Co-Investigator Dr. Robert Bristow
Project 4 takes the SPOP mutation discovery made by the WCM team in collaboration with the Broad Institute and explores the translational opportunities in targeting SPOP mutant PCa. This highly collaborative project brings together experienced investigators with a track record of successful collaboration to study the translational aspects and clinical targeting of SPOP mutant PCa. Using innovative organoids, state-of-the-art mouse models, and cutting-edge analyses of patient samples, we hope to make a broad impact on the rational design and analysis of clinical trials using DNA-damaging agents. Successful realization of this project will require leveraging the significant resources and infrastructure already built by our team and will identify opportunities to transform the therapeutic management of PCa.
Based on novel observations from our SPORE team using Whole Genome Sequencing (WGS), we demonstrated that around 10 percent of clinically localized PCa harbor recurrent point mutations in SPOP and E3 ubiquitin ligase. Tumor samples with SPOP mutations display significantly higher numbers of genomic rearrangements, raising the possibility that SPOP mutation–an early event in prostate tumorigenesis– promotes genomic instability.
Our recently published in vitro work demonstrates that prostate cells expressing SPOP mutations accumulate DNA double-strand breaks (DSBs) traceable to altered DNA repair. We also found that SPOP mutation results in increased sensitivity to DNA-damaging therapeutic agents such as ionizing radiation, a standard-of- care therapy for men with PCa. Finally, our analysis of human PCa samples shows that SPOP mutation precedes evidence of genomic instability in these tumors. These results suggest that SPOP mutation is an early event underlying a distinct class of PCa, which is predisposed to genomic rearrangements through impaired DSB repair. Based on these preliminary findings, we hypothesize that the SPOPmut subclass of PCa is selectively responsive to DNA-damaging therapeutics, nominating specific management strategies.
Aim 1: Analyze the Impact of SPOP Mutation on Genomic Instability and Therapeutic Vulnerability Using Novel In Vitro Platforms;
Aim 2: Generation and Analysis of a Mouse Model of SPOP Mutation;
Aim 3: Determine the Association of SPOP Mutation With Response to Radiotherapy in Patients with Clinically Localized Prostate Cancer.