Systems analysis of aggressive prostate cancer pathology
- Systems analysis of aggressive prostate cancer pathology
Tissue pathology is a manifestation of the genomic aberrations that define cancer (i.e. stage, grade, type). In prostate cancer, the best prognostic marker is Gleason score, the composite tumor grading system that summarizes primary tumor morphology. Subsets of patients with localized disease inevitably develop metastases, a point where it is often too late for curative treatment. Thus, we propose to model and therapeutically target molecular subtypes that drive aggressive primary prostate cancer. We start from large, –omic datasets and use tissue pathology and gene expression as the readout of disease development. To evaluate the direct effect of molecular drivers of aggressive primary disease, we use a novel prostate stem cell, tissue recombination mouse model that recapitulates prostate development and tissue pathology. To model specific molecular subtypes, we will genetically engineer mouse prostate stem cells to introduce gene knockouts or Tet-regulated genes. These engineered cells will then be combined with fetal urogenital mesenchyme and engrafted under the mouse kidney capsule to produce prostate structures. We will evaluate tissue pathology and isolate regions of interest with aggressive tissue morphology (e.g., cribriform patterning) for RNA sequencing. Using this approach to model three mutually exclusive molecular subtypes, we can directly compare and contrasts gene expression and pathways changes to identify common and subtype-specific effects. Using these data, along with –omic data from patients, we will use two network-based computational models to identify novel therapeutic treatments and capture the systems-level gene regulation and functional relationships. The therapeutic predictions will be screened in vitro using engineered mouse and human cells with promising treatments being promoted for testing in the tissue recombination mouse model. Overall, through this project, we will study drivers of aggressive primary prostate cancer, characterize mechanisms of disease development, and identify pre-clinical pharmacological treatment strategies. Computational models and the prostate stem cells will be valuable resources for the CSBC and larger research communities.
James C Costello, PhD
Dr. Costello is an Assistant Professor in the Department of Pharmacology at the University of Colorado Anschutz Medical Campus. He holds a PhD in Informatics from Indiana University, Bloomington with a focus on data integration and gene function prediction Drosophila. He continued his research career as an HHMI postdoctoral researcher in the lab of Jim Collins, PhD, where he expanded his research into developing gene regulatory network methods for reconstruction of bacterial networks to understand drug resistance. Dr. Costello made his final shift in research to cancer where the methods he developed for network inference and function prediction were applied to understand NRAS-mutant melanoma. He held a Research Instructor position at Brigham and Women’s Hospital and Harvard Medical School before starting his faculty position at the University of Colorado Anschutz Medical Campus in 2014. Dr. Costello’s lab has a balance of wet and dry research with a focus on cancer genomics and pharmacology, including the study of cancer development and progression in the wet lab and developing mechanistic computational models leveraging genomics data in the dry lab. Dr. Costello is also a Director of Systems Biology DREAM Challenges and an Affiliate Member of Sage Bionetworks. He has been involved with the DREAM Challenges since 2009 and continues to develop and direct Challenges in cancer and other areas of research.
Scott D Cramer, PhD
Dr Cramer is a Professor in the Department of Pharmacology at the University of Colorado Anschutz Medical Campus. He holds a Ph.D. in Biology from the University of California, Santa Cruz. His thesis focused on reproductive endocrinology studying placental/hepatic signaling to regulate fetal growth. He did two post-doctoral fellowships at Stanford University School of Medicine. The first fellowship was in Endocrinology in David Feldman’s laboratory studying Vitamin D and steroid receptor signaling in prostate cancer. A second postdoctoral fellowship in Urology in Donna Peehl’s laboratory focused on prostate histopathology, primary human prostate culture models, and the role of PSA enzymatic activity on regulation of hormonal activity. As an Assistant Professor at Wake Forest University School of Medicine he was the first to describe single nucleotide polymorphisms in the PSA promoter and their effects on promoter activity and circulating levels of PSA in men absent of clinical prostate cancer. He developed novel methods for the isolation, growth and characterization of mouse prostatic stem cells and adapted tissue recombination strategies to characterize these stem cells in vivo. This work led to his current focus on assessing the effects of putative tumor suppressors located in regions of genomic deletion in prostate cancer for their effects on tissue pathology and signaling. Using these models, his work led to the demonstration of MAP3K7 (TAK1) as a prostate suppressor. Subsequent work led to the description of the aggressive molecular subtype of ERG-translocation negative prostate cancer that has deletion of MAP3K7 on chr6q21 in combination with deletion of CHD1 (Chromodomain Helicase DNA-Binding Protein 1) on chr5q15. In 2011, Dr. Cramer was promoted to Full Professor at the University of Colorado Anschutz Medical Campus. Recent studies have focused on androgen signaling alterations and methods to therapeutically target MAP3K7/CHD1 deleted prostate cancer. Additional novel molecular subtypes are being modeled with tissue recombination and evaluated for their effects on tissue pathology and signaling pathways.