Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

O’Donoghue, Anthony J.; Ivry, Sam L.; Chaudhury, Chaity; Hostetter, Daniel R.; Hanahan, Douglas; Craik, Charles S.

doi:10.1515/hsz-2016-0138

Cited by 11 publications

(5 citation statements)

References 57 publications

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“…At the P1 and P1′ positions, which flank the cleavage site, there was a predominant enrichment of hydrophobic amino acids with the aromatic residues tyrosine and tryptophan more favored at P1. This mirrors the previously reported substrate specificity of lysosomal aspartyl proteases (41,42). …”

Section: Resultssupporting

confidence: 91%

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts

Ivry

Sharib

Dominguez

et al. 2017

Clinical Cancer Research

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Purpose Pancreatic cysts are estimated to be present 2–3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts. Experimental Design We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid. Results We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. Immunohistochemical analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity. Conclusions Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions.

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Section: Resultssupporting

confidence: 91%

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts

Ivry

Sharib

Dominguez

et al. 2017

Clinical Cancer Research

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“…ELISA-based methods have provided an incomparable wealth of data about protein expression and are now a mainstay in research and clinical laboratories. However, immunoassays quantify the amount of protein present, which can be ambiguous when investigating enzyme markers as active (or activatable) enzymes are responsible for signaling cascades, metabolism, and phenotypical responses (57)(58)(59). There have been publications over the years examining protease cleavage, enzymatic redox reactions, and other activity measurements.…”

Section: Protease Activity As a Functional Biomarkermentioning

confidence: 99%

Addressing the unmet clinical need for low-volume assays in early diagnosis of pancreatic cancer

Sheik,

Byers,

Thomas

et al. 2023

Front. Gastroenterol.

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The incidental detection of pancreatic cysts, an opportunity for the early detection of pancreatic cancer, is increasing, owing to an aging population and improvements in imaging technology. The classification of pancreatic cystic precursors currently relies on imaging and cyst fluid evaluations, including cytology and protein and genomic analyses. However, there are persistent limitations that obstruct the accuracy and quality of information for clinicians, including the limited volume of the complex, often acellular, and proteinaceous milieu that comprises pancreatic cyst fluid. The constraints of currently available clinical assays lead clinicians to the subjective and inconsistent application of diagnostic tools, which can contribute to unnecessary surgery and missed pancreatic cancers. Herein, we describe the pathway toward pancreatic cyst classification and diagnosis, the volume requirements for several clinically available diagnostic tools, and some analytical and diagnostic limitations for each assay. We then discuss current and future work on novel markers and methods, and how to expand the utility of clinical pancreatic cyst fluid samples. Results of ongoing studies applying SERS as a detection mode suggest that 50 µL of pancreatic cyst fluid is more than sufficient to accurately rule out non-mucinous pancreatic cysts with no malignant potential from further evaluation. This process is expected to leave sufficient fluid to analyze a follow-up, rule-in panel of markers currently in development that can stratify grades of dysplasia in mucinous pancreatic cysts and improve clinical decision-making.

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“…In contrast to these results, O’Donoghue et al (2017) assessed the effect of ritonavir as a molecular inhibitor of cathepsin E (reported to be overexpressed in pancreatic cancer) on the tumor burden of PDAC mice. Although mouse PDAC tumors presented high levels of cathepsin E, ritonavir did not reduce the tumor burden in vivo [ 71 ]. However, no other effects of ritonavir in cancer cells were investigated in this study.…”

Section: Drug Repurposing Candidates For Pancreatic Cancer Treatmementioning

confidence: 99%

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

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Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

Cited by 11 publications

References 57 publications

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts

Addressing the unmet clinical need for low-volume assays in early diagnosis of pancreatic cancer

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

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