All the above strategies leading to the discovery of new biomarkers, are validated in specifically designed tissue microarrays using immuno-histochemistry in FFPE samples from radical prostatectomies.

Prostate cancer (PC) is the second leading cause of death for cancer in men of the western Countries. While considerable advances have been made in the treatment of localized, organ-confined tumors, metastatic PC is virtually incurable and most deaths from this disease are due to the high resistance of metastasis to conventional therapies (androgen-depletion-therapy, ADT). Therefore, more precise markers for the detection of the incipient resistant tumor and more effective targets that eliminate the resistant clones are needed.

A principal aim is to identify relevant molecular pathways specifically active in aggressive prostate cancer, useful for an early detection of ADT resistant tumors and for treatment strategies.

In our studies, we have discovered the human Prostate Tumor OVerexpressed-1 (PTOV1) gene, later called Acid-2, and a second gene with a PTOV module, PTOV2, later called MED25, a component of Mediator (1-2).

The detection of PTOV1 in high-grade PIN (HGPIN) premalignant lesions is helpful to identify patients with higher probability to develop PC (3). PTOV1 ectopic expression promotes proliferation, invasion and metastasis of ADT resistant cells (1,2,4,5). PTOV1 induces the epithelial-mesenchymal-transition (EMT) and increased metastasis of PC3 cells (4). Mechanistically, PTOV1 is implicated in multiple processes controlling cell fate: it promotes mRNA translation leading to a specific increased synthesis of c-Jun and Snai1 oncogenes (4), and it is a transcriptional repressor of HES1 and HEY1 genes, leading to inhibition of Notch signalling in metastatic PC (5). PTOV1 significantly affect the self-renewal potential of the cancer stem cell populations of PC3 cells (5).  

Current objectives of our line of research are: (i) Determine the role of PTOV1 in the resistance to ADT and chemotherapy (taxols). (ii) Characterize the sub-clonal cancer stem cell populations (CSC) present in metastatic primary tumors and the genes and factors responsible for the development of the resistance to ADT.

1) Benedit P, et al. Oncogene 2001;20:1455–1464.

2) Santamaria A, et al. Am J Pathol 2003;162:897–905.

3) Morote J, et al. Clin Cancer Res 2008:14:2617-2622.

4) Marqués N, et al. Oncogene 2014;33(9):1124-34.

5) Alaña L et al., Mol Cancer 2014;13:74.

Once the tumor metastasizes to bone, the metastatic disease become incurable and current therapies are palliative. Thus, to better understand the biology of PC bone metastasis and to investigate new therapeutic options it is crucial to develop new animal models.

We have established new experimental models of PC bone metastasis by inoculation (intratibial and intracardiac) of human PC cell lines in immunodeficient mice to make a suitable model for evaluating novel compounds as future therapeutic approaches. Extensive bone metastases were monitored by in vivo bioluminescence imaging. By applying different strategies we have described new molecular targets involved in the mechanisms of PC bone metastasis.

1) Garcia M, et al. BJU Int. 2014;113:E164-77.

2) Doll A, et al. Arch Esp Urol. 2013;66:463-74.

Prostate cancer (PC) is the second leading cause of death for cancer in men of the western Countries. While considerable advances have been made in the treatment of localized, organ-confined tumors, metastatic PC is virtually incurable and most deaths from this disease are due to the high resistance of metastasis to conventional therapies (androgen-depletion-therapy, ADT). Therefore, more precise markers for the detection of the incipient resistant tumor and more effective targets that eliminate the resistant clones are needed.

A principal aim is to identify relevant molecular pathways specifically active in aggressive prostate cancer, useful for an early detection of ADT resistant tumors and for treatment strategies.

In our studies, we have discovered the human Prostate Tumor OVerexpressed-1 (PTOV1) gene, later called Acid-2, and a second gene with a PTOV module, PTOV2, later called MED25, a component of Mediator (1-2).

The detection of PTOV1 in high-grade PIN (HGPIN) premalignant lesions is helpful to identify patients with higher probability to develop PC (3). PTOV1 ectopic expression promotes proliferation, invasion and metastasis of ADT resistant cells (1,2,4,5). PTOV1 induces the epithelial-mesenchymal-transition (EMT) and increased metastasis of PC3 cells (4). Mechanistically, PTOV1 is implicated in multiple processes controlling cell fate: it promotes mRNA translation leading to a specific increased synthesis of c-Jun and Snai1 oncogenes (4), and it is a transcriptional repressor of HES1 and HEY1 genes, leading to inhibition of Notch signalling in metastatic PC (5). PTOV1 significantly affect the self-renewal potential of the cancer stem cell populations of PC3 cells (5).  

Current objectives of our line of research are: (i) Determine the role of PTOV1 in the resistance to ADT and chemotherapy (taxols). (ii) Characterize the sub-clonal cancer stem cell populations (CSC) present in metastatic primary tumors and the genes and factors responsible for the development of the resistance to ADT.

1) Benedit P, et al. Oncogene 2001;20:1455–1464.

2) Santamaria A, et al. Am J Pathol 2003;162:897–905.

3) Morote J, et al. Clin Cancer Res 2008:14:2617-2622.

4) Marqués N, et al. Oncogene 2014;33(9):1124-34.

5) Alaña L et al., Mol Cancer 2014;13:74.