VHIR scientists identify protein PTOV1 as responsible for the resistance to docetaxel in prostate cancer

A study led by Dr. Rosanna Paciucci, principal investigator of the Biomedical Research Group in Urology of the Vall d'Hebron Research Institute (VHIR), points to the PTOV1 protein as a potential new therapeutic target for patients with aggressive prostate cancer and open the door to personalized medicine. In Castration-Resistant Prostate Cancer (CRPC), the expression of this protein induces resistance to one of the drugs most commonly used in this type of cancer, the Docetaxel.

This medication is very used and effective in patients with castration-resistant tumours. However, in many cases, patients develop a very aggressive cancer that is resistant to this drug. Until now, the mechanism by which this resistance originates was not clear, but the group of Dr. Paciucci has identified in a work published in the magazine Oncotarget the protein PTOV1 as responsible for the activation of genes that give resistance to this drug and give an aggressive phenotype of this type of cancer cells.

VHIR scientists have observed that levels of the protein PTOV1 are especially high in cell lines derived from castration-resistant prostate cancer, as well as metastatic tumours. By contrast, non-metastatic tumour cells do present lower levels of PTOV1. Likewise, they have shown that this protein is necessary for the survival and proliferation of these cells.

To demonstrate the role of PTOV1 in the resistance to Docetaxel, they increased the levels of this protein in prostate cancer cells and analysed its response to medication. The group of Dr. Paciucci noted that an increase in the levels of PTOV1 protected cells from the toxicity of the drug. On the contrary, they observed no effect against a similar second generation drug, Cabazitaxel, which shows the specificity of PTOV1. Mechanistically, they determined that an increase of PTOV1 caused an increase in the levels of other proteins involved in the process, as for example ABCB1, a protein in the cell membrane that confers resistance to various drugs since it is responsible for of expelling foreign substances from the cell. "It is interesting to remark that ABCB1 expels more specifically Docetaxel, not Cabazitaxel, which directly links it with PTOV1 and Docetaxel-resistance," says Dr. Rosanna Paciucci.

In addition, they showed that the PTOV1 participation in the drug resistance is associated with the acquisition of the ability to auto-renewal of prostate cancer cells, i.e. to generate cells equal to it. This ability is typical of cancer stem cells, and has been suggested as the cause of relapse and metastasis.

Finally, the group discussed the levels of PTOV1 and other genes in in databases of tumours of patients who have never been treated. They observed higher levels of PTOV1 in those patients who had developed metastatic prostate cancer. In addition, the levels of this protein are correlated with levels of other proteins involved in the development of metastasis.

"One of the implications of the results of this study is that it takes us closer to personalized medicine." If the biopsy of a patient with aggressive prostate cancer or metastases present high levels of PTOV1, it is likely to develop resistance to Docetaxel, so this resistance can be prevented using another drug, Cabazitaxel-for example," concludes Dr. Paciucci.

The PTOV1 (Prostate-Tumour-Overexpressed-1) protein

PTOV1 (Prostate-Tumour-Overexpressed-1) was identified for the first time by this same group in 2001 and it is highly expressed in prostate cancer, to be confirmed as a marker for this type of cancer, presenting especially high levels in more aggressive tumours. It is also expressed in other cancers as for example in the breast, bladder, ovary, larynx and liver, in which is also marker of more aggressive tumours.

Castration-resistant prostate cancer (CRPC)

In Western countries, prostate cancer is the third leading cause of death by cancer, after lung and colon. The most common treatment is surgery, but in cases of patients with metastasis surgery is not indicated. These patients undergo a treatment of androgen suppression, very effective at the beginning. But it often develops to a castration-resistant prostate cancer (CRPC), which usually presents metastasis and continues to grow although the levels of testosterone in the body are very low. Chemotherapy is administered then, usually Docetaxel is given. However, many patients treated with this medication develop a very aggressive cancer resistant. Currently, a combined Docetaxel and androgen suppression therapy is administered from the first moment. And although this combination has better results, recently also has begun to see some cases of resistance. For this reason, it is interesting research into personalized medicine allowing to predict whether a given patient will generate resistance and which treatment is best suited in their case.