Biomarker Developmental Laboratory

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Project Summary/Abstract This application proposes the formation of the Michigan-Vanderbilt University Medical Center (VUMC) EDRN Biomarker Characterization Center (BCC). This BCC represents a collaborative, multi-disciplinary team of academic (University of Michigan (U-M) and VUMC) and industry (LynxDx) partners focused on discovering, developing, and scaling clinical-grade assays for the early detection of aggressive prostate cancer. Through previous EDRN efforts, our team characterized multiple important prostate cancer biomarkers, most notably the TMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. Sanda PI), we developed, validated, and clinically implemented MyProstateScore (MPS), an early detection test incorporating urine quantification of two prostate cancer-specific transcripts—the TMPRSS2:ERG gene fusion and the long non-coding RNA (lncRNA) PCA3. Introduced in our CLIA laboratory, MPS informs shared decision making after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Here, pairing the cancer-specific components of the MPS test with recent discovery of high-grade cancer-specific biomarkers, we outline the development, optimization, and clinical validation of the next generation of diagnostic tests – capable of reliably, selectively detecting potentially lethal cancers that stand to benefit from early curative treatment. Our Biomarker Developmental Laboratory (BDL) will employ the experimental platform, MPS-SEQ, for capture RNA-seq analysis of urine samples to detect aggressive prostate cancer transcripts, lncRNAs, circular RNAs, fusion transcripts, mutations, indels, and splice variants. Our Biomarker Reference Laboratory (BRL) will in parallel develop a clinical grade urine assay, MPS-50, for the multiplex QPCR analysis of up to 50 amplicons. While the first 50 amplicons of MPS-50 have already been nominated, future improvements of the assay content and platform will be informed by work carried out in our BDL. To fuel these studies, our BCC has identified urine biospecimen cohorts collected under rigorous standard operating procedures in compliance with PRoBE criteria including the Michigan Prostate SPORE, Emory University, the Center for Prostate Disease Research, University of Texas San Antonio Health, Eastern Virginia Medical School, and VUMC/Meharry Medical College. The overall Aims of this BCC serve to develop, assess, and optimize MPS-SEQ and MPS-50 for identifying high-grade prostate cancer in diverse at-risk populations. Our BRL will also focus on standardizing clinically-validated biomarker assays for consistent and reliable use in accordance with CLIA/CAP guidelines at the U-M Center for Translational Pathology in order to facilitate network consortium studies and at LynxDx in order to scale, commercialize, and obtain FDA approvals. As recognized by the EDRN, novel biomarkers specific for aggressive prostate cancer are urgently needed. Importantly, our mission and efforts extend beyond our BCC and prostate cancer, as we actively participate in the EDRN biomarker community and support continued collaborative efforts with other BCCs and CVCs to advance the overall EDRN mission.