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Member institutions and other sites of the Early Detection Research Network.

Biomarker Developmental Laboratories

Breast and Ovarian

Investigator Site
Fred Hutchinson Cancer Research Center
Baylor College of Medicine
A Unique Approach Combining Avatar Mice and Targeted Mass Spectrometry to Identify Blood Biomarkers for Early Detection of Breast Cancer
Project Summary
Tens of millions of women undergo population-based screening for breast cancer by mammography. Despite the life-saving potential of early detection, s...
Tens of millions of women undergo population-based screening for breast cancer by mammography. Despite the life-saving potential of early detection, screening guidelines for mammography are controversial and continue to evolve. At issue are the specificity of mammography for distinguishing benign vs cancerous lesions, the sensitivity of mammography in some patient populations (e.g. women with dense breasts), and concerns regarding over-diagnosis (e.g. some ductal carcinoma in situ). Our ultimate clinical aim is to develop a blood test for early detection of breast cancer that can be used in conjunction with mammography to improve sensitivity and specificity during screening, and thus have enormous clinical impact by detecting treatable cancers missed by mammography (reducing mortality) and by avoiding unnecessary invasive procedures for benign or non-life-threatening disease. <br>Despite considerable effort, attempts to identify blood-based screening biomarkers for early detection of breast cancer have failed, due to technological and methodological limitations. Clearly new approaches are warranted. We are proposing a completely novel strategy, based on the initial discovery of candidate biomarkers in the plasma of “avatar mice” (harboring early passage human breast cancer xenografts), and followed by biomarker triage and validation using a novel biomarker pipeline based on a targeted form of mass spectrometry (MS), multiple reaction monitoring (MRM). If successful, this study could provide a road map for applying this general approach to other cancer sites, beyond breast cancer.<br>Briefly, candidate circulating biomarkers identified in the avatar mouse plasma will be verified in the plasma from the human patients and prioritized for further testing based on integrative proteo-genomic analyses using large breast cancer datasets generated by NCI genomic and proteomic consortia (TCGA and CPTAC). A novel, multiplex MRM-based assay will be developed and analytically validated (according to established fit-forpurpose guidelines) to quantify up to 50-100 prioritized biomarker candidates. Candidate biomarkers will be evaluated in an existing, strongly unbiased collection of plasma samples in which plasmas were collected prior to biopsy, compliant with PRoBE study design criteria, under an SOP from women with undiagnosed mammographic lesions. Performance of the candidate biomarkers will initially be assessed in a training set (100 cases, 100 controls) to verify which candidates show a mean difference in plasma levels between cases vs controls, and to test the possibility of building a multiple marker prediction model. Subsequently, individual candidate biomarkers (as well as a potential multiple marker prediction model) will be assessed in an independent validation set (150 cases, 150 controls) to estimate the sensitivity and specificity of the markers/panel. <br>

Investigator Site
Duke University Medical Center
Creatv MicroTech Inc.
Breast Cancer Detection Consortium
Project Summary
Mammography is an early detection modality for breast cancer that is implemented widely in the United States, has established benchmarks of performanc...
Mammography is an early detection modality for breast cancer that is implemented widely in the United States, has established benchmarks of performance, and in most studies throughout the world has been demonstrated to reduce mortality due to the disease. This relatively inexpensive x-ray imaging of the breast also provides a location that can be directly sampled through needle biopsy which leads generally to an unambiguous pathologic diagnosis of invasive cancer, carcinoma in situ, or benign findings. No system is perfect and mammographic screening, particularly in the US, prompts over 1.6 million biopsies per year detecting approximately 230,000 invasive and 60,000 non-invasive cancers for a positive predictive value of less than 20%. There may be substantial room to improve on this and reduce the number of biopsies but this improvement must not sacrifice detection rates so the negative predictive value (NPV, identification of true negatives) must remain very high. In this Biomarker Development Laboratory application, we propose to test whether a combination of mammographic feature analysis and candidate biomarkers that we have identified can achieve an NPV that would be acceptable to patients and providers to prevent unnecessary breast biopsies. One of the biomarkers is a type of circulating giant cell termed “Cancer Associated Macrophage Like” (CAML) that can only be detected using freshly drawn whole blood, we propose to conduct a prospective trial at Duke University in women undergoing breast cancer diagnosis. Our realistic goal is to accrue ~1000 women over the course of 4 years for which full field digital mammography has been performed. The images will undergo feature extraction for decision modeling. Blood will be analyzed for the presence and type of CAML cells, immunosignaturing using the high density peptide arrays developed by Stephen Johnston at Arizona State, and measurements of two specific analytes that have the highest sensitivity and specificity for basal type cancers, CA125 and TP53 autoantibodies. As feature analysis from imaging alone can achieve, at least for masses on mammography, an AUC of ~0.9, the study is designed to determine whether the biomarkers have sufficient complementary information to the imaging and each other to increase the AUC to 0.95 allowing us to identify a threshold where there is a 98% NPV. We will make use of the most careful and consistent standard operating procedures, the best candidate biomarkers, and the most well developed imaging algorithms to make this a definitive study.

Investigator Site
Arizona State University
Arizona State University
Novel Approaches to Study Immune Responses to Post Translational Modifications for Cancer Detection
Project Summary
Despite advances in screening and treatment, mortalities from breast and lung cancers have remained high in the US over the last 20 years. It is widel...
Despite advances in screening and treatment, mortalities from breast and lung cancers have remained high in the US over the last 20 years. It is widely accepted that early detection is critical to improving outcomes in both diseases. Both also rely on imaging for screening, but false positive and false negative detection are associated with unnecessary biopsies, missed diagnoses, and costs. There is an urgent need for biochemical markers that improve the performance of imaging technologies. Our laboratories have been successful at identifying useful cancer biomarkers by exploiting patients’ own ability to produce antibodies against tumorassociated antigens (TAA), referred to as tumor-associated autoantibodies (TAAb). With prior EDRN support, we developed high-throughput programmable protein display methods for the rapid detection and validation of autoantibody biomarker signatures in breast and lung cancers. Our breast cancer TAAb biomarkers have been licensed and integrated into Videssa™ Breast that is now available as CLIA-certified test. Our triple negative breast cancer markers have been validated in blinded phase 2 multicenter validation studies. These demonstrate the great utility of TAAb in cancer early detection. However, the sensitivities of most TAAbs is moderate and there is a suggestion that greater sensitivity and specificity could be obtained by examining TAAb directed at aberrantly modified proteins in cancers. Our central hypothesis is that aberrant protein glycosylation, a hallmark of breast and lung cancers, induces glycoprotein-specific TAAb that can be measured as specific serum biomarkers of these cancers. Alterations in glycosylation are highly immunogenic, and there is strong historical evidence for significant antibody responses to cancer-altered glycoproteins. However, all current protein (or polypeptide) display tools allow limited or no post-translational modification. This historical roadblock has prevented the identification of these biomarkers because of the lack of screening methods that test immunogenic structural glycoproteins. We introduce a tool for the high-throughput display of full-length proteins decorated with cancer-specific O-glycan structures. This will revolutionize the opportunity to screen glycan-protein epitopes in their natural context. Our team comprises strong expertise in functional proteomics, biomarker development, glycoproteomics, medical oncology and biostatistics. Targeted proteins will include: the extra-cellular domains of relevant single pass membrane proteins, proteins known to be O-glycosylated and overexpressed in the two cancers, and all known mucins. They will be translated in situ using human ribosomes and chaperone proteins and then systematically decorated with Tn and STn O-GalNAc-type glycans by consecutive addition of recombinant glycosyltransferases and sugar nucleotides to mirror what occurs in the two cancers. Adhering to the principles of PRoBE design, we will screen these arrays with cancer patient and control sera. Our study will focus on cancer patients and non-cancer subjects with positive imaging findings. Study design will include Phase I discovery (arrays/ELISA) and Phase II validation using ELISA.

Colon and Esophagus

Investigator Site
Fred Hutchinson Cancer Research Center
Case Western Reserve University
Case Western Reserve University
Biomarkers for Reducing Mortality of Cancers of the Colon and Esophagus
Project Summary
The goal of this EDRN renewal proposal is the discovery and validation of biomarkers for reducing mortality from gastrointestinal cancers. We particul...
The goal of this EDRN renewal proposal is the discovery and validation of biomarkers for reducing mortality from gastrointestinal cancers. We particularly target cancers of the colon (CRC), the second leading cause of U.S. cancer deaths, and adenocarcinomas of the esophagus (EAC), the fastest increasing cause of U.S. cancer deaths. In our first funding period, our group prominently advanced early detection of colon cancers through detection of aberrantly methylated tumor DNA in stools. Our work testing methylated VIM (M-VIM) DNA in stools led to an EDRN prospective validation study (GLNE-10), a commercial colon cancer test (ColoSure, from Exact Sciences & LabCorp), and to proof of principal for the Exact Cologuard test of methylated stool DNA that is now FDA approved. Our work studying the 15-PGDH tumor suppressor gene identified the first biomarker for personalized chemoprevention, showing NSAIDs lower colon cancer risk only in individuals with high, but not low, colon 15-PGDH expression. And our further studies of M-VIM showed this biomarker to also be highly sensitive and specific for detecting Barrett’s esophagus (BE) and EAC, specifically in tests using esophageal brushings. In this renewal application, for colon cancer we propose EDRN phase 2 validation studies testing biomarkers that identify individuals at high risk of developing colon cancer by testing normal colon mucosa for RNA and DNA markers of elevated cancer risk that are: a) low levels of 15-PGDH transcript expression, and/or b) high levels of DNA methylation at specific colon cancer risk loci. For EAC, we first propose an EDRN phase 2 validation study testing sensitivity and specificity of a panel of candidate DNA methylation biomarkers for identifying BE, the currently best recognized marker of EAC susceptibility, in assays of samples collected from esophageal brushings. We follow these BE assays by then proposing an EDRN phase 2 study of a set of markers that detect EAC, and its precursor lesion HGD, while not detecting BE, thus providing surveillance markers for catching early BE progression, again by testing samples from esophageal brushings. Our candidate progression marker panel includes DNA loci we find aberrantly methylated in HGD and EAC (but not BE); novel non-coding lincRNAs we find highly expressed in EAC (but not in BE); and mutations in TP53. We also further test the ability of this panel to discriminate low grade BE dysplasias (LGD) that are or are not associated with progression to HGD and EAC. Last, we propose new biomarker discovery to identify methylated DNA and/or RNA biomarkers that, in esophageal brushings, will detect the minority subset of EAC or HGD that are negative for our current EAC/HGD marker panel. Our goals are to: 1) develop effective risk stratification assays to optimize primary prevention of CRC; and 2) replace the current ineffective paradigm for preventing EAC deaths by developing inexpensive biomarker based tests of non-endoscopic esophagus brushings, thus: enabling cost-effective population screening to detect BE, enabling cost effective surveillance to catch early progression of BE to HGD and EAC, reducing EAC deaths, and reducing over-treatment of LGD.

Colorectal

Investigator Site
University of Pittsburgh Cancer Institute
Johns Hopkins University School of Medicine
ctDNA for the Early Detection and Monitoring of Colorectal Cancer
Project Summary
A blood test for early detection of cancer would provide a valuable, additional means for screening the population at risk. Blood-based biomarkers for...
A blood test for early detection of cancer would provide a valuable, additional means for screening the population at risk. Blood-based biomarkers for monitoring cancer could enhance care by earlier identification of subjects at risk of recurrence, better prognostic assessment, and potentially, improvements in survival or quality of life due to earlier implementation of alternative therapy. Thus, a “liquid biopsy” for early detection and for non-invasive assessment of tumor and tumor characteristics during treatment would represent a significant medical advance. Circulating tumor DNA (ctDNA) are small fragments of nucleic acid that originate from apoptotic or necrotic tumor cell turnover. Characteristic of the malignant process, ctDNA can be assessed in plasma, and offers the potential of a sensitive and specific biomarker for a host of applications including diagnosis or early detection of tumors, prognostic information on disease-free or overall survival, and predictive information on resistance and probability of lack of response to treatment. Previous ctDNA studies have been implemented by identifying characteristic mutations in the primary tumor and subsequently interrogating plasma DNA from the same patient for the presence of those mutations. The next step in evaluating ctDNA as a screening modality is to construct a panel of mutations amenable to detection in plasma (a "PlasmaSeq" panel) to assess the sensitivity and specificity of plasma ctDNA in identifying cancer without prior knowledge of which mutations are present in the tumor of the patient whose plasma is assayed. In Aim 1, we will prospectively recruit patients with colorectal cancer (CRC), disease-free controls, and subjects with adenomas prior to definitive surgical or endoscopic treatment and systematically evaluate a PlasmaSeq panel to explore the utility of ctDNA as a marker for early detection. Previous studies suggest that ctDNA can be used to monitor cancer in subjects under treatment or at risk for recurrent disease. In Aim 2, we will recruit newly diagnosed stage III CRC patients, determine their tumor mutational profile, and systematically collect high volume (>10 ml), serial plasma specimens every 3 months for up to 4 years for ctDNA and concurrent CEA measurement. Clinical outcome and survival will be tracked and parameters of ctDNA assessment, including absolute level, velocity of change, and degree of fluctuation will be evaluated in relation to clinical outcome, stratified by tumor stage classification (stage IIIA-IIIC). The resulting data will permit assessment of ctDNA as a prognostic marker for disease-free and overall survival. This research will further advance study on the use of ctDNA in early detection and monitoring of CRC. ctDNA testing is also applicable to many other cancers. Thus, advancement in this technology is potentially of great impact to cancer care.

Lung

Investigator Site
Wistar
Integration of Biomarker Signatures from Peripheral Blood for Diagnosis, Prognosis, Remission and Recurrence of Lung Cancer
Project Summary
The National lung Screening Trial has demonstrated that a 20% reduction in lung cancer mortality is associated with routine LDCT screening of older in...
The National lung Screening Trial has demonstrated that a 20% reduction in lung cancer mortality is associated with routine LDCT screening of older individuals with a heavy smoking history, but of the patients that had a positive screen for lung cancer based on lung nodules detected, approximately 96% proved to be false positives. These statistics highlight two unmet medical needs required to maximize the diagnostic potential of LDCT: 1) the development of diagnostic platforms that will distinguish malignant from benign nodules identified by routine LDCT, and 2) the development of inexpensive, non-invasive methods that can identify at risk individuals who would benefit from follow up with LDCT.<br><br>The proposed research in Project 1 capitalizes on technical advances for assaying gene expression and abundant prior evidence that tumors are highly interactive with the immune system. Our previous studies demonstrated that it is possible to diagnose early-stage lung cancer with 90% sensitivity and 80% specificity using gene expression signatures from PBMC. The proposed research translates the PBMC diagnostic to a more clinically viable sample collection platform with the additional goal of increasing accuracy and assessing immunological processes affected by the presence or removal of a lung tumor. We present preliminary studies that support the hypothesis that this can be done. We have enriched the signature development process by assessing both mRNA and miRNA expression profiles to assess complimentary mechanisms for regulating gene expression and will also integrate Natural Killer cell and Myeloid cell markers associated with prognosis. We also introduce in Project 2 an assay for tumor associated antigens, the cancer testis antigens (CTAs) also associated with circulating tumor cells, cancer cell derived exosomes or other potentially important cells such as cancer stem cells. We provide strong preliminary evidence that detection of the mRNA for the CTA AKAP4 in PBMC derived RNA is possible and that detection is very highly correlated with the verified presence of a lung tumor. Strong preliminary results are presented for both projects. We also propose to integrate and expand the signatures from these 2 studies and assess accuracy on a single reliable platform that can assess both mRNA and miRNA expression, and is already FDA approved for a breast cancer prognosis signature, the nCounter from Nanostring.<br>

Investigator Site
New York University School of Medicine
University of Hawaii
The EDRN Mesothelioma Biomarker Discovery Laboratory
Project Summary
The asbestos-related malignancy, malignant pleural mesothelioma (MPM), is often detected in late stages with little chance for survival. Biomarkers ar...
The asbestos-related malignancy, malignant pleural mesothelioma (MPM), is often detected in late stages with little chance for survival. Biomarkers are needed to (1)determine which patients have been asbestos exposed (AE) (2) distinguish AE and non-MPM malignancies from MPM patients and (3) determine which MPM patients are at highest risk for early recurrence or death. The EDRN Mesothelioma Biomarker Discovery Laboratory will refine and validate three novel MPM blood/effusion based markers (FBLN3, SOMAmer 13 classifier, HMGB1 Isoforms) and investigate whether immuneoncologic gene expression differences in the cellular component of the circulating blood microenvironment can stratify AE and MPM from other control cohorts. All of these in Phase I/II discovery studies have yielded AUCs > 0.9. An in-house, novel Luminex based assay (Soma 14 NYU MPM) consisting of 13 slow-off-rate-modified-aptamers (SOMAmers) and a newly constructed FBLN3 SOMAmer will be assembled and technically validated using identical specimens that were used to discover these 14 analytes. Diagnostic and prognostic capabilities in both plasma and pleural effusion will be performed with healthy, non-AE exposed, AE, MPM, and non- MPM cancer cohorts, followed by a blinded validation in specimens provided by the Princess Margaret Cancer Center. The University of Hawaii/Cedar Sinai Medical Center, using 202 NYU pleural effusions, will evaluate a unique, technically validated, electrospray ionization liquid chromatography tandem mass spectrometry assay for HMGB1 and its isoforms to differentiate MPM from non-MPM benign and malignant effusions. The HMGB1 effusion results will be compared to those obtained with the Soma 14 NYU MPM using validation cohorts from an approved EDRN MPM screening program in Santiago, Chile and South Glasgow University Hospital. Finally we will refine and validate our buffy coat/PBMC MPM profile of 5 immunooncology genes which in Phase II studies can separate non AE individuals vs AE individuals vs MPM with AUCs of 1.0. These studies could lead to 3 novel platforms which individually or combined could significantly improve chances for early diagnosis and accurate prognostication of patients with MPM.

Investigator Site
University of Pittsburgh School of Medicine
Johns Hopkins Whiting School of Engineering
Ultrasensitive Detection of Tumor Specific DNA Methylation Changes for the Early Detection of Lung Cancer
Project Summary
This proposal seeks to improve upon the management of lung cancer through detection of tumor specific abnormal DNA methylation. Despite highly publici...
This proposal seeks to improve upon the management of lung cancer through detection of tumor specific abnormal DNA methylation. Despite highly publicized advances in genomics and proteomics, the promise of non-invasive diagnostics and personalized medicine remains largely unrealized. Recently, comprehensive determination of genetic and epigenetic aberrations has become a major activity in cancer research since it is well understood that these aberrations provide clues to the process of tumorigenesis. The applicants have developed extremely sensitive assays for the detection of hypermethylated DNA sequences. They have also optimized the isolation and processing of circulating cell free DNA from tumors for these sensitive methods. The comprehensive genome wide analysis of molecular changes in cancer completed by The Cancer Genome Atlas (TCGA) has been used to identify many highly frequent cancer specific methylation events in lung cancer that will be combined with an integrated approach to sample processing and preparation and novel sensitive detection strategies to provide utrasensitive detection of tumor specific changes in DNA methylation in blood and sputum samples. With a large population based screening cohort, the Pittsburgh Lung Screening Study, they will develop and characterize the performance of sensitive methods for detecting cancer specific changes in DNA methylation. This molecular detection will compliment CT screening to address the important issue of early detection of lung cancer

Ovarian

Investigator Site
Johns Hopkins
Johns Hopkins University School of Medicine
Development of in vitro Diagnostic Mulitvariate Index Assay Using Liquid-based Cervical Cytology Specimen and/or Serum/Plasma Biomarkers for the Detection of Early Stage or Low-volume Ovarian Cancer
Project Summary
We have assembled a multidisciplinary team including biomarker researchers, cancer biologist, pathologist, gynecologic oncologist, proteomic technolog...
We have assembled a multidisciplinary team including biomarker researchers, cancer biologist, pathologist, gynecologic oncologist, proteomic technologists, and experts in biostatistics, epidemiology, and bioinformatics to establish a Biomarker Developmental Laboratory for the NCI’s Early Detection Research Network with the objective to develop an in vitro diagnostic multivariate index assay (IVDMIA) to detect ovarian cancer at low tumor volume. The intended use of such a test is to further enrich ovarian cancer prevalence in high-risk populations to allow for cost-effective additional workup tests. The rationale is based on 1) prognosis of ovarian cancer patients, in addition to stage/grade at diagnosis, is affected by the initial size of the metastatic disease and the size of residual disease after cytoreductive surgery; and 2) newly developed cancer-specific biomarkers detecting mutant DNAs in liquid-based cervical cytology specimens and circulating tumor DNA (ctDNA) in plasma have demonstrated a remarkable specificity. We hypothesize that combining such biomarkers with additional sensitive and disease burden-associated biomarkers in an IVDMIA will allow us to detect ovarian cancer at low volume which currently represents an unmet clinical need.

Investigator Site
Massachusetts General Hospital
Massachusetts General Hospital
Proteomic, Genomic, and Longitudinal Pathways to Ovarian Cancer Biomarker Discovery
Project Summary
The application’s broad, long-term objectives are to discover a blood test for early detection of ovarian cancer that will reduce ovarian cancer mor...
The application’s broad, long-term objectives are to discover a blood test for early detection of ovarian cancer that will reduce ovarian cancer mortality through regular testing of targeted populations. Initially these populations would include women at high risk due to family history and/or presence of a BRCA1 or BRCA2 mutation within the family, and all postmenopausal women. This is the age group where the incidence of disease is highest. The test requires high sensitivity for early stage disease and very high specificity so that few false positive tests will occur for each true positive test.<br><br>The specific aims are 1) to discover high probability candidate biomarkers through longitudinal proteomic analysis of serial plasma obtained from screening studies of large cohorts, 3) prioritize candidate protein biomarkers for verification by change-point analysis and ranking by earliest change-point, 4) construct targeted mass spectrometric assays for the top 50 protein candidates and measure these candidates in longitudinal plasma in cases prior to clinical detection and in controls, where cases and controls are from an ovarian cancer screening trial, 4) determine which candidates have earliest sensitivity by estimating the change-point at which the candidate rises significantly above baseline, and 5) discover high probability candidate DNA mutational biomarkers from genomic analysis of cervico-vaginal fluid in women with malignant and benign pelvic masses, 6) validate DNA mutational candidates in an independent validation sample set of CVF from cases and benign controls.<br><br>Further refinement and testing of proteomic and genomic biomarkers and their combination to identify the best panel and classifier of early detection ovarian cancer biomarkers in the biorepositories of larger scale screening studies is planned but is outside the scope of this application. <br>

Pancreas

Investigator Site
Van Andel Research Institute
Memorial Sloan Kettering Cancer Center
University of Pittsburgh
The Detection and Prognosis of Early Stage Pancreatic Cancer by Interdependent Plasma Markers
Project Summary

Prostate

Investigator Site
Eastern Virginia Medical School
Ontario Institute for Cancer Research
University of Toronto University Health Network
Development of Protein Biomarkers in Post-DRE Urine for use in Liquid Biopsy of Prostate Cancer
Project Summary
Prostate cancer (PCa) remains the most common non-skin malignancy afflicting men in the United states. It is the second leading cause of cancer-relate...
Prostate cancer (PCa) remains the most common non-skin malignancy afflicting men in the United states. It is the second leading cause of cancer-related death. The clinical diversity of PCa is dramatic, ranging from asymptomatic disease to metastatic and fatal malignancy. One cause of this clinical diversity is the remarkable intra- and inter-tumoural heterogeneity in disease genomics. As a result, currently clinically-used risk-stratification strategies do not robustly discriminate aggressive from indolent diseases, leading to systemic over- and undertreatment. Approximately 40% of men diagnosed with PCa who seek curative treatment undergo surgical removal of their prostate (radical prostatectomy, RP). Of these, approximately 30% are found at surgery to have disease outside their prostate (non-organ-confined, non-OC). These men are candidates for multi-modal adjuvant treatment with chemo- and hormonetherapy to improve outcomes. We therefore propose to tackle this problem, using fluid biomarkers to circumvent the molecular heterogeneity of the disease. Our proposal leverages an active and productive multi-investigator, multi-institutional proteomic collaboration to develop biomarkers for the early detection of locally aggressive non-organ-confined disease. Our two lead biomarkers are 1) A multiple peptide panel that discriminates OC from non-OC in EDRN phase 2 equivalent validation (Nature Communications, in press). 2) Surface expression of CUB Domain Containing Protein 1 on exosomes differentiates PCa aggressiveness (EDRN Phase 1 equivalent discovery, Oncotarget, 2016). We propose both validation of these targets in a globally-unique biobank of expressed prostatic secretions, as well as novel biomarker discovery/development strategies to extend them in the same clinical context and sample matrix. Successful completion of our proposed studies will result in validation of at least two biomarkers for clinical utility in separation of OC vs. non-OC disease, helping to personalize therapy for a tumour type that afflicts 1 in 7 North American men.

Investigator Site
University of Michigan
University of Michigan
Discovery and Quantification of Transcriptomic Biomarkers for the Early Detection of Aggressive Prostate Cancer
Project Summary
This application proposes the formation of a University of Michigan (UM) EDRN Biomarker Development Lab (BDL). Through previous EDRN BDLs, our team ha...
This application proposes the formation of a University of Michigan (UM) EDRN Biomarker Development Lab (BDL). Through previous EDRN BDLs, our team has characterized multiple important prostate cancer biomarkers, most notably TMPRSS2-ETS gene fusions. Through collaboration with an EDRN Clinical Validation Center (CVC; Dr. Sanda PI), we have developed, validated and clinically implemented Mi-Prostate Score (MiPS), a prostate cancer early detection test incorporating urine quantification of two prostate cancer specific transcripts—the TMPRSS2:ERG gene fusion and PCA3—with serum PSA. Introduced in our CLIA laboratory (and now with New York State approval), MiPS helps shared decision making after PSA testing based on individualized risk predictions of aggressive prostate cancer on biopsy. Here, using this work as a model, we will discover and characterize aggressive prostate cancer transcriptomic biomarkers, focusing on long non-coding RNAs (lncRNAs). Although lncRNA biomarker utility has been largely unexplored, we recently characterized the lncRNA compendium (“MiTranscriptome”), identifying several prostate cancer-specific and aggressive prostate cancer-specific lncRNAs. Supporting our proposed approach, we have performed initial validation of the lncRNA SChLAP1 as an aggressive prostate cancer specific biomarker in tissues. Likewise, we have developed RT-PCR based next generation sequencing (NGS) panels capable of quantifying multiplexed transcriptomic biomarkers in archived tissue and urine. Here, in three Aims, we will nominate and develop transcriptomic biomarkers as predictors of aggressive prostate cancer both at and prior to diagnosis. In Aim 1, we will identify novel aggressive prostate cancer-associated transcriptomic alterations from our MiTranscriptome analysis. We will develop single gene and multiplexed NGS assays to study these lncRNAs/coding transcripts as aggressive prostate cancers specific biomarkers. In Aim 2 we will characterize transcripts from Aim 1 as tissue based aggressive prostate cancer biomarkers. Following our previous approach with SChLAP1, we will develop individual in situ hybridization assays and a multiplexed NGS panel to characterize these transcripts in well characterized prostate cancer tissue cohorts. In Aim 3, we will characterize transcripts identified in Aim 1 as non-invasive, urine-based aggressive prostate cancer early detection biomarkers. Through collaboration with Hologic/Gen-Probe (our industry partner on MiPS), we will develop and assesses the performance of individual prioritized biomarkers using their platform on our biobanked urine samples. Additionally, using multiplexed NGS, we will also characterize the performance of a panel of transcriptomic biomarkers as an alternative/complementary approach. As recognized by the EDRN, novel aggressive prostate cancer specific biomarkers are urgently needed. Importantly, our approach extends beyond prostate cancer and our BDL, and our group has actively participated in the EDRN biomarker community and anticipates continuing work with other BDLs and CVCs to facilitate the overall EDRN mission.

Investigator Site
Johns Hopkins University School of Medicine
Institute for Molecular Systems Biology
Glycoprotein Biomarkers for Early Detection of Aggressive Prostate Cancer
Project Summary
Prostate cancer is the most prevalent type of cancer and it is the second highest contributor to cancer death among men in the U.S. A major issue in p...
Prostate cancer is the most prevalent type of cancer and it is the second highest contributor to cancer death among men in the U.S. A major issue in prostate cancer detection and therapy is that we currently have no method to reliably distinguish aggressive prostate cancer from non-aggressive prostate cancer. This leads to significant unnecessary suffering among prostate cancer patients. We hypothesize that specific glycoproteins or their glycosylation specifically altered in aggressive prostate cancer cells can be used as biomarkers to distinguish patients with aggressive from those with non-aggressive prostate cancer. We propose in four specific aims to develop novel glycoprotein biomarkers that can detect aggressive cancer in pre-surgical urine or biopsy tissues. In Aim 1, we will analyze urinary glycoproteins from patients with aggressive cancer and non-aggressive cancer using high throughput glycoproteomics and mass spectrometry to identify glycoproteins associated with aggressive prostate cancer. In Aim 2, we will validate the identified candidate urinary glycoproteins by targeted analysis of candidate glycoproteins from additional urine samples in independent testing sets of prostate cancer urine specimens from the EDRN network. In Aim 3, we will develop highly sensitive, specific, and high throughput ELISA or mass spectrometry based selective reaction monitoring assays as noninvasive urine tests using the glycoprotein biomarkers identified and validated from Aim 1 and Aim 2 and validate the performance of the tests for aggressive prostate cancer biomarkers. We will further determine the clinical utility of the validated tests to detect patients with aggressive prostate cancer in active surveillance program. In Aim 4, we will develop and optimize the immunohistochemistry assays for the glycoproteins associated aggressive prostate cancer tissues and validate these tissue glycoproteins using tissue microarrays. We will then further determine the clinical utility of the immunohistochemistry assays as biopsy based tissue tests for the early detection of patients with aggressive prostate cancer in active surveillance program. If successful, the identified and validated biomarkers will be tested by EDRN biomarker reference laboratory (BRL) and clinical validation center (CVC) in retrospective and prospective studies. Biomarkers capable of distinguishing aggressive from nonaggressive prostate cancer will allow men with aggressive prostate cancer to receive appropriate treatment earlier in the course of their diseases and prevent men with nonaggressive prostate cancer from overtreatment.

Biomarker Reference Laboratories

Clinical Validation Centers

Site Investigator Organ
The University of Texas MD Anderson Cancer Center Ovary
University of Nebraska Medical Center Pancreas
University of Pittsburgh Pancreas
University of Michigan Colorectal
Fred Hutchinson Cancer Research Center Breast cancer (female), Ovary
H. Lee Moffitt Cancer Center and Research Institute Breast cancer (female), Lung
H. Lee Moffitt Cancer Center and Research Institute Inc. Breast cancer (female), Lung
Fred Hutchinson Cancer Research Center Colorectal
University of Texas Health Science Center at San Antonio Prostate
H. Lee Moffitt Cancer Center and Research Institute Inc. Breast cancer (female), Lung
Fred Hutchinson Cancer Research Center Breast and Ovarian
The University of Texas M D Anderson Cancer Center Pancreas
Vanderbilt -Ingram Cancer Center Lung
Emory University Bladder, Breast cancer (female), Ovary, Prostate
H. Lee Moffitt Cancer Center and Research Institute Inc. Breast cancer (female), Lung

Data Management and Coordinating Center

Informatics Center

National Cancer Institute

Associate Members

This section lists associate EDRN members.

Associate Member A — EDRN Funded

Associate Member B

Site Investigator
AIBioTech
Baylor College of Medicine
Beth Israel Deaconess Medical Center
Biosite Incorporated
Biosystems International SAS
Brigham and Womens Hospital
Brigham and Womens Hospital
British Columbia Cancer Agency
British Columbia Cancer Research Centre/Cancer Genetics and Development Biology
Burlington Urology
CURC/Carolina Urologic Research Center
Cangen Biotechnologies Inc.
Case Western Reserve University
Center for Asbestos Related Diseases
Cleveland Clinic
Columbia University Medical Center
DKFZ-German Cancer Research Center
Dana Farber Cancer Institute-BWH
Eastern Virginia Medical School
Eastern Virginia Medical School
Emory University School of Medicine
Exact Sciences
Fox Chase Cancer Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Geisinger Health System
George Washington University
Georgetown University
Greenville Health System
Harborview Medical Center
Henry Ford Health Systems
Hershey-Penn State Medical Center
Hologic Gen-Probe Incorporated
INOVA Diagnostics Inc.
Instituto Valenciano de Infertilidad
Johns Hopkins
Johns Hopkins Medical Institute
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University Department of Urology
Kaiser Permanente Los Angeles California
Kaiser Permanente San Francisco Medical Center
Kalloger Consulting
LURN-Daytona Beach
LURN-New Jersey
LURN-Orange City
Lab DKFZ-German Cancer Research Center
LabCorp Molecular Biology & Pathology
Mayo Clinic
Mayo Clinic
Mayo Clinic Jacksonville
Mayo Clinic-Jacksonville
McGill University
Medical College of Georgia
Memorial Sloan Kettering Cancer Center
Memorial Sloan-Kettering
Memorial Sloan-Kettering Cancer Center
Miami Veterans Affairs Hospital
Moffitt Cancer Center
Mount Sinai Hospital
Mount Sinai Medical Center
Mt. Sinai Medical Center
Mt. Sinai Medical Center
National Cancer Institute
National Cancer Institute at Frederick
National Cancer Institute-PLCO
New York University
New York University School of Medicine
NorthShore University HealthSystem
Saint Louis University
San Diego Clinical Trials
San Diego State University
Source MDx
St. Michaels Hospital
St. Michaels Hospital
Stanford University
Stanford University
Stanford University
Stanford University Medical Center
The Fe/Male Health Clinic
The Johns Hopkins University
The Male Health Centre
The Male/Female Health and Research Center
The Ohio State University
The University of California San Francisco
The University of Texas MD Anderson Cancer Cente
The University of Texas MD Anderson Cancer Center
The Urology Group
Thomas Jefferson University
TwinStrand Biosciences
UT Southwestern Medical Center
UT Southwestern Medical Center at Dallas
Univ of Michigan
University of Alabama at Birmingham
University of British Columbia
University of Calgary Colon Cancer Screening Centre
University of California Irvine
University of California Los Angeles
University of California Los Angeles
University of California Los Angeles
University of California San Francisco
University of California San Francisco
University of Chicago Urology Center
University of Illinois at Chicago
University of Kansas Medical Center
University of Miami Miller School of Medicine
University of Michigan
University of Michigan
University of Michigan
University of Michigan
University of Michigan
University of Michigan
University of Michigan
University of Michigan
University of Minnesota
University of Nebraska
University of Nebraska Medical Center
University of North Carolina
University of Pennsylvania
University of Pittsburgh
University of Rochester Medical Center
University of Southern California/Norris Cancer Center
University of Texas Health Science Center San Antonio
University of Toronto
University of Washington
University of Washington
University of Western Australia
University of York
Urotec
VA Medical Center Seattle
Vanderbilt University
Vejle Hospital
Wako Diagnostics
Washington University
Weill Cornell Medical College
Wistar

Associate Member C

Site Investigator
20/20 GeneSystems Inc. Corp.
Abbott
Abbott Laboratories
AmberGen Inc.
Ambergen Inc.
Arizona Cancer Center
Arizona State University
Baylor
Beckman Coulter
Beckman Coulter
Beckman Research Institute of the City of Hope
Bio-Rad
Biochain Institute Inc.
Boston University
Brigham and Womens Hospital
Brigham and Womens Hospital
Brighton Consulting Group
CHRISTUS Santa Rosa Medical Center Hospital
CRUK Cambridge Research Institute
Centers for Disease Control
Commonwealth Scientific & Industrial Research Organisation
Creighton University
Dana Farber Cancer Institute/Harvard Medical School
Drexel University College of Medicine
Drexel University College of Medicine
Duke University
Duke University Medical Center
Emory University
Exploit Technologies PTE Ltd.
Fox Chase Cancer Center
Fox Chase Cancer Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Genetica Inc.
Genteomics USA Inc.
Genteomics USA Inc.
GlaxoSmithKline
H. Lee Moffitt Cancer Center
H. Lee Moffitt Cancer Center
HonorHealth Research Institute
Houston Methodist Research Institute
Iceland Genomics Corporation
Indiana University
Insightful Inc.
Institute of Cancer Research
Instituto Nazionale Tumori Regina Elena
Johns Hopkins Medical Institutions
Johns Hopkins School of Medicine
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University
Johns Hopkins University School of Medicine
Johns Hopkins University School of Medicine
Johns Hopkins University School of Medicine
Johns Hopkins University School of Medicine
Karmanos Cancer Institute
Lombardi Comprehensive Cancer Center
Lombardi Comprehensive Cancer Center
Lovelace Respiratory Research Institute
MD Anderson Cancer Center
MDxHealth Inc.
Medical University of South Carolina
Medical University of South Carolina
Meharry Medical College School of Medicine
Meso Scale Diagnostics
Metabolon
Metabolon Inc.
Milagen Inc.
Mitchell Cancer Institute
Mitchell Cancer Institute
Mitchell Cancer Institute
Mount Sinai Hospital
Mount Sinai Medical Center
NOX Technologies
NanoInk Inc.
National Cancer Institute
National Cancer Institute Tumor Glycome Laboratory
National Institute of Standards and Technology
National Institute of Standards and Technology
New York University School of Medicine
NextGen Sciences
Nidaan Inc.
North Dakota State University
NorthShore University HealthSystem
Northwestern University
Northwestern University Feinberg School of Medicine
Northwestern University Feinberg School of Medicine
Pacific Nanoscience Inc.
Pacific Northwest National Laboratory
Pacific Northwest National Laboratory
Perelman School of Medicine/University of Pennsylvania
Perelman School of Medicine/University of Pennsylvania
Peter MacCAllum Cancer Institute
PrimeraDx
Private Consultant
Provista Diagnostics
Qorvo
Quanterix
Rheinische Friedrich-Wilhelms-Universitat
Roche Diagnostics
Sage Bionetworks
Samsung Medical Center
Sanford-Burnham Medical Research Institute
SomaLogic
Stanford University
Stanford University
Stanford University
The Ohio State University
The Ohio State University College of Pharmacy
The Ohio State University Medical Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
The University of Texas MD Anderson Cancer Center
Transgenomic Inc.
Tufts University Medical Center
UT Health Science Center San Antonio
UT Southwestern Medical Center
UT Southwestern Medical Center
University of Alabama at Birmingham
University of California Davis
University of California Los Angeles
University of California Los Angeles
University of California San Diego
University of California San Francisco
University of California at Los Angeles
University of California at San Francisco
University of Colorado Health Science Center
University of Copenhagen/Hvidovre Hospital
University of Georgia
University of Hawaii Cancer Center
University of Maryland
University of Maryland Baltimore
University of Massachusetts Boston
University of Michigan
University of Michigan
University of Michigan Medical Center
University of Michigan Medical School
University of Michigan Medical School
University of Michigan Medical School
University of Nebraska Medical Center
University of New Mexico
University of North Carolina at Chapel Hill
University of Pittsburgh Cancer Instititute
University of Pittsburgh Cancer Institute
University of Texas at San Antonio
University of Toronto
University of Washington
University of Washington
Urological Sciences Research Foundation
VU Medical Center
Vanderbilt Medical Center
Vanderbilt Medical Center
Vanderbilt University Medical Center
Ventana
Ventana
Veridex LLC
VolitionRx
Weizmann Institute of Science
Xenomics
Yale University
Yale University School of Medicine
diaDexus
diaDexus

SPOREs

Non-EDRN Sites

This section lists non-EDRN sites.

Non-EDRN Site

Site Investigator
Abbott Diagnostics R
Atrium Medical Center
Boston University School of Medicine
Boston University School of Medicine
CanDiag Inc
Canary Foundation
Carle Cancer Center
Case Comprehensive Cancer Center/Case Western Reserve University
Center of Oncology, Cracow Division
Cleveland Clinic
Clínica Las Condes/Universidad de Chile
Duke University Medical Center
EIC Laboratories Inc.
Eppley Institute for Cancer Research/University of Nebraska Medical Center
Essentia Health Duluth CCOP
Ewha Womans University, Seoul, Korea
Food and Drug Administration
Forsyth Regional Cancer Center
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
Fujirebio Diagnostics Inc.
Genomic Health Inc.
Grand Rapids Clinical Oncology Program
Gundersen Lutheran
Harvard Medical School
Henry Ford Hospital
IFOM, The FIRC Institute for Molecular Oncology Foundation
Institute of Medical Science, The University of Tokyo
International Prevention Research Institute (iPRI)
Johns Hopkins Medical Institutions
Johns Hopkins University
Lab Corps
Lahey Hospital and Medical Center
Marshfield Clinic
Mayo Clinic
Memorial Sloan Kettering Cancer Center
Mercy Physicians of Oklahoma
Mount Sinai Hospital
NASPCC/Mountain Foundation For Lung Cancer
Nanjing University
Natalie Warren Bryant Cancer Center
National Cancer Center Research Institute
National Cancer Institute
National Cancer Institute
National Cancer Institute
National Institute of Standards and Technology
New York University School of Medicine
North Eastern University
Northwestern University Feinberg School of Medicine
Novartis
Novartis Institutes for BioMedical Research Inc.
Orange County Urological Associates
Pacific Northwest National Laboratory (PNNL)
Quest Diagnostics
Research Advocacy Network
Roswell Park Cancer Institute
Rush University Medical Center
SUNY Upstate Medical Hospital
Safety Mutual of the Chilean Chamber of Construction
Sanford Cancer Center Oncology Clinic
Sanford Clinic North-Fargo
Second Military Medical University
Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins University
SomaLogic
St. Vincent CCOP
Temple University
The Ohio State University Comprehensive Cancer Center
The University of Nottingham, UK
Tripler Army Medical Center
University of Arkansas Medical Sciences
University of Bari
University of Chicago
University of Colorado School of Medicine
University of Halle-Wittenberg
University of Hawaii MBCCCOP
University of Kentucky
University of Kentucky College of Medicine
University of Michigan
University of North Carolina School of Medicine
University of Southern California Norris Cancer Center
University of Toledo Medical Center
University of Washington
University of Washington School of Medicine
Upstate Carolina CCOP
Vanderbilt University Medical Center
Vanderbilt University School of Medicine
Vanderbilt University School of Medicine
Vanderbilt-Ingram Cancer Center
Wako Diagnostics
Washington University in St. Louis
Weiss Memorial Hospital
Wichita CCOP
William Beaumont Hospital
Announcement



EDRN Founder Honored

Dr. Sudhir Srivastava was honored with the Distinguished Service Award from the American Pancreatic Association at the group's annual meeting this year, for his outstanding commitment to pancreatology.