Written By: Sakshi Thakare M.Pharm Pharmacology
Pancreatic ductal adenocarcinoma (PDAC) is broadly recognized as one of the most fatal forms of cancer, characterized by a low five-year survival rate. This poor prognosis is attributed to the fact that PDAC often remains asymptomatic until it reaches an advanced stage, where therapeutic interventions are not effective. The pancreas’s deep anatomical location and the complexity of early symptoms further delay timely diagnosis. Current diagnostic methods are limited in their sensitivity and specificity, particularly for early-stage detection, creating an urgent need for more effective screening methods.
In a landmark study published in Science Translational Medicine, Oregon Health & Science University (OHSU) scientists introduced a progressive diagnostic approach known as PAC-MANN, short for Protease Activity-based Assay using a Magnetic Nanosensor. Unlike traditional methods that rely on imaging or single biomarkers, PAC-MANN utilizes the enzymatic activity of proteases, which are unregulated in cancer cells, to identify the presence of PDAC with high precision.
Background
Current diagnostic tools for pancreatic cancer, such as Carbohydrate Antigen 19-9 (CA 19-9), are commonly used to monitor disease progression and predict prognosis. While CA 19-9 has proven valuable in later stages of the disease, it lacks the sensitivity and specificity needed for early-stage detection. As a result, most cases of pancreatic cancer are diagnosed only after the disease has progressed to the point where therapeutic options are limited and outcomes are poor.
The other methods, such as endoscopic ultrasound (EUS) or some liquid biopsy techniques, which can be invasive, time-consuming, and require large volumes of blood or specialized imaging equipment, the PAC-MANN assay introduces a more patient-friendly approach. One of the most important features of PAC-MANN is a minimal sample requirement of just 8 microliters of blood. The test operates using a simple fluorescence readout. This streamlined design allows the entire diagnostic process to be completed in approximately 45 minutes. Another added advantage of the PAC-MANN test is the cost per test, which is less than one cent, positioning PAC-MANN as a scientifically advanced tool and an economical innovation.
The Science behind PAC-MANN
Certain protease enzymes that break down proteins are often overactive in cancerous tissues, including those affected by pancreatic ductal adenocarcinoma (PDAC). These enzymes play a critical role in cancer progression by changing the tumor microenvironment, assisting in tumor invasion, and promoting metastasis. Recognizing this biological signature, PAC-MANN was designed to leverage the elevated protease activity as a biomarker for early cancer detection. PAC-MANN technology is based on a magnetic nanosensor system combined with a matrix metalloproteinase (MMP)-sensitive peptide probe.
MMPs are a class of zinc-dependent endopeptidase (proteases) enzymes with broad and potent biological activity. These enzymes are not only capable of degrading extracellular matrix (ECM) proteins, which facilitates tumor invasion and metastasis, but they also participate in the modulation of multiple signaling pathways critical to cancer progression. MMPs can process and activate or inactivate a variety of bioactive molecules, influencing key cellular behaviors. For example, MMPs are involved in the cleavage of cell surface receptors, the release of apoptotic ligands like FAS ligand, and the inactivation of chemokines and cytokines, all of which play crucial roles in tumor immune evasion and cellular communication within the tumor microenvironment.
MMP’s are commonly unregulated in PDAC. When a small blood sample is introduced into the assay, any active MMPs present cleave the peptide probe. This cleavage event triggers a fluorescent signal, which is detected by the nanosensor, serving as a direct and quantifiable indicator of MPP protease activity linked to malignancy.
Clinical Performance and Validation
In a blinded retrospective clinical study, the PAC-MANN assay showed impressive diagnostic performance for detecting pancreatic ductal adenocarcinoma (PDAC) across all disease stages. The test achieved a specificity of 98%, indicating a very low rate of false positives, and a sensitivity of 73%, reflecting its ability to correctly identify patients with PDAC. These results are particularly notable for detecting pancreatic cancer in its early, asymptomatic stages.
When PAC-MANN is used along with the CA 19-9 diagnostic test, it has shown synergistic performance. When combined, these assays achieved an 85% sensitivity and 96% specificity for stage I PDAC, the stage at which diagnosis and intervention have the highest potential to improve survival outcomes. This dual-biomarker approach enhances the diagnostic efficacy of early detection strategies. It also addresses the limitations of using CA 19-9 alone.
PAC-MANN has also shown promise as a tool for monitoring treatment response. In patients who underwent surgical resection of pancreatic tumors, a 16% decrease in protease activity was observed in postoperative blood samples. This suggests that the test could potentially be used to track residual disease activity or recurrence, providing valuable real-time feedback for clinicians managing post-treatment care.
These findings highlight PAC-MANN’s ability to serve as both a diagnostic and prognostic tool, offering a low-cost solution for tackling one of the most challenging cancers in oncology.
Implications for the Future
The introduction of PAC-MANN represents a significant advancement in the early detection of pancreatic cancer. Its high accuracy, rapid results, and low cost could transform screening practices, leading to earlier diagnoses and improved survival rates. Ongoing and future clinical trials aim to further validate the assay’s efficacy and explore its integration into routine clinical practice, especially for individuals at high risk of developing PDAC.
References
Montoya Mira, J. L., et al. (2025), Early detection of pancreatic cancer by a high-throughput protease-activated nanosensor assay, Science Translational Medicine, 17(785), eadq3110.
Stewart MR, Quentel A, Manalo E, Montoya Mira J, Ranganathan S, Branchaud BP, Fischer JM, Tu E, Civitci F, Chiu YJ, Yildirim A. Profiling protease cleavage patterns in plasma for pancreatic cancer detection. Sci Rep. 2024 Dec 30; 14(1):31809. doi: 10.1038/s41598-024-83077-0. PMID: 39738320; PMCID: PMC11686259.
Kunovsky L, Tesarikova P, Kala Z, Kroupa R, Kysela P, Dolina J, Trna J. The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer. Can J Gastroenterology Hepatol. 2018 Aug 14;2018:5389820. Doi: 10.1155/2018/5389820. PMID: 30186820; PMCID: PMC6112218.
Breakthrough Nanosensor Test Identifies Pancreatic Cancer Earlier, 18 March 2025, European Medical Journal, https://www.emjreviews.com/gastroenterology/news/breakthrough-nanosensor-test-identifies-pancreatic-cancer-earlier/
The article is extensively reviewed and fact-checked by the editorial team of pharmacally.com
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