoglycan GPC-1 (glypican-1) was enriched on cancer-cell-derived exosomes, GPC1 circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of both patients and mice with cancer.

GPC1 crExos were detected in the serum of pancreatic cancer patients “with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer,” the MD Anderson report stated. Levels of GPC1 crExos also correlated with both tumor burden and survival of both pre- and post-surgical patients.

Furthermore, the team found that GPC1 crExos from patients and mice with spontaneous pancreatic tumors possessed specific KRAS gene mutations, and reliably signaled the presence of pancreatic intraepithelial lesions in mice even though these did not appear on MRI (magnetic resonance imaging).“GPC1 crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy,” concluded the report.

Raghu Kalluri, M.D., Ph.D., MD Anderson Cancer Center ​Kalluri noted to Drug Discovery & Development his team looked at 250 pancreatic cancer patients, “some earlier stage, and some late stage. All were positive. A few with very early disease were also identified. They were found incidentally... We hope to add more cohorts of patients soon, and we also hope others will do it after the paper comes out.”

Korc, who has extensively studied GPC1, told Drug Discovery & Development that “GPC1 is a surface-anchored heparan sulfate proteoglycan that is known to be shed by pancreatic cancer cells. The current study documents its presence on the surface of PDAC-derived exosomes, and demonstrates the utility of the assay in mouse models and in humans. Thus, the findings are highly important.”

Friedl told Drug Discovery & Development: “This is an extremely interesting study that identifies GPC1 as a marker of cancer cell-derived exosomes. GPC1+ exosomes are detected in the bloodstream of mice and patients with pancreatic carcinomas. GPC1+ exosomes dramatically outperform existing tumor markers such as Ca-19-9 both in terms of sensitivity and specificity of cancer detection. In fact, in two cohorts of 190 and 56 pancreas carcinoma patients, GPC1 exosomes perfectly discriminate cancer from normal or non-malignant conditions. Importantly, elevation of GPC1+ exosomes was not limited to advanced cancers, but was even detected even in premalignant lesions.”

Other cancers

In her companion piece, Thery noted the marker may not work for other cancers, although breast cancer should be re-examined. She explained to Drug Discovery & Development that, “in the article itself, analysis of GPC1 in breast cancer patients did not allow clear discrimination of the patients from the healthy controls, because of very high variability among patients... For breast cancer, it would be interesting to analyze other cohorts of patients, with longitudinal follow up, and try to figure out if the GPC1-, GPC1+ or GPC1++ patients have different long-term survival or other clinical criteria.”

With regard to other cancers, she said, “I don't know if GPC1 is expressed or not.”

Kalluri agreed more work needs to be done on breast cancer samples. His team’s breast cancer patient cohort “was small. And there are many subtypes in breast cancer, so more studies have to be performed.”

Regarding other malignancies, Kalluri said his team “never tested any other cancer so how could we say it does not work for other cancers?” This will be studied, he said.

Korc, in turn, said: “We previously reported that GPC1 is also important in breast cancer, and others reported that in hepatocellular cancer GPC3, but not GPC1, is overexpressed. So, it could be useful in other cancers, but the case will need to be made for each cancer.”

Future questions

Other issues will need to be addressed. Beyond the fact that larger, earlier, and more expansive studies need to be done, an antibody to GCP1 will have to be generated for commercial testing.

Said Friedl: “Remaining questions for me include: ‘Can this study be validated independently in a larger set of patients and controls? Is GPC1 just a marker or does it have a function in exosome generation? Do GPC1+ exosomes perhaps drive tumor growth or progression? Could the concept be extended to liver cancer, where glypican-3 is elevated?’”

If it is found that GPC1-marked exosomes drive tumor growth, a way to block or destroy them will need to be found, as no such vehicle right now exists, said Korc.

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