Biotechnology

Researchers find potential therapeutic targets to prevent spread

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A new study led by Cláudia C. Faria, researcher in the lab of João Taborda Barata in Institute of Molecular Medicine João Lobo Antunes (iMM, Lisbon) and neurosurgeons in North Lisbon University Hospital Center (CHULN-Santa Maria Hospital, Lisbon), identified proteins present in brain metastases that could be potential therapeutic targets for limiting disease progression. The work, published today in a scientific journal Advances in Neuro-Oncology*, show that the presence of high levels of UBE2C protein in brain metastatic samples from patients with various types of cancer is associated with a poorer disease prognosis.

A new study led by Cláudia C. Faria, researcher in the lab of João Taborda Barata in Institute of Molecular Medicine João Lobo Antunes (iMM, Lisbon) and neurosurgeons in North Lisbon University Hospital Center (CHULN-Santa Maria Hospital, Lisbon), identified proteins present in brain metastases that could be potential therapeutic targets for limiting disease progression. The work, published today in a scientific journal Advances in Neuro-Oncology*, show that the presence of high levels of UBE2C protein in brain metastatic samples from patients with various types of cancer is associated with a poorer disease prognosis.

The researchers started by analyzing common gene expression in samples of brain metastases from 30 cancer patients from different organs. “We analyzed which genes were present at higher levels in brain metastases. Among the five most promising genes, we identified a gene derived from the UBE2C protein, a protein involved in the cell cycle. To confirm the clinical relevance of these findings, we analyzed a larger cohort of patients with brain metastases (89 patients with various types of cancer), and found that the presence of high levels of UBE2C was associated with a worse prognosis,” explained Cláudia C Faria, chair of the study. Using mice as a model, the researchers found that high levels of UBE2C increased the spread of tumor cells in the central nervous system, which can also occur in cancer patients, making the disease more aggressive and difficult to treat.

With the aim of finding therapeutic targets that can be used in the clinic, the research team is trying to identify compounds that are able to modulate UBE2C levels. “We tested 650 drugs that have been approved for patient use by the FDA (Food and Drug Administration, USA) or are used in phase 3 or 4 clinical trials, and identified small molecule inhibitors that lowered UBE2C levels and prevented the spread of tumor cells in the central nervous system, when given in the early stages of the disease,” added Eunice Paisana, PhD student at iMM, and first author of the study. “Our focus during this research has always been on contributing to the discovery of new therapeutic targets. In our team, we study biological samples from patients to generate knowledge that can contribute to future clinical practice,” added Eunice Paisana.

“In fact, brain metastases are a major cause of morbidity and mortality associated with cancer. The prognosis is very negative when tumor cells spread throughout the central nervous system, making the disease more aggressive and difficult to respond to current treatments. This is why it is urgent to develop new therapies,” added Cláudia C. Faria about the clinical relevance of this study.

In this work, the researchers found that the UBE2C protein is associated with the spread of cancer cells in the central nervous system, which is an indication of disease prognosis, and a potential therapeutic target to prevent brain metastases.

This work was developed at iMM in collaboration with the Department of Neurosurgery and Neuropathology Laboratory of the Santa Maria Hospital, Centro Hospitalar Universitário de Lisboa Norte (Portugal), Department of Anatomical Pathology Instituto Português de Oncologia Francisco Gentil (Portugal), German Cancer Consortium (DKTK, Germany) and the Department of Pediatric Oncology, Hematology and Clinical Immunology of the University of Düsseldorf Heinrich Heine and the University School of Medicine and Hospitals of Düsseldorf (Germany). This study was funded by the Portuguese Foundation for Science and Technology (FCT), the bcp Millennium Foundation and private funds.

*Paisana E, Cascão R, Custódia C, Qin N, Picard D, Pauck D, Carvalho T, Ruivo P, Barreto C, Doutel D, Cabeçadas J, Roque R, Pimentel J, Miguéns J, Remke M, Barata JT, Faria CC (2023) UBE2C promotes leptomeningeal spread and is a therapeutic target in brain metastatic disease. Advances in Neuro-oncology. DOI: 10.1093/noajnl/vdad048


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