A Master Regulator of Aggressive Prostate Cancer Variants
Abstract
Aggressive forms of prostate cancer arise spontaneously or as a result of adaptive responses by tumor cells to therapy. Complicated forms of prostate cancer are now emerging in response to treatment with next-generation drugs, such as abiraterone acetate and enzalutamide, both of which are directed against the hormonal requirements of prostate adenocarcinoma. Our understanding of these drug-resistant forms of prostate cancer is poor. There is currently much debate about the nature of aggressive prostate cancer variants, and arguments among professionals in the field often resemble political disputes rather than scientific interchanges. The central problem lies in our limited understanding of the mechanisms through which aggressive variants arise and evolve. We also don t understand the meaning of the appearance of advanced forms of the disease in the microscope, even when we use biomarkers claimed to be informative. Our laboratory has used a novel computational approach to address the question of how "epigenetic" mechanisms, that is, mechanisms that do not require specific mutations in the tumor DNA, might drive the formation of aggressive prostate cancer variants. We assembled a large series of prostate cancer gene expression profiles (~4,000) and used over 2,000 of these to develop a novel method of prostate cancer classification that suggests the existence of epigenetic states that may exist throughout the course of the disease. We used this new approach to uncover a "master regulator" network that appears to operate in drug-resistant, metastatic prostate cancer. There were no pre-existing assumptions in the construction of this network. We did not use existing "signatures" or definitions. Instead, we used a combination of patterns of transcription factor (proteins that control gene expression) levels and their calculated activity in metastases based on knowledge of their target genes (the genes the transcription factors regulate). This master regulator transcriptional network contains 10 proteins, some of which are already known to be involved in castration-resistant prostate cancer (CRPC). The proteins in the network are linked together in a defined way. We have focused on one of these potential master regulator proteins in depth, a transcription factor named ONECUT2 (OC2), in an attempt to uncover its functional role. OC2 is predicted to be among the most active components of our CRPC network, but it has not been studied in prostate cancer. Its function in general is not well understood; however, it has been linked to nervous system (brain, eye, spinal cord), liver, and pancreas development. Our bioinformatics and experimental studies have provided compelling evidence that OC2 is a novel driver of aggressive prostate cancer variants, particularly in the case where normal hormonal (androgen) signals are relatively suppressed. Our experiments have shown that inhibition of OC2 blocks CRPC cell growth, suggesting this protein is a novel drug target. OC2 also appears to be most active in tumors where hormone suppression therapy is unlikely to be of clinical benefit. In this Idea Development Award project, we will use molecular, cellular, animal modeling, computational, next-generation DNA sequencing, and automated quantitative pathology methods to understand how OC2 functions in castration resistance and metastasis, and how it can be targeted for therapy. Our studies originate from a novel biomarker approach to the disease, and we have accumulated substantial preliminary data about the mechanism of action of OC2, and the human tumor subtypes where it operates. As a result, this project will lead to new opportunities for therapeutic targeting against aggressive forms of prostate cancer that at present are poorly characterized. The project will also lead to novel indicators of tumor phenotype and susceptibility, thereby increasing the likelihood of success following therapeutic intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610567
Entities
People
- Michael R Freeman
Organizations
- Cedars-Sinai Medical Center
- United States Army