Johns Hopkins Molecular and Cellular Characterization Laboratory (Prostate)

Together this work will yield highly relevant information that can be directly applied to the clinical management of localized prostate cancer. Specifically, it will yield an integrated signature that distinguishes localized – indolent tumors from localized tumors with lethal potential. Additionally we believe these signature will be critical in determining treatment strategies for individuals with prostate cancers of indeterminate kinetics.

There are several critical unmet needs in the management of localized prostate cancer. Central among them is the development of minimally invasive tools to distinguish localized cancers that are truly indolent from cancers that are progressive and potentially lethal. To address this key need, we first propose to perform an integrated, multi-dimensional genomic, epigenomic and expression analysis to uncover novel molecular pathways that characterize indolent vs. aggressive prostate cancers. In this approach we define indolent tumors as those screen detected (e.g. PSA screening) lesions that are Gleason score 6 (or less) that are organ confined at radical prostatectomy. We consider these tumors indolent as they do not appear capable of metastasis. In contrast, we equate Gleason score 8-10 tumors as “interval” or symptomatic since, even with primary treatment, these tumors often recur and metastasize at high frequencies. Additionally, we will validate our key markers/pathways discovered in this project using additional populations with long term outcomes. We hypothesize that our multi-modality genomic-based integrated approach, contrasting these two divergent tumor types, will reveal signatures that distinguish cancers with dichotomous phenotypes. We also hypothesize that these signatures will vary based on race and thus in parallel we will comprehensively characterize African American prostate cancers to reveal molecular features driving racial disparities in outcomes. We will validate the signatures obtained using large cohorts of cases with established outcomes including: (1) the Johns Hopkins Active surveillance cohort and (2) Prostate cancer cases from the BLSA (Baltimore Longitudinal Study of Aging), an observational cohort of men followed since 1954 with autopsy documented indolent or aggressive/lethal disease. We also propose that these signatures will be able to predict outcomes of cancers with indeterminate kinetics and propose to test this through analysis of cases of intermediate risk prostate cancer with long-term follow-up and known outcomes from Johns Hopkins and in collaboration with colleagues from Harvard, from the Physician’s Health and Health Professionals follow-up studies. Together this work will yield highly relevant information that can be directly applied to the clinical management of localized prostate cancer. Specifically, it will yield an integrated signature that distinguishes localized – indolent tumors from localized tumors with lethal potential. Additionally we believe these signature will be critical in determining treatment strategies for individuals with prostate cancers of indeterminate kinetics.

Aim 1: Develop Integrated Genomic, Epigenomic and Expression Profiling Signatures of Indolent and Aggressive Prostate Cancer from both White and African-American Men. Using a discovery set of enriched fresh frozen prostate cancer lesions, we will use Next Generation DNA sequencing to perform genome wide profiling of indolent (Gleason grade 6) and aggressive (Gleason grade 8-10) cancers, separately procured from both White and African American men that includes: mRNA (RNAseq), DNA methylation changes (qMDBseq), variant/mutation and copy number alterations (whole exome sequencing), and genomic rearrangements (low pass whole genome sequencing). We will then apply state of the art bioinformatics approaches for data analysis to determine the number and extent of changes and then perform integrated data analysis to develop molecular signatures that accurately separate indolent from aggressive lesions. Once molecular/pathway alterations are discovered we will prioritize biomarkers/signatures based on whether they correlate with Gleason grade, using both solution-based multiplex profiling as well as in situ based technologies to determine cell type specific alterations. Further, we will also characterize the heterogeneous nature of key changes, as well as determine whether such changes occur primarily in tumor cells or within nontumor microenvironmental cell types.


Aim 2: Validate Biomarkers and Pathways in Active Surveillance and Autopsy Patients.  Markers obtained from the preliminary validation phase from Aim 1 will be used for validation by immunohistochemistry (IHC) and/or in situ hybridization (ISH) on a number of datasets. The first is a large active surveillance cohort of ~1100 men serially biopsied and followed expectantly, and the second is a TMA available from the Baltimore Longitudinal Study of Aging observational cohort generated at autopsy from men who died with either indolent or aggressive prostate cancer.


Aim 3: Validate Biomarkers in Relation to Patient Outcome, with Emphasis on Intermediate Risk
and African American Patients. Further validation will be done with IHC and ISH on multiple highly
annotated prostate cancer specific outcome datasets using TMAs from JHU (both existing and to be
developed) as well as the Harvard health Professionals and Physician Health Study datasets.

Angelo De Marzo - Co-Principal Investigator

Ken Pienta - Co-Principal Investigator

 

Alex Baras

Srinivasan Yegnasubramanian

Contents
Publications

Presentations, papers, articles, and other publications produced by this protocol.