June 13, 2024

Protein UCHL1 Identified as Potential Biomarker and Therapeutic Target for Aggressive Neuroendocrine Carcinomas

A team of investigators from UCLA Health Jonsson Comprehensive Cancer Center has discovered a protein called UCHL1 in highly aggressive neuroendocrine carcinomas and neuroblastoma. This protein has the potential to be used as a molecular biomarker for diagnosing these cancers and predicting and monitoring responses to therapy.

The researchers also found that using a UCHL1 inhibitor, either alone or in combination with chemotherapy, significantly delayed the growth and spread of neuroendocrine carcinomas and neuroblastoma in pre-clinical models.

These findings have been published in the journal Cell Reports Medicine.

Dr. Tanya Stoyanova, associate professor of molecular and medical pharmacology and urology at the David Geffen School of Medicine at UCLA and senior author of the study, stated, “Our study demonstrates the therapeutic potential of targeting UCHL1 and its utility as a detection tool in neuroendocrine carcinomas and neuroblastoma in pre-clinical models, creating a critical translational link between the study and the diagnosis and treatment of patients with these malignancies.”

The study also revealed the detailed mechanism of action of UCHL1 and its role in regulating protein stability and the nuclear import of proteins that regulate gene expression, according to Dr. Shiqin (Laura) Liu, first author and a postdoctoral fellow in Dr. Stoyanova’s laboratory.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, occur in cells that release hormones into the body and can develop in different organs like the prostate and lung. Although not the most common type of cancer in those organs, these cancers often have a poor prognosis and limited therapeutic options currently available. Current treatments include combinations of chemotherapy, radiation, and immunotherapy.

Neuroblastoma is a type of cancer most commonly found in young children, which develops from immature nerve cells. It primarily occurs in the adrenal glands but can also develop in nerve tissue along the spine, chest, abdomen, or pelvis. However, existing treatments only extend patients’ survival for a few months, underscoring the necessity for better therapeutic targets and minimally invasive diagnostic approaches for these malignancies.

To identify potential targets for neuroendocrine carcinomas and neuroblastoma, the researchers analyzed publicly available proteomics data and found UCHL1 to be one of the top druggable proteins. The team then examined UCHL1 levels in tissues from patients with various types of neuroendocrine carcinomas and discovered elevated levels of UCHL1 in neuroendocrine prostate cancer, lung carcinoid, small cell lung cancer, neuroblastoma, and other neuroendocrine neoplasms.

These findings suggest that UCHL1 could serve as a common target for drug development in neuroendocrine cancers due to its higher expression in these tumors compared to non-neuroendocrine tissues. The team subsequently tested the therapeutic potential of blocking UCHL1 in pre-clinical models of neuroendocrine carcinomas and neuroblastoma.

This research has the potential to inform the development of new minimally invasive blood-based tests for detecting and monitoring responses to therapies in patients with neuroendocrine carcinomas, including highly aggressive neuroendocrine prostate cancer and small cell lung cancer, as well as neuroblastoma. Additionally, these findings lay the groundwork for new clinical trials to investigate the inhibition of UCHL1 as a novel treatment approach that could help reduce deaths associated with these aggressive diseases.

The senior author of the study is Dr. Tanya Stoyanova, who is also a member of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Dr. Shiqin (Laura) Liu, a postdoctoral scholar in the Stoyanova laboratory, is the first author of the study. Other authors from UCLA include Michelle Shen, Dr. Alifiani Hartono, Christopher Massey, Chung Lee, and Dr. Arnold Chin.

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