Investigators have found that the protein UCHL1 may be used as a molecular biomarker for diagnosing patients with highly aggressive neuroendocrine carcinomas and neuroblastoma and predicting and monitoring responses to therapy, according to a study published by Liu et al in Cell Reports Medicine. The recent findings indicate that the use of UCHL1 inhibitors, either alone or in combination with chemotherapy, may delay the growth and spread of these tumors in preclinical models.
Background
Neuroendocrine carcinomas—including neuroendocrine prostate cancer and small cell lung cancer—develop in cells that release hormones into the body and different organs such as the prostate and lungs. Although they are not the most common types of cancers in those organs, neuroendocrine carcinomas often have a poor prognosis and limited therapeutic options. Patients with these tumors are currently treated with combinations of chemotherapy, radiation, and immunotherapy.
Neuroblastoma is a type of cancer that most commonly occurs in pediatric patients and develops from immature nerve cells often occurring in the adrenal glands; however, neuroblastoma can also develop in nerve tissue along the spine, chest, abdomen, or pelvis. Depending on the stage and risk groups, typical treatments may extend patients’ survival for only a few months, representing the need for more effective therapeutic targets and minimally invasive approaches to diagnosing these malignancies.
Study Methods and Results
In this study, investigators analyzed publicly available proteomics data and identified the UCHL1 protein as a potential therapeutic target for neuroendocrine carcinomas and neuroblastoma.
The investigators then examined the presence of UCHL1 protein in tissue samples from patients with various types of neuroendocrine carcinomas and discovered elevated protein levels in neuroendocrine prostate cancer, lung carcinoid, small cell lung cancer, neuroblastoma, and other neuroendocrine neoplasms. They suggested the UCHL1 protein may be a common target for drug development based on its higher expression in neuroendocrine carcinomas compared with non–neuroendocrine tissues. The investigators further evaluated the therapeutic potential of blocking UCHL1 in preclinical models of neuroendocrine carcinomas and neuroblastoma.
Conclusions
“Our study demonstrates the therapeutic potential of targeting UCHL1 and its utility as a detection tool in neuroendocrine carcinomas and neuroblastoma in preclinical models creating a critical translational link between the study and the diagnosis and treatment of patients with these malignancies,” highlighted senior study author Tanya Stoyanova, PhD, Associate Professor of Molecular and Medical Pharmacology and Urology at the David Geffen School of Medicine and a member of the Health Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA).
“In addition, we also revealed a detailed mechanism of action of UCHL1 and its role in regulating protein stability and nuclear import of proteins that regulate gene expression,” underscored lead study author Shiqin Liu, MD, PhD, a postdoctoral fellow in Dr. Stoyanova’s laboratory at UCLA.
The investigators hope their new findings may help to guide the development of new minimally invasive blood-based tests to detect and monitor responses to therapies for patients with neuroendocrine carcinomas as well as neuroblastoma. The research may also lay the groundwork for new clinical trials testing UCHL1 inhibition as a new treatment approach to reduce the mortality rates associated with aggressive disease.
Disclosure: The research in this study was supported in part by the National Cancer Institute, the U.S. Department of Defense, and the UCLA Health Jonsson Comprehensive Cancer Center. For full disclosures of the study authors, visit cell.com.
