Role of ATAD2 in Prostate Cancer Bone Metastasis

Objective and Rationale: Prostate cancer represents one of the main causes of cancer-related death in men. Most of these deaths are related to the capability of prostate tumors to metastasize, which means the spreading of tumor cells beyond the prostate to other tissues in the body. The common site of prostate tumor metastasis is bone, which can be very painful and, unfortunately, there is no cure for this condition. In order to find a specific an effective treatment, it is necessary to understand what leads to the prostate tumor to metastasize in bone. However, the study of prostate cancer bone metastasis has always represented a big challenge because it has been difficult to create models that allow us to understand what is really happening in the whole body during the natural course of this disease. Bone metastasis occurs during the final stages of prostate tumor evolution, so is it mandatory to understand the characteristics of the tumor cells themselves and the tumor environment that explain this outcome. Therefore, finding a reliable model of metastatic prostate cancer reproducing the disease characteristics since it arises (named tumor initiation), expands and spreads (named tumor progression), and is essential to understand how it appears and which are the main characters involved in its evolution in the context of the whole organism.

After massive efforts, our laboratory generated a mouse model that develops prostate cancer with substantial similarities to the human disease, since it metastasizes to bone as well as other relevant tissues. The study of this animal model and the comparison of this model with human patients led us to identify a group of 16 genes – named META-16 gene signature – that can anticipate the evolution of the disease. This signature is elevated in patients who are at risk to develop bone metastasis and is present in those patients with low possibilities to be cured despite receiving treatment.

This project will focus on one of the META-16 genes, named ATAD2, which is highly expressed in bone metastases of patients when compared with primary prostate tumors. Moreover, ATAD2 high expression has also been found in other tumors and was associated to an adverse outcome. Altogether, this evidence suggests that ATAD2 is important for the primary tumor to metastasize and for the malignant behavior of the disease. Therefore, I believe that ATAD2 is responsible for tumor progression towards bone metastasis, which means it could represent the 'Achilles heel' of this disease. With this project, I aim to (1) understand the mechanisms of action of ATAD2 and (2) its importance for prostate cancer bone metastasis—towards the ultimate goal of its validation as a new prognostic marker and therapeutic target for bone metastasis.

Applicability of the Research: My objectives are relevant for two of the four overarching challenges of the Prostate Cancer Research Program. They are 'design to elucidate ATAD2 role in bone metastasis,' which is directly related to the overarching challenge of 'defining the biology of lethal prostate cancer to reduce death.' As the near-term clinical applicability, these results will allow us to evaluate ATAD2 prognostic potential to predict the risk of patients with prostate cancer to develop bone metastases and to predict chances for success if receiving therapeutic treatment. Moreover, by identifying the leading mediators of bone metastasis, we expect that, in the long term, all of this information will position us one step closer to the development of treatments that improve outcomes for men with lethal prostate cancer.

Principal Investigator's Career Goals: From the very beginning of my career, I have been interested in the study of human cancer, with the ultimate goal of contributing with the design of more accurate and indolent diagnostic methods and effective therapies for patients. It is my desire to devote my career to the study of aggressive cancers because, despite collective efforts and considerable scientific advances in terms of diagnosis and treatment, cancer remains to be one of the main causes of death worldwide. This means that there is a lot of work to do towards the understanding, and therefore the defeating, of this extremely complex disease. Metastatic prostate cancer is the leading cause of cancer-related death in men; hence, it is my personal motivation to pursue a scientific career within the field of prostate tumor metastasis. Towards this goal, it is a great motivation joining Dr. Cory Abate-Shen's laboratory, since she is a renowned leader in prostate cancer research whose work has led to the discovery of new biomarkers for early detection, as well as advances in cancer prevention and treatment. Her countless contributions to the community reflect her capability not only to conduct research projects at the highest level but also to train the future generation of scientists. I am strongly convinced that, with my commitment, together with the support and qualified guidance of Dr. Abate-Shen, I will be able to accomplish all of the proposed aims and necessary training to build a solid scientific career as an independent investigator in the field of prostate cancer research.