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Promising novel therapeutic target for cancer identified

February 20, 2012 - London

After years of studying the molecular bases of glioblastoma - the most common brain tumour and one of the most aggressive of all cancers - scientists have identified a new therapeutic target for the fatal disease.

The group led by Dr. Joan Seoane , Director of Translational Research at the Vall d'Hebron Institute of Oncology (VHIO) and ICREA Research Professor identified USP15 as a critical protein in cancer which, thanks to its molecular characteristics, shows enormous therapeutic promise.

USP15 promotes tumor progression by activating the TGFa pathway. Playing a highly significant oncogenic role in glioblastoma, TGFa is a powerful immunosuppressant allowing the tumour to escape the host immune system.

It also acts as an angiogenic factor inducing blood vessels, promotes tumoral invasion, activates cancer stem cells, and in some tumors, induces metastases.

Dr. Seoane's team has unmasked the USP15 enzyme as activator of the TGFa chain reaction. In tumours the USP15- TGFa axis is deregulated due to USP15 gene amplification leading to an aberrant TGFa activation.

USP15 acts by controlling and correcting the TGFa activity in the same way that a thermostat regulates temperature. If the TGFa activity is high, it reduces; and if it is low, it increases the TGFa activity. USP15 therefore achieves optimal TGFa activity.

protein stability is regulated through the elimination or aggregation of ubiquitins, small proteins that establish which molecules need to be eliminated. This process is finely regulated by deubiquitinating enzymes (DUBs) such as USP15, which determine the correct level of a protein under certain physiological conditions.

In this orchestrated manner, USP15 controls and adapts the TGFa receptor stability and, therefore, the activity of the pathway.

The problem arises when, in some tumors, the USP15 gene is amplified due to genetic mutations and the enzyme is over produced.

The thermostat breaks down and is therefore only sensing the "cold" resulting in the overactivation of the TGFa pathway. Remarkably, this is not only a phenomenum of glioblastomas since the USP15 gene has also been found activated in other types of cancer such as breast or ovarian cancer.

Dr. Joan Seoane explained "When we inhibited USP15 in a real model of human glioblastoma, TGFa activity decreased and the tumor did not develop. USP15 regulates tumor progression and is critical in cancer."

Sometimes potentially powerful therapeutic targets are found but are not pharmacologically accessible due to their biochemical characteristics.

"Enzymes in general - particularly deubiquitinating enzymes (DUBs) such as USP15, can easily be deactivated and are therefore good therapeutic targets", Seoane commented.

"Our results, generated thanks to the funding received from the Spanish Association Against Cancer (AECC), show exciting new promise in improved treatment of cancer patients," he added.

The finding has been published in Nature Medicine.


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