Abstract 3882: Patient-specific druggable networks in lethal prostate cancer through proteome-guided multi-omic integration
Authors: Drake Justin M. , Paull Evan O. , Graham Nicholas A. , Lee John K. , Smith Bryan A. , Stoyanova Tanya , Faltermeier Claire M. , Carlin Daniel E. , Vashisht Ajay , Huang Jiaoti , Wohlschlegel James A. , Graeber Thomas G. , Witte Owen N. , Stuart Joshua M. 
Published: July 2016

Metastatic castration resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. The need to identify new actionable targets in this disease is crucial as we begin to examine the resistance mechanisms related to androgen withdrawal. Pathway activation of signaling proteins, such as kinases, are hypothesized to drive the progression of lethal CRPC. We set out to define the global picture of signaling pathways in lethal prostate cancer through dataset integration. We used clinical tissue from lethal metastatic CRPC patients obtained at rapid autopsy to evaluate and integrate previously published genomic and transcriptomic datasets combined with a new complete and extensive dataset of the phosphoproteome in metastatic CRPC for pathway analysis. This included extending our analysis of the phosphoproteome to phosphoserine and phosphothreonine peptides with our published phosphotyrosine peptide data. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues relative to treatment naïve prostate cancer to synthesize a robust signaling network consisting of druggable kinase pathways for therapy. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Further, we were able to gather mRNA and phosphoproteome data from six individual patients where the integration of tissue samples from a single autopsy program allowed us to make inferences on the connections between the mRNA and phosphoproteome datasets. Individual patient profiles developed using these hallmarks revealed clinically relevant pathway information suitable for patient stratification and targeted therapies in lethal prostate cancer. Here we describe these pathways: personalized cancer hallmarks using an integrative phospho-signature (pCHIPs) that sheds light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

Citation Format: Justin M. Drake, Evan O. Paull, Nicholas A. Graham, John K. Lee, Bryan A. Smith, Tanya Stoyanova, Claire M. Faltermeier, Daniel E. Carlin, Ajay Vashisht, Jiaoti Huang, James A. Wohlschlegel, Thomas G. Graeber, Owen N. Witte, Joshua M. Stuart. Patient-specific druggable networks in lethal prostate cancer through proteome-guided multi-omic integration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3882.