Identification and Validation of Master Regulators of Castration-Resistant Prostate Cancer

I am a dedicated scientist in cancer biology with the primary goal of establishing my own independent laboratory at an academic institution in order to conduct basic and translational research in prostate cancer to discover effective therapies and to enhance the well-being of men with this disease. This Prostate Cancer Research Program Postdoctoral Training Award will provide me a comprehensive training in cancer biology and systems biology. I will gain a better understanding of the cutting-edge technologies and key challenges in prostate cancer field and will expand this proposed work here to address my research interest in my future lab.

My training will primarily take place at Herbert Irving Comprehensive Cancer Center of Columbia University Medical Center, where I will collaborate with experienced cancer and systems biologists including Drs. Cory Abate-Shen and Andrea Califano to use the latest resources and technology to conduct research. I will also have the opportunities to attend local seminars as well as international conferences to present my work and exchange ideas with other attendees. My mentor, Dr. Michael Shen, is a renowned leader in the prostate cancer field and has extensive experience with training successful independent researchers in their transition to an advanced independent career. Under his supervision, I will learn how to design and perform experiments, how to write and publish scientific papers, how to give scientific talks and more importantly, how to skillfully apply what I have learned to my future independent position, and to make valuable contributions in helping prostate cancer patients.

This proposed study investigates the mechanisms that cause resistance after the treatment of prostate cancer with surgical castration or chemical drugs. This so-called castration-resistant prostate cancer (CRPC) has no curative therapies, and patients often have poor survival rates. Knowledge of CRPC is limited to a small number of genes participating in a few cell biology pathways, with the full scope of the regulatory network remaining hard to understand. This is partly due to the lack of effective bioinformatic tools to interpret large datasets derived from castration resistance patient samples and genetically engineered mouse models. To solve this problem, the Shen lab has collaborated with Cory Abate-Shen and Andrea Califano's labs and used a novel bioinformatic tool to construct a large database (termed 'interactome') that integrates various human and mouse datasets representing different types of prostate cancer, including CRPC.

For the first part of my proposal, I will use an unbiased computational approach to identify important molecular drivers regulating the onsite and progress of castration resistance from our interactome. This innovative method does not depend on any previous knowledge of castration resistance and it's likely to identify a large number of candidate genes, contributing to a better understanding of the molecular basis of CRPC.

For the second part of my proposal, I will experimentally test the candidate genes. I will alter the level of each candidate genes in cell culture and monitor the change of cellular response to culture conditions that mimic a castration scenario. In addition, I will also alter candidate gene levels in prostate tumors, graft the tumors into mice, and test the response of the tumor to castration. These techniques in cell culture and mouse models will determine the accuracy of our bioinformatics approach in identifying bona fide molecular regulators of CRPC.

In summary, this proposal will establish an innovative approach to identify the driving force that is regulating CRPC. Molecular factors associated with CRPC will be identified and validated by multiple experimental approaches. The identified factors will provide insight to the research community in understanding the mechanisms of CRPC. These findings should have significant clinical applications to help with early diagnosis of CRPC, as well as new and more effective therapeutics. Ultimately, the findings of this study will increase the likelihood of treatment success for patients with advanced prostate cancer extending patient lives, especially those who developed resistance following conventional surgical or chemical treatment.