Functional Identification of Master Regulators of Prostate Cancer Metastasis through Crispr/Cas9 Screening

Objective and rationale: New strategies for the treatment of advanced prostate cancer are urgently needed. When the tumor is confined to the prostate, the disease is now essentially curable. However, when it spreads to organs such as bone, liver, or lung, this process, called metastasis, accounts for more than 90% of prostate cancer deaths. Strikingly, however, very little is known about the genes that actually drive this process. We call these genes 'master regulators of metastasis,' and it is our goal to first identify them, and then to evaluate which of them can be blocked to prevent metastatic growth. In this way, my study will provide the rationale for designing new therapeutic drugs against the most deadly aspect of prostate cancer: metastasis.

Career goals, training and mentoring plan: I have a strong desire to pursue a career in prostate cancer research devoted to understanding the most profound aspects of this disease and how this knowledge may be effectively translated to harness new and better therapies that improve patient care. For my postdoctoral training, I have chosen the laboratory led by Cory Abate-Shen, a leader in mouse models of prostate cancer, who has studied this disease for more than 20 years and has ample experience in mentoring postdoctoral students. The laboratory is located at Columbia University Medical Center, one of the top universities in the country, has strong collaborations with other research groups, and is an ideal place for me to obtain the necessary training to launch my career in prostate cancer research. Our laboratory has recently developed two important and cutting-edge tools that will be instrumental for me to carry out this ambitious research proposal. First, the generation of specialized computer programs that enable the identification of the responsible genes of metastasis. Second, a unique mouse model that always produces metastases, something very important since the lack of suitable models with which to study metastasis has been one of the main reasons for its current lack of understanding. With these unique specialized resources of our laboratory, I am finally in a position to experimentally test which of these genes can be inhibited to prevent metastasis from occurring. Moreover, our computational analyses will guarantee that the knowledge gained in mouse models may be applied to human cancer.

Ultimate applicability: The identified 'master regulators of metastasis' will be excellent candidates for future studies to develop therapeutic strategies against them. This means that our studies will identify against which genes future drugs should be aimed to inhibit metastatic growth. Given that metastasis is the ultimate cause of death from prostate cancer, we expect these studies to contribute towards eradicating this deadly facet of the disease. Patients with aggressive disease that are expected to develop metastasis may benefit from future therapies directed against the genes discovered in this project and be spared from metastatic spread. Targeting some of these genes may also inhibit the growth of already established metastases. We will also study if the expression of these genes in localized tumors may predict the occurrence of metastasis, and in that case, this may lead to earlier identification of aggressive disease.

Contributions to advance prostate cancer research: We expect that specifically targeting the metastatic cascade will provide a fundamentally different therapeutic strategy than that of present-day therapies and therefore provide new tools to combat this deadly disease. We will also contribute to the knowledge of the genes that are responsible for metastasis, as well as the overall understanding of aggressive prostate cancer. Therefore, this project will provide much needed tools to improve therapeutic outcomes in prostate cancer.