Project title: UCHL1 as a minimally invasive molecular indicator for gastroenteropancreatic neuroendocrine tumors

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Description

What critical problem/question will researchers try to answer?
In collaboration with Dr. J. Randolph Hecht, I will lead a project to test a novel, minimally invasive blood biomarker and therapeutic target for gastroenteropancreatic neuroendocrine tumors (NETs). The primary goal is to evaluate the utility of a protein hydrolase as a minimally invasive molecular indicator for carcinoid tumors of the gastrointestinal tract and pancreatic NETs. Additionally, the project aims to test the therapeutic efficacy of protein hydrolase inhibitors in treating gastroenteropancreatic NETs.

Why is this important?
The successful completion of this project could lead to the discovery of innovative strategies for screening, early detection, and potential prognostication of gastroenteropancreatic NETs. It may also result in the development of new treatments for patients with these tumors. Plasma protein hydrolase could serve as a minimally invasive biomarker to aid in therapeutic decision-making and monitoring treatment responses in patients with gastroenteropancreatic NETs.

What will the researchers do?
The study aims to identify a novel blood biomarker and therapeutic strategy for gastroenteropancreatic NETs. For the first time, the project will analyze protein hydrolase levels in a large cohort of patient-matched tissue and blood samples. Researchers will also test the therapeutic efficacy of protein hydrolase inhibitors in preclinical models of gastroenteropancreatic NETs. This study represents the first comprehensive evaluation of protein hydrolase as both a molecular indicator in tissue and blood and as a therapeutic target for gastroenteropancreatic NETs.

How might this improve treatment of neuroendocrine cancer?
This research could guide the development of novel, minimally invasive biomarkers and innovative treatments for patients with gastroenteropancreatic NETs. The proposed inhibitors may ultimately be used in clinical settings for patients with NETs. By testing the therapeutic potential of protein hydrolase inhibitors in preclinical models, this study establishes a critical translational link between research findings and patient care. The project holds the potential to significantly enhance detection, prognosis, and therapeutic options, ultimately improving outcomes and quality of life for patients suffering from gastroenteropancreatic NETs.

What is the next step?
The next step involves the development of a rapid, cost-effective, and minimally invasive test for the detection and prognostication of gastroenteropancreatic NETs. Additionally, the study will advance the testing of these novel therapeutic strategies for patients with gastroenteropancreatic NETs.

Outcomes:

Neuroendocrine tumors can arise from multiple sites throughout the body, including the gastrointestinal tract, pancreas, lungs, and other organs. Gastroenteropancreatic neuroendocrine tumors comprise neuroendocrine tumors of the gastrointestinal tract and pancreas. These tumors are often already disseminated to distant organs at the time of diagnosis, posing a major clinical challenge. Current neuroendocrine markers show substantial variability across individuals, often requiring the use of multiple markers for reliable diagnosis. This variability makes early detection difficult and limits treatment options.

Our research focuses on the deubiquitinating enzyme UCHL1, which plays a key role in maintaining the neuroendocrine state of cancer cells and promoting tumor growth. We found that UCHL1 levels are significantly higher in both tumor tissue and blood from patients with cancers showing neuroendocrine features. These findings highlight UCHL1 as both a biomarker to help identify and classify neuroendocrine tumors and a therapeutic target.

In preliminary studies, we identified UCHL1 protease as a promising marker and therapeutic target for gastroenteropancreatic neuroendocrine tumors and other neuroendocrine neoplasms. We hypothesized that UCHL1 represents a rational blood biomarker and therapeutic target for patients with gastroenteropancreatic neuroendocrine tumors. The proposed project is to test the utility of UCHL1 as a new tissue biomarker and blood-based biomarker for gastroenteropancreatic neuroendocrine tumors in a large cohort of patient samples. In addition, we proposed to test the therapeutic efficacy UCHL1 inhibitors for gastroenteropancreatic neuroendocrine tumors in pre-clinical models.

We first tested UCHL1 as a tissue marker for neuroendocrine tumors by examine UCHL1 expression in normal tissues, adenocarcinoma tissues, and neuroendocrine tumor tissues from gastroenteropancreatic using immunohistochemistry. We found that UCHL1 was overexpressed in about 84% of gastrointestinal and pancreatic neuroendocrine tumors we analyzed. Normal pancreas tissues showed non-detectable UCHL1 expression, adenocarcinomas displayed low to moderate levels, and neuroendocrine tumors showed the highest levels. These findings support UCHL1 as a specific marker enriched in neuroendocrine tumors and useful for diagnosis.

Early experiments using UCHL1 inhibitors suggest that blocking this protein can slow tumor growth, pointing to its potential as a new treatment strategy. We further evaluated the therapeutic potential of UCHL1 inhibition. We tested two UCHL1 inhibitors in neuroendocrine tumor cell lines, using a UCHL1-negative cell line as a negative control. Both inhibitors significantly reduced cell growth and proliferation of UCHL1-positive cell lines, suggesting that UCHL1 inhibition could be an effective therapeutic strategy for patients with neuroendocrine tumors.

Conclusion: Our progress provides strong support for the hypothesis that UCHL1 can serve both as a tissue marker for diagnosis and as a promising therapeutic target for neuroendocrine tumors, particularly those of the gastrointestinal tract and pancreas.

Our study suggests UCHL1 as a marker for neuroendocrine tumor detection and potentially prognostic marker of gastroenteropancreatic neuroendocrine tumors. Our study also provides UCHL1 inhibition as a new treatment option for patients with gastroenteropancreatic neuroendocrine tumors. Plasma UCHL1 may also be used as a blood biomarker to assist with therapeutic decision-making and monitoring treatment responses in patients with gastroenteropancreatic neuroendocrine tumors. Our study may ultimately have a positive impact on the outcome and quality of life of patients with gastroenteropancreatic neuroendocrine tumors.

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