A door opens to a new combined therapy to treat the most aggressive and resistant prostate cancers. This is one of the conclusions reached by researchers from the Institute of Biomedical Research of Bellvitge (IDIBELL), led by Dr. Álvaro Aytés. The work team, which has just published its latest results in Nature Communications, also includes researchers from the Catalan Institute of Oncology, Columbia University in New York and the University of Bern in Switzerland .
The study identified a new vulnerability to attack aggressive, metastatic prostate cancers that have become resistant to hormonal therapies available today. In particular, researchers have shown that these tumors generate increasing levels of the NSD2 protein as tumor progression progresses and the acquisition of resistance to therapies. In addition, they have been able to validate experimentally that these tumors, to continue growing and disseminating themselves, are dependent on this protein. For these reasons, NSD2 represents an emerging therapeutic target against which to direct new treatments.
To reach these results, researchers have used a series of transgenic mouse lines that carry prevalent mutations in prostate cancer patients. These mutations are only active in the cells of the prostate epithelium of mice, as in the vast majority of patients. Based on these models, once mice have developed cancer, cells have been isolated from both primary prostate tumors and metastases, and the gene expression patterns have been analyzed. Through the use of bioinformatics tools, researchers have identified no candidate to represent a vulnerability in such aggressive tumors. Thanks to this experimental approach, the factors that, differently, are present in malignization and metastasis have been identified.
NSD2 is a protein with enzymatic activity that introduces chemical modifications (in particular, methyl groups) to proteins that provide structural support to DNA strands, called histones. This process of chemical modification of DNA, or epigenetics, is often associated with control, temporal and in different tissues, of gene expression. Specifically, modifications in these histones produced by NSD2 action result in a relaxation in the levels of compaction of the DNA filaments (known as the chromatin name), triggering the activation of the expression of " a set of genes with tumorigenic potential.
One of the main hypotheses of the researchers that sign this study is that the activation of these genes as a result of the action of NSD2 is responsible for the resistance to chemotherapeutic treatments that are usually administered to patients of prostate cancer In this sense, the researchers work with molecules that can inhibit the function of NSD2 and, therefore, reduce the malignancy of prostate tumors in mice. Indeed, the study has shown that the pharmacological inhibition of NSD2 results in an increase in the survival of the experimental model, a decrease in metastasis and a reduction in tumor size.
Thanks to these results, the researchers conclude that the inhibition of NSD2 could lead to re-sensitizing prostate tumors that are resistant to common antiandrogenic treatments. This fact opens up a promising lead to the implementation of a combination therapy that would include the administration of an NSD2 inhibitory drug in conjunction with conventional anti-androgenic drugs.
provided by Bellvitge Biomedical Research Institute – IDIBELL.