Sites
Also try the member finder.
- Biomarker Characterization Centers
- Biomarker Developmental Laboratories
- Biomarker Reference Laboratories
- Clinical Validation Centers
- Data Management and Coordinating Center
- Informatics Center
- National Cancer Institute
- Associate Members
- SPOREs
- Non-EDRN Sites
- Advancement of Head and Neck Cancer Early Detection Research (AHEAD)
Biomarker Characterization Centers
The Biomaker Characterization Centers (BCCs) identify, specify, and make distinctive new biomarkers or refine existing biomarkers. There are two kinds of BCCs:
Breast
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
812 | Paulovich, Amanda, M.D., Ph.D. | Fred Hutchinson Cancer Center | Contact PI | BCC, BDL |
1048 | Hoofnagle, Andrew, M.D., Ph.D. | University of Washington | MPI | BCC, BRL |
1051 | Wang, Pei, Ph.D. | Icahn School of Medicine at Mount Sinai | MPI | BCC |
Colon and Esophagus
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
160 | Grady, William, M.D. | Fred Hutchinson Cancer Center | Contact PI | BCC, BDL |
1016 | Yeung, Cecilia, M.D. | Fred Hutch Cancer Center | MPI | BCC, BRL |
uses a substantial proportion of healthcare resources. Of the GI cancers, colorectal cancer (CRC) and
esophageal cancer (EAC) account for a majority of the cancer related deaths, and both are preventable by
screening and surveillance. The current screening tests are suboptimal and have variable success.
A major goal of CRC screening tests is to identify advanced tubular and serrated adenomas, which are
high-risk for becoming CRC, as well as early stage CRC. The risk for CRC is variable with some people being
at high risk because of family histories of CRC, hereditary cancer syndromes, or a personal history of adenomas.
High risk people are placed on aggressive colonoscopy based surveillance programs and low-risk people are
placed on minimal surveillance programs. Unfortunately, our current system for identifying high and low CRC
risk is suboptimal resulting in under and over surveillance and preventable interval CRCs. Better risk markers
for CRC to are needed to prevent interval CRCs and improve the overall effectiveness of CRC screening.
Analogous to CRC, EAC arises from a precancerous condition of the esophagus called Barretts
esophagus (BE), which is a specialized intestinal metaplasia of the esophagus and the highest risk factor for
EAC. It is present in 5% of the US population. BE progresses to EAC through successive histologic steps of
low grade dysplasia (LGD), high grade dysplasia (HGD) and then EAC. Screening and surveillance for BE is
recommended using serial upper endoscopy, which is controversial in its effectiveness for preventing deaths
from EAC. This is in part because, as with CRC, BE patients have variable risk of EAC and are placed on highrisk
and low-risk screening programs. However, the current system for assigning risk is not accurate and the
current screening test is expensive. More cost effective and accurate EAC and HGD screening/surveillance
assays and accurate BE risk biomarkers are needed.
We propose to develop an EDRN BCC that is integrated into the EDRN consortium and, through
collaborations within and outside the EDRN, will develop effective GI cancer screening biomarkers. We propose
to identify, validate, and develop accurate CLIA compliant risk biomarkers for CRC and for EAC in order to
prevent EAC and CRC missed under current screening protocols. Moreover, the accurate risk stratification of
patients for CRC and EAC will reduce the financial impact of current CRC and EAC prevention programs. We
also propose to identify and validate accurate CLIA compliant early detection markers for HGD and early stage
EAC that can be used in an inexpensive, non-endoscopic surveillance test.
Lung
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
813 | Herman, James, M.D. | University of Pittsburgh School of Medicine | Contact PI | BCC, BDL, BRL |
201 | Stass, Sanford, M.D. | University of Maryland School of Medicine | MPI | BCC, BRL |
818 | Wang, Tza-Huei (Jeff), Ph.D. | Johns Hopkins Whiting School of Engineering | MPI | BCC, BDL |
Network (EDRN) seeks to improve the management of lung cancer through detection of cancerspecific
DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) which
will optimize the methylation detection methods, implementation of these methods for clinical use
through a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testing
in a clinical setting, and an Administrative Core facilitating the interactions between the BDL and
BRL, and with other EDRN investigators and the NCI. Previous work by the applicants has
demonstrated the potential of DNA methylation detection for cancer diagnostics, and they have
developed extremely sensitive assays for the detection of hypermethylated DNA sequences and
optimized the isolation and processing of circulating cell-free DNA from tumors for these novel
assays. The approach has been used to detect circulating cancer-specific DNA methylation
changes for the early diagnosis of lung cancer in patients with screen-detected pulmonary
nodules. Although sensitivity and specificity of the assay are promising, additional improvements
in the performance are required for implementation of this approach in the setting of cancer
screening. In this BCC, detection of cancer-specific DNA methylation changes in the plasma will
be further improved, and new approaches developed and implemented to address the challenges
of ultrasensitive detection of DNA methylation in the blood. In addition, we will assess the potential
of these methods to detect other common and lethal malignancies. Our bioinformatic analysis of
DNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequent
cancer-specific methylation events common to all cancers, including lung cancer, that will be
developed into universal cancer detection assays. The use of TCGA data has also resulted in the
identification of other methylation alterations that allow determination of the origin (organ site) of
this cancer-specific signal. The combination of optimal sample processing, ultrasensitive
methylation detection, developed with universal cancer and histology specific loci detection, will
allow improved lung cancer early detection in the setting of CT screening and management of
detection of other cancer-specific DNA methylation from blood.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
594 | Lenburg, Marc, Ph.D. | Boston University | Contact PI | BCC, BDL |
1014 | Beane-Ebel, Jennifer E., Ph.D. | Boston University School of Medicine | MPI | BCC, BDL |
1033 | Bulman, William, | Veracyte Inc | Co-Investigator | BCC, BRL |
241 | Dubinett, Steve, M.D. | University of California Los Angeles | MPI | BCC, BDL |
1015 | Hsu, William, Ph.D. | UCLA School of Engineering | MPI | BCC, BDL, BRL |
1035 | Pagano, Paul, Ph.D. | LungLife AI, Inc | Co-Investigator | BCC, BRL |
1034 | Palazzolo, Michael, M.D., Ph.D. | University of California, Los Angeles | Co-Investigator | BCC, BRL |
dilemma for which there is little consensus about appropriate follow up due to a lack of sensitive and specific
approaches for the detection of lung cancer absent invasive tissue sampling, and concerns about costs and
harms from invasive tissue sampling in this large clinical population. Minimally invasive approaches that could
accurately reclassify individuals from the intermediate risk group (5-65% risk of malignancy) to either low (< 5%)
or high (>65%) risk would reduce uncertainty and transform the diagnostic workup of intermediate risk IPN.
Developing, evaluating, standardizing, and validating such minimally invasive biomarkers so that they are ready
for clinical use is the goal of the proposed BU-UCLA Lung Cancer Biomarker Characterization Center (BCC). In
previous EDRN-funded work we established lung-cancer associated gene expression patterns in nasal
epithelium collected with a swab from the inferior turbinate as a lung cancer biomarker. A test based on this
innovative approach to lung cancer detection is being launched for clinical use as a CLIA LDT by our long-time
collaborator Veracyte, Inc., which is participating in this BCC. We will evaluate the nasal biomarker for lung
cancer in the setting of intermediate risk IPN. To further improve the ability to clinically discriminate benign from
malignant intermediate risk IPN, the BU-UCLA Lung Cancer Biomarker Discovery Lab embedded within the BCC
will develop and test lung cancer detection approaches that incorporate detection of circulating tumor cells (CTC)
using a CLIA LDT assay from our collaborator LungLife AI, Inc. as well as blood based immune biomarkers,
advanced imaging biomarkers, and refined nasal gene expression biomarkers. We will additionally determine if
longitudinal biomarker assessment improves lung cancer detection over cross-sectional measurements.
Promising assays will be refined, standardized, and validated by the BU-UCLA Lung Cancer Biomarker
Reference Lab embedded within the BCC to advance them toward clinical adoption. These studies are enabled
by biospecimens and imaging data that are being prospectively collected from diverse populations of patients
undergoing workup for intermediate risk IPN in several large-scale ongoing clinical studies including VA LPOP,
DECAMP 1-Plus, and UCLA IDx; lung cancer research programs at UCLA and Lahey; and our EDRN
collaborators at Nashville VA and Vanderbilt. The BU-UCLA Lung Cancer BCC Team has the required multidisciplinary
expertise in lung cancer, translational and clinical pulmonary medicine, biomarker discovery, clinical
assay development, biostatistics, clinical epidemiology, pathology, imaging, artificial intelligence, biological
sciences, bioinformatics, genomics, and complex scientific program management to accomplish these goals. An
Administrative Core embedded within the BCC will ensure that the BCC delivers on its aim to substantially
advance novel lung cancer biomarkers from discovery to clinical application and make significant contributions
to the Early Detection Research Network.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1049 | Segal, Leopoldo, M.D. | New York University Grossman School of Medicine | Contact PI | BCC, BDL, BRL |
176 | Pass, Harvey Ira, M.D. | New York University School of Medicine | MPI | BCC, BDL, BRL |
Lung and Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
523 | LaBaer, Joshua, M.D., Ph.D. | Arizona State University | Contact PI | BCC, BDL |
230 | Anderson, Karen, M.D., Ph.D. | Arizona State University | MPI | BCC, BDL |
1032 | Stengelin, Martin, Ph.D. | Meso Scale Diagnostics | Co-Investigator | BCC, BRL |
the development of biologically-relevant circulating immune biomarkers. The scientific approach of our Center is
based on several fundamental principles. First, that altered cancer protein expression, structure, and posttranslational
modifications induce host autoantibodies to create circulating biomarkers. Second, that alterations
in microbial antigen expression (such as respiratory pathogens) also induce immunity, often detected in benign
rather than malignant disease. Third, that the protein modifications, as well as the immune response to these
neoantigenic structures, are heterogeneous between people, and that serologic biomarkers may complement
circulating protein biomarkers. We will take a systems immunology approach to discover three types of
antibodies, anti-microbial antibodies, autoantibodies and anti-aberrant glycoprotein antibodies. Our proposal
builds on our extensive experiences with cancer biomarker discovery and immunoproteomics technology
development. Our previous results on autoantibody biomarkers have been confirmed in blinded phase 2
multicenter validation studies and led to a CLIA-certified commercial blood test. Our results have shown that
multiplexed panels of autoantibodies are required for adequate predictive value. With prior EDRN support, we
have developed a set of innovative immunoproteomics technologies, namely high-density nucleic acid
programmable protein array (HD-NAPPA), contra-capture protein array (CCPA) and multiplexed in solution
protein array (MISPA), that, together with the largest full-length human and microbial gene collection at our
DNASU plasmid repository, enable us to study antibodies against the full human proteome, microbial proteomes
and the human O-glycoproteome for antibody biomarker signatures in cancer. Our Meso Scale Diagnostics
(MSD) team has fielded over 3,000 instruments worldwide, and over 700 commercially available biomarker assay
kits. Our expertise at serologic assay development was selected by Operation Warp Speed to use the V-PLEX®
serology panels as the basis of its standard binding assays for immunogenicity assessments in all funded Phase
III clinical trials of COVID vaccines. We will use our MSD MultiArray platform to migrate the top serologic and
protein markers for their utility in our target clinical applications. We will collaborate with experts on lung and
ovarian cancer screening at Vanderbilt University Medical Center, Boston University, MD Anderson Cancer
Center, and German Cancer Research Center, who will also provide access to high-quality well-characterized
samples to develop circulating biomarkers to enhance ovarian cancer screening or to distinguish benign from
malignant pulmonary nodules. Adhering to the principles of PRoBE design, we will perform Phase I discovery by
screening protein arrays with cancer patient and control sera for cancer or control-specific antibodies. Candidate
biomarkers for both lung and ovarian cancers will undergo Phase 2 validation.
Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
800 | Zhang, Zhen, Ph.D. | Johns Hopkins University | Contact PI | BCC, BDL |
200 | Chan, Daniel, Ph.D. | Johns Hopkins Medical Institutions | Co-Investigator | BCC, BRL |
829 | Shih, le-Ming, M.D., Ph.D. | Johns Hopkins University School of Medicine | MPI | BCC, BDL |
cancer. The overarching goal of the proposed Biomarker Characterization Center (BCC) is to apply a bydesign
approach based on biology of HGSOC pathogenesis and unmet clinical needs to identify, verify and
prioritize, and validate biomarkers, and to develop them into an in vitro diagnostic multivariate index assay
(IVDMIA) with the intended use to capture HGSOC in high-risk women at the early stages including i)
precursors, ii) confinement to the ovary/fallopian tube or iii) low-volume diseases in high-risk women (BRCA1/2
carriers). The biomarkers that we propose to discover and validate in this proposal are intended for early
detection but not necessarily for screening in general population. The BCC’s capability in advanced data
generation technologies, multiplexed target assay development, and bioinformatics/data science will serve as
resources for the EDRN. Based on the success of our current EDRN projects, this BCC will continue our ongoing
biomarker development studies including the validation of candidate biomarkers that we have identified
through the current BDL. We propose the following specific aims:
1. To optimize and use novel specimen collection and processing technologies, and an iterative and
cumulative process that takes advantage of our newly gained knowledge of the biology in ovarian cancer
pathogenesis. BDL
2. To optimize and apply innovative bioinformatics, data sciences, and AI/ML tools that incorporate existing
knowledge and data to improve discovery of low frequency biomarkers that with their functionally shared
pathways/networks could collectively deliver an improved sensitivity while retaining a high specificity. BDL
3. To further develop and optimize the process for efficient multiplex targeted assay development with respect
to analytical performance, throughput, and specimen volume requirement for a broad spectrum of
candidate biomarkers using a “fit for purpose” approach. BRL
4. To optimize and apply a by-design approach to translating discoveries into clinical tests. Its application had
been critical in the development of two FDA cleared tests by JHU team members for the preoperative
assessment of ovarian malignancy risk. BDL/BRL
5. To provide expertise and analytical and data science capabilities to the entire EDRN community.
The multi-disciplinary team that we have assembled (molecular cancer biology, pathology, clinical chemistry,
mass spectrometry, biostatistics, data science, bioengineering), the unique, novel yet biologically and
statistically sound approaches, and our long-standing experience in biomarker research and translating
discoveries to FDA cleared clinical tests all together ensure the success of this proposed BCC.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
610 | Skates, Steven, Ph.D. | Massachusetts General Hospital | Contact PI | BCC, BDL |
1031 | Kulasingam, Vathany, Ph.D. | University Health Network | Co-Investigator | BCC, BRL |
1002 | Patel, Abhijit, M.D. | Yale University | MPI | BCC, BDL |
detection of ovarian cancer in normal risk postmenopausal women failed to show a cancer-specific mortality
reduction. The likely fundamental reason for the failure is the short window of opportunity provided by a
blood-based signal. The proposed BCC will seek to identify an alternative biospecimen for the source of signal
which has a much greater window of time for detection in early-stage disease so that an annual testing
frequency will have a high likelihood of detecting ovarian cancer during its curable stages. Due to the direct
connection of the uterus to the fallopian tube, where the cell of origin resides, a uterine lavage will likely
contain the earliest biological signals of the presence of ovarian cancer. Identifying a minimal ovarian cancer
signal amongst a much greater background of uterine epithelium cells and cellular material requires a very
sensitive test. Our BCC will build on a recently developed innovative genome-wide methylation test and
combine it with a sensitive antibody based proteomic test. Having optimized the combined test to detect a
signal in uterine lavage, the BCC will determine its sensitivity in Pap smears. The BCC will optimize the
combined test on training uterine lavage samples, validate the test on independent validation cohort of
uterine lavage samples, and assess its performance in Pap smear samples. If the optimized test is sensitive in
Pap smears, then the overall goal of a clinically acceptable and readily performed test (Pap smear) conducted
at a feasible frequency of every 12 months will be a crucial step towards an annual test for the early detection
of ovarian cancer in normal risk postmenopausal women, the population in which 80% of ovarian cancers
occur. The long-term goal is an early detection program resulting in a significant reduction in ovarian cancer
mortality. The intended use of the test developed by the BCC will be as a clinical decision-support tool for
screening normal risk postmenopausal women for early detection of ovarian cancer. Such a test will fill an
unmet health gap since there is currently no early detection test for ovarian cancer.
Prostate
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
188 | Chinnaiyan, Arul M., M.D., Ph.D. | University of Michigan | Contact PI | BCC, BDL |
1030 | Kitchen, John, Ph.D. | LynxDx | Co-Investigator | BCC, BRL |
1011 | Tosoian, Jeffrey, M.D. | Vanderbilt University Medical Center | MPI | BCC, BRL |
1029 | Xiao, Lanbo, Ph.D. | University of Michigan | Co-Investigator | BCC, BRL |
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.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
92 | Semmes, John, Ph.D. | Eastern Virginia Medical School | Contact PI | BCC, BRL |
823 | Boutros, Paul, Ph.D. | The University of California, Los Angeles | MPI | BCC, BRL |
822 | Kislinger, Thomas, Ph.D. | Princess Margaret Cancer Centre, University Health Network, University of Toronto | MPI | BCC, BDL |
distinguishing indolent from aggressive and life-threatening cancers. Biomarkers are urgently needed to
identify those patients who harbor aggressive disease and will derive benefit from definitive treatment. We
therefore, propose to apply complimentary proteogenomic-based discovery approaches to identify and then
validate molecular features in prostate proximal fluids and tumor tissues that will be utilized in accurate early
detection of aggressive forms of prostate cancer and improve disease risk stratification. The intended use of
these biomarkers will be the early identification of men at risk for grade progression and improved riskstratification
for them.
We have three biomarker development laboratory aims: 1) Validate our existing urine-based biomarkers for
grade progression in a ProBE-compliant study selected from our own cohorts and the EDRN GU upgrading
study. 2) Develop and validate urine and tissue-based biomarkers for the risk-stratification of MRI “invisible”
high-grade lesions. 3) Develop and validate biomarkers to sub-stratify risk associated with deleterious
germline BRCA2 variants.
Our biomarker reference laboratory will develop and validate targeted clinically robust assays for multi-protein
biomarkers panels. We will also develop decision algorithms that are cross-referenced for statistical rigor and
benchmarked for optimal clinical performance. In addition to these BCC activities, we will develop robust
PRM-MS assays and statistically rigorous decision tools for other EDRN BCCs and CVCs.
Taken together, our EDRN biomarker characterization center will be a core part of the the EDRN ecosystem.
We will continue to actively participate in trans-Network activities, and to share patient cohorts, protocols,
datasets and analysis approaches and expertise. We will supplement these activities by focusing on
promoting the growth of new and diverse talent in biomarker development through fostering junior investigator
involvement across the full spectrum of biomarker development.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1047 | Chan, Daniel, Ph.D. | The Johns Hopkins University | Contact PI | BCC, BRL |
448 | Zhang, Hui L., Ph.D. | Johns Hopkins University School of Medicine | MPI | BCC, BDL |
Biomarker Developmental Laboratories
Biomarker Developmental Laboratories (BDLs) discover and develop new biomarkers or refine existing biomarkers. They are the primary source of new biomarkers or panels of biomarkers on which the EDRN conducts validation trials. They also develop assays to detect candidate biomarkers and conduct pre-validation studies.
Breast
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
812 | Paulovich, Amanda, M.D., Ph.D. | Fred Hutchinson Cancer Center | Contact PI | BCC, BDL |
Colon and Esophagus
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
160 | Grady, William, M.D. | Fred Hutchinson Cancer Center | Contact PI | BCC, BDL |
uses a substantial proportion of healthcare resources. Of the GI cancers, colorectal cancer (CRC) and
esophageal cancer (EAC) account for a majority of the cancer related deaths, and both are preventable by
screening and surveillance. The current screening tests are suboptimal and have variable success.
A major goal of CRC screening tests is to identify advanced tubular and serrated adenomas, which are
high-risk for becoming CRC, as well as early stage CRC. The risk for CRC is variable with some people being
at high risk because of family histories of CRC, hereditary cancer syndromes, or a personal history of adenomas.
High risk people are placed on aggressive colonoscopy based surveillance programs and low-risk people are
placed on minimal surveillance programs. Unfortunately, our current system for identifying high and low CRC
risk is suboptimal resulting in under and over surveillance and preventable interval CRCs. Better risk markers
for CRC to are needed to prevent interval CRCs and improve the overall effectiveness of CRC screening.
Analogous to CRC, EAC arises from a precancerous condition of the esophagus called Barretts
esophagus (BE), which is a specialized intestinal metaplasia of the esophagus and the highest risk factor for
EAC. It is present in 5% of the US population. BE progresses to EAC through successive histologic steps of
low grade dysplasia (LGD), high grade dysplasia (HGD) and then EAC. Screening and surveillance for BE is
recommended using serial upper endoscopy, which is controversial in its effectiveness for preventing deaths
from EAC. This is in part because, as with CRC, BE patients have variable risk of EAC and are placed on highrisk
and low-risk screening programs. However, the current system for assigning risk is not accurate and the
current screening test is expensive. More cost effective and accurate EAC and HGD screening/surveillance
assays and accurate BE risk biomarkers are needed.
We propose to develop an EDRN BCC that is integrated into the EDRN consortium and, through
collaborations within and outside the EDRN, will develop effective GI cancer screening biomarkers. We propose
to identify, validate, and develop accurate CLIA compliant risk biomarkers for CRC and for EAC in order to
prevent EAC and CRC missed under current screening protocols. Moreover, the accurate risk stratification of
patients for CRC and EAC will reduce the financial impact of current CRC and EAC prevention programs. We
also propose to identify and validate accurate CLIA compliant early detection markers for HGD and early stage
EAC that can be used in an inexpensive, non-endoscopic surveillance test.
Lung
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
813 | Herman, James, M.D. | University of Pittsburgh School of Medicine | Contact PI | BCC, BDL, BRL |
818 | Wang, Tza-Huei (Jeff), Ph.D. | Johns Hopkins Whiting School of Engineering | MPI | BCC, BDL |
Network (EDRN) seeks to improve the management of lung cancer through detection of cancerspecific
DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) which
will optimize the methylation detection methods, implementation of these methods for clinical use
through a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testing
in a clinical setting, and an Administrative Core facilitating the interactions between the BDL and
BRL, and with other EDRN investigators and the NCI. Previous work by the applicants has
demonstrated the potential of DNA methylation detection for cancer diagnostics, and they have
developed extremely sensitive assays for the detection of hypermethylated DNA sequences and
optimized the isolation and processing of circulating cell-free DNA from tumors for these novel
assays. The approach has been used to detect circulating cancer-specific DNA methylation
changes for the early diagnosis of lung cancer in patients with screen-detected pulmonary
nodules. Although sensitivity and specificity of the assay are promising, additional improvements
in the performance are required for implementation of this approach in the setting of cancer
screening. In this BCC, detection of cancer-specific DNA methylation changes in the plasma will
be further improved, and new approaches developed and implemented to address the challenges
of ultrasensitive detection of DNA methylation in the blood. In addition, we will assess the potential
of these methods to detect other common and lethal malignancies. Our bioinformatic analysis of
DNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequent
cancer-specific methylation events common to all cancers, including lung cancer, that will be
developed into universal cancer detection assays. The use of TCGA data has also resulted in the
identification of other methylation alterations that allow determination of the origin (organ site) of
this cancer-specific signal. The combination of optimal sample processing, ultrasensitive
methylation detection, developed with universal cancer and histology specific loci detection, will
allow improved lung cancer early detection in the setting of CT screening and management of
detection of other cancer-specific DNA methylation from blood.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
594 | Lenburg, Marc, Ph.D. | Boston University | Contact PI | BCC, BDL |
1014 | Beane-Ebel, Jennifer E., Ph.D. | Boston University School of Medicine | MPI | BCC, BDL |
241 | Dubinett, Steve, M.D. | University of California Los Angeles | MPI | BCC, BDL |
1015 | Hsu, William, Ph.D. | UCLA School of Engineering | MPI | BCC, BDL, BRL |
dilemma for which there is little consensus about appropriate follow up due to a lack of sensitive and specific
approaches for the detection of lung cancer absent invasive tissue sampling, and concerns about costs and
harms from invasive tissue sampling in this large clinical population. Minimally invasive approaches that could
accurately reclassify individuals from the intermediate risk group (5-65% risk of malignancy) to either low (< 5%)
or high (>65%) risk would reduce uncertainty and transform the diagnostic workup of intermediate risk IPN.
Developing, evaluating, standardizing, and validating such minimally invasive biomarkers so that they are ready
for clinical use is the goal of the proposed BU-UCLA Lung Cancer Biomarker Characterization Center (BCC). In
previous EDRN-funded work we established lung-cancer associated gene expression patterns in nasal
epithelium collected with a swab from the inferior turbinate as a lung cancer biomarker. A test based on this
innovative approach to lung cancer detection is being launched for clinical use as a CLIA LDT by our long-time
collaborator Veracyte, Inc., which is participating in this BCC. We will evaluate the nasal biomarker for lung
cancer in the setting of intermediate risk IPN. To further improve the ability to clinically discriminate benign from
malignant intermediate risk IPN, the BU-UCLA Lung Cancer Biomarker Discovery Lab embedded within the BCC
will develop and test lung cancer detection approaches that incorporate detection of circulating tumor cells (CTC)
using a CLIA LDT assay from our collaborator LungLife AI, Inc. as well as blood based immune biomarkers,
advanced imaging biomarkers, and refined nasal gene expression biomarkers. We will additionally determine if
longitudinal biomarker assessment improves lung cancer detection over cross-sectional measurements.
Promising assays will be refined, standardized, and validated by the BU-UCLA Lung Cancer Biomarker
Reference Lab embedded within the BCC to advance them toward clinical adoption. These studies are enabled
by biospecimens and imaging data that are being prospectively collected from diverse populations of patients
undergoing workup for intermediate risk IPN in several large-scale ongoing clinical studies including VA LPOP,
DECAMP 1-Plus, and UCLA IDx; lung cancer research programs at UCLA and Lahey; and our EDRN
collaborators at Nashville VA and Vanderbilt. The BU-UCLA Lung Cancer BCC Team has the required multidisciplinary
expertise in lung cancer, translational and clinical pulmonary medicine, biomarker discovery, clinical
assay development, biostatistics, clinical epidemiology, pathology, imaging, artificial intelligence, biological
sciences, bioinformatics, genomics, and complex scientific program management to accomplish these goals. An
Administrative Core embedded within the BCC will ensure that the BCC delivers on its aim to substantially
advance novel lung cancer biomarkers from discovery to clinical application and make significant contributions
to the Early Detection Research Network.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1049 | Segal, Leopoldo, M.D. | New York University Grossman School of Medicine | Contact PI | BCC, BDL, BRL |
176 | Pass, Harvey Ira, M.D. | New York University School of Medicine | MPI | BCC, BDL |
Lung and Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
523 | LaBaer, Joshua, M.D., Ph.D. | Arizona State University | Contact PI | BCC, BDL |
230 | Anderson, Karen, M.D., Ph.D. | Arizona State University | MPI | BCC, BDL |
the development of biologically-relevant circulating immune biomarkers. The scientific approach of our Center is
based on several fundamental principles. First, that altered cancer protein expression, structure, and posttranslational
modifications induce host autoantibodies to create circulating biomarkers. Second, that alterations
in microbial antigen expression (such as respiratory pathogens) also induce immunity, often detected in benign
rather than malignant disease. Third, that the protein modifications, as well as the immune response to these
neoantigenic structures, are heterogeneous between people, and that serologic biomarkers may complement
circulating protein biomarkers. We will take a systems immunology approach to discover three types of
antibodies, anti-microbial antibodies, autoantibodies and anti-aberrant glycoprotein antibodies. Our proposal
builds on our extensive experiences with cancer biomarker discovery and immunoproteomics technology
development. Our previous results on autoantibody biomarkers have been confirmed in blinded phase 2
multicenter validation studies and led to a CLIA-certified commercial blood test. Our results have shown that
multiplexed panels of autoantibodies are required for adequate predictive value. With prior EDRN support, we
have developed a set of innovative immunoproteomics technologies, namely high-density nucleic acid
programmable protein array (HD-NAPPA), contra-capture protein array (CCPA) and multiplexed in solution
protein array (MISPA), that, together with the largest full-length human and microbial gene collection at our
DNASU plasmid repository, enable us to study antibodies against the full human proteome, microbial proteomes
and the human O-glycoproteome for antibody biomarker signatures in cancer. Our Meso Scale Diagnostics
(MSD) team has fielded over 3,000 instruments worldwide, and over 700 commercially available biomarker assay
kits. Our expertise at serologic assay development was selected by Operation Warp Speed to use the V-PLEX®
serology panels as the basis of its standard binding assays for immunogenicity assessments in all funded Phase
III clinical trials of COVID vaccines. We will use our MSD MultiArray platform to migrate the top serologic and
protein markers for their utility in our target clinical applications. We will collaborate with experts on lung and
ovarian cancer screening at Vanderbilt University Medical Center, Boston University, MD Anderson Cancer
Center, and German Cancer Research Center, who will also provide access to high-quality well-characterized
samples to develop circulating biomarkers to enhance ovarian cancer screening or to distinguish benign from
malignant pulmonary nodules. Adhering to the principles of PRoBE design, we will perform Phase I discovery by
screening protein arrays with cancer patient and control sera for cancer or control-specific antibodies. Candidate
biomarkers for both lung and ovarian cancers will undergo Phase 2 validation.
Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
800 | Zhang, Zhen, Ph.D. | Johns Hopkins University | Contact PI | BCC, BDL |
829 | Shih, le-Ming, M.D., Ph.D. | Johns Hopkins University School of Medicine | MPI | BCC, BDL |
cancer. The overarching goal of the proposed Biomarker Characterization Center (BCC) is to apply a bydesign
approach based on biology of HGSOC pathogenesis and unmet clinical needs to identify, verify and
prioritize, and validate biomarkers, and to develop them into an in vitro diagnostic multivariate index assay
(IVDMIA) with the intended use to capture HGSOC in high-risk women at the early stages including i)
precursors, ii) confinement to the ovary/fallopian tube or iii) low-volume diseases in high-risk women (BRCA1/2
carriers). The biomarkers that we propose to discover and validate in this proposal are intended for early
detection but not necessarily for screening in general population. The BCC’s capability in advanced data
generation technologies, multiplexed target assay development, and bioinformatics/data science will serve as
resources for the EDRN. Based on the success of our current EDRN projects, this BCC will continue our ongoing
biomarker development studies including the validation of candidate biomarkers that we have identified
through the current BDL. We propose the following specific aims:
1. To optimize and use novel specimen collection and processing technologies, and an iterative and
cumulative process that takes advantage of our newly gained knowledge of the biology in ovarian cancer
pathogenesis. BDL
2. To optimize and apply innovative bioinformatics, data sciences, and AI/ML tools that incorporate existing
knowledge and data to improve discovery of low frequency biomarkers that with their functionally shared
pathways/networks could collectively deliver an improved sensitivity while retaining a high specificity. BDL
3. To further develop and optimize the process for efficient multiplex targeted assay development with respect
to analytical performance, throughput, and specimen volume requirement for a broad spectrum of
candidate biomarkers using a “fit for purpose” approach. BRL
4. To optimize and apply a by-design approach to translating discoveries into clinical tests. Its application had
been critical in the development of two FDA cleared tests by JHU team members for the preoperative
assessment of ovarian malignancy risk. BDL/BRL
5. To provide expertise and analytical and data science capabilities to the entire EDRN community.
The multi-disciplinary team that we have assembled (molecular cancer biology, pathology, clinical chemistry,
mass spectrometry, biostatistics, data science, bioengineering), the unique, novel yet biologically and
statistically sound approaches, and our long-standing experience in biomarker research and translating
discoveries to FDA cleared clinical tests all together ensure the success of this proposed BCC.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
610 | Skates, Steven, Ph.D. | Massachusetts General Hospital | Contact PI | BCC, BDL |
1002 | Patel, Abhijit, M.D. | Yale University | MPI | BCC, BDL |
detection of ovarian cancer in normal risk postmenopausal women failed to show a cancer-specific mortality
reduction. The likely fundamental reason for the failure is the short window of opportunity provided by a
blood-based signal. The proposed BCC will seek to identify an alternative biospecimen for the source of signal
which has a much greater window of time for detection in early-stage disease so that an annual testing
frequency will have a high likelihood of detecting ovarian cancer during its curable stages. Due to the direct
connection of the uterus to the fallopian tube, where the cell of origin resides, a uterine lavage will likely
contain the earliest biological signals of the presence of ovarian cancer. Identifying a minimal ovarian cancer
signal amongst a much greater background of uterine epithelium cells and cellular material requires a very
sensitive test. Our BCC will build on a recently developed innovative genome-wide methylation test and
combine it with a sensitive antibody based proteomic test. Having optimized the combined test to detect a
signal in uterine lavage, the BCC will determine its sensitivity in Pap smears. The BCC will optimize the
combined test on training uterine lavage samples, validate the test on independent validation cohort of
uterine lavage samples, and assess its performance in Pap smear samples. If the optimized test is sensitive in
Pap smears, then the overall goal of a clinically acceptable and readily performed test (Pap smear) conducted
at a feasible frequency of every 12 months will be a crucial step towards an annual test for the early detection
of ovarian cancer in normal risk postmenopausal women, the population in which 80% of ovarian cancers
occur. The long-term goal is an early detection program resulting in a significant reduction in ovarian cancer
mortality. The intended use of the test developed by the BCC will be as a clinical decision-support tool for
screening normal risk postmenopausal women for early detection of ovarian cancer. Such a test will fill an
unmet health gap since there is currently no early detection test for ovarian cancer.
Prostate
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
188 | Chinnaiyan, Arul M., M.D., Ph.D. | University of Michigan | Contact PI | BCC, BDL |
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.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
92 | Semmes, John, Ph.D. | Eastern Virginia Medical School | Contact PI | BCC |
822 | Kislinger, Thomas, Ph.D. | Princess Margaret Cancer Centre, University Health Network, University of Toronto | MPI | BCC, BDL |
distinguishing indolent from aggressive and life-threatening cancers. Biomarkers are urgently needed to
identify those patients who harbor aggressive disease and will derive benefit from definitive treatment. We
therefore, propose to apply complimentary proteogenomic-based discovery approaches to identify and then
validate molecular features in prostate proximal fluids and tumor tissues that will be utilized in accurate early
detection of aggressive forms of prostate cancer and improve disease risk stratification. The intended use of
these biomarkers will be the early identification of men at risk for grade progression and improved riskstratification
for them.
We have three biomarker development laboratory aims: 1) Validate our existing urine-based biomarkers for
grade progression in a ProBE-compliant study selected from our own cohorts and the EDRN GU upgrading
study. 2) Develop and validate urine and tissue-based biomarkers for the risk-stratification of MRI “invisible”
high-grade lesions. 3) Develop and validate biomarkers to sub-stratify risk associated with deleterious
germline BRCA2 variants.
Our biomarker reference laboratory will develop and validate targeted clinically robust assays for multi-protein
biomarkers panels. We will also develop decision algorithms that are cross-referenced for statistical rigor and
benchmarked for optimal clinical performance. In addition to these BCC activities, we will develop robust
PRM-MS assays and statistically rigorous decision tools for other EDRN BCCs and CVCs.
Taken together, our EDRN biomarker characterization center will be a core part of the the EDRN ecosystem.
We will continue to actively participate in trans-Network activities, and to share patient cohorts, protocols,
datasets and analysis approaches and expertise. We will supplement these activities by focusing on
promoting the growth of new and diverse talent in biomarker development through fostering junior investigator
involvement across the full spectrum of biomarker development.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1047 | Chan, Daniel, Ph.D. | The Johns Hopkins University | Contact PI | BCC |
448 | Zhang, Hui L., Ph.D. | Johns Hopkins University School of Medicine | MPI | BCC, BDL |
Biomarker Reference Laboratories
Biomarker Reference Laboratories (BRLs) conduct assays for EDRN validation trials. The assays are performed on blinded biospecimens to minimize bias in the analysis and independently verify the assay performance. BRLs also serve as the primary resource for analytical validation of biomarkers, technological development, standardization, assay refinement and quality control.
All Organs
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
611 | He, Hua-Jun, Ph.D. | National Institute of Standards & Technology | Contact PI | BRL |
No summary available for the above ↑ site at this time.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
234 | Liu, Tao, Ph.D. | Pacific Northwest National Laboratory | Contact PI | BRL |
No summary available for the above ↑ site at this time.
Breast
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
812 | Paulovich, Amanda, M.D., Ph.D. | Fred Hutchinson Cancer Center | Contact PI | BCC |
1048 | Hoofnagle, Andrew, M.D., Ph.D. | University of Washington | MPI | BCC, BRL |
Colon and Esophagus
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
160 | Grady, William, M.D. | Fred Hutchinson Cancer Center | Contact PI | BCC |
1016 | Yeung, Cecilia, M.D. | Fred Hutch Cancer Center | MPI | BCC, BRL |
uses a substantial proportion of healthcare resources. Of the GI cancers, colorectal cancer (CRC) and
esophageal cancer (EAC) account for a majority of the cancer related deaths, and both are preventable by
screening and surveillance. The current screening tests are suboptimal and have variable success.
A major goal of CRC screening tests is to identify advanced tubular and serrated adenomas, which are
high-risk for becoming CRC, as well as early stage CRC. The risk for CRC is variable with some people being
at high risk because of family histories of CRC, hereditary cancer syndromes, or a personal history of adenomas.
High risk people are placed on aggressive colonoscopy based surveillance programs and low-risk people are
placed on minimal surveillance programs. Unfortunately, our current system for identifying high and low CRC
risk is suboptimal resulting in under and over surveillance and preventable interval CRCs. Better risk markers
for CRC to are needed to prevent interval CRCs and improve the overall effectiveness of CRC screening.
Analogous to CRC, EAC arises from a precancerous condition of the esophagus called Barretts
esophagus (BE), which is a specialized intestinal metaplasia of the esophagus and the highest risk factor for
EAC. It is present in 5% of the US population. BE progresses to EAC through successive histologic steps of
low grade dysplasia (LGD), high grade dysplasia (HGD) and then EAC. Screening and surveillance for BE is
recommended using serial upper endoscopy, which is controversial in its effectiveness for preventing deaths
from EAC. This is in part because, as with CRC, BE patients have variable risk of EAC and are placed on highrisk
and low-risk screening programs. However, the current system for assigning risk is not accurate and the
current screening test is expensive. More cost effective and accurate EAC and HGD screening/surveillance
assays and accurate BE risk biomarkers are needed.
We propose to develop an EDRN BCC that is integrated into the EDRN consortium and, through
collaborations within and outside the EDRN, will develop effective GI cancer screening biomarkers. We propose
to identify, validate, and develop accurate CLIA compliant risk biomarkers for CRC and for EAC in order to
prevent EAC and CRC missed under current screening protocols. Moreover, the accurate risk stratification of
patients for CRC and EAC will reduce the financial impact of current CRC and EAC prevention programs. We
also propose to identify and validate accurate CLIA compliant early detection markers for HGD and early stage
EAC that can be used in an inexpensive, non-endoscopic surveillance test.
Lung
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
813 | Herman, James, M.D. | University of Pittsburgh School of Medicine | Contact PI | BCC, BDL, BRL |
201 | Stass, Sanford, M.D. | University of Maryland School of Medicine | MPI | BCC, BRL |
Network (EDRN) seeks to improve the management of lung cancer through detection of cancerspecific
DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) which
will optimize the methylation detection methods, implementation of these methods for clinical use
through a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testing
in a clinical setting, and an Administrative Core facilitating the interactions between the BDL and
BRL, and with other EDRN investigators and the NCI. Previous work by the applicants has
demonstrated the potential of DNA methylation detection for cancer diagnostics, and they have
developed extremely sensitive assays for the detection of hypermethylated DNA sequences and
optimized the isolation and processing of circulating cell-free DNA from tumors for these novel
assays. The approach has been used to detect circulating cancer-specific DNA methylation
changes for the early diagnosis of lung cancer in patients with screen-detected pulmonary
nodules. Although sensitivity and specificity of the assay are promising, additional improvements
in the performance are required for implementation of this approach in the setting of cancer
screening. In this BCC, detection of cancer-specific DNA methylation changes in the plasma will
be further improved, and new approaches developed and implemented to address the challenges
of ultrasensitive detection of DNA methylation in the blood. In addition, we will assess the potential
of these methods to detect other common and lethal malignancies. Our bioinformatic analysis of
DNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequent
cancer-specific methylation events common to all cancers, including lung cancer, that will be
developed into universal cancer detection assays. The use of TCGA data has also resulted in the
identification of other methylation alterations that allow determination of the origin (organ site) of
this cancer-specific signal. The combination of optimal sample processing, ultrasensitive
methylation detection, developed with universal cancer and histology specific loci detection, will
allow improved lung cancer early detection in the setting of CT screening and management of
detection of other cancer-specific DNA methylation from blood.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
594 | Lenburg, Marc, Ph.D. | Boston University | Contact PI | BCC |
1033 | Bulman, William, | Veracyte Inc | Co-Investigator | BCC, BRL |
1015 | Hsu, William, Ph.D. | UCLA School of Engineering | MPI | BCC, BDL, BRL |
1035 | Pagano, Paul, Ph.D. | LungLife AI, Inc | Co-Investigator | BCC, BRL |
1034 | Palazzolo, Michael, M.D., Ph.D. | University of California, Los Angeles | Co-Investigator | BCC, BRL |
dilemma for which there is little consensus about appropriate follow up due to a lack of sensitive and specific
approaches for the detection of lung cancer absent invasive tissue sampling, and concerns about costs and
harms from invasive tissue sampling in this large clinical population. Minimally invasive approaches that could
accurately reclassify individuals from the intermediate risk group (5-65% risk of malignancy) to either low (< 5%)
or high (>65%) risk would reduce uncertainty and transform the diagnostic workup of intermediate risk IPN.
Developing, evaluating, standardizing, and validating such minimally invasive biomarkers so that they are ready
for clinical use is the goal of the proposed BU-UCLA Lung Cancer Biomarker Characterization Center (BCC). In
previous EDRN-funded work we established lung-cancer associated gene expression patterns in nasal
epithelium collected with a swab from the inferior turbinate as a lung cancer biomarker. A test based on this
innovative approach to lung cancer detection is being launched for clinical use as a CLIA LDT by our long-time
collaborator Veracyte, Inc., which is participating in this BCC. We will evaluate the nasal biomarker for lung
cancer in the setting of intermediate risk IPN. To further improve the ability to clinically discriminate benign from
malignant intermediate risk IPN, the BU-UCLA Lung Cancer Biomarker Discovery Lab embedded within the BCC
will develop and test lung cancer detection approaches that incorporate detection of circulating tumor cells (CTC)
using a CLIA LDT assay from our collaborator LungLife AI, Inc. as well as blood based immune biomarkers,
advanced imaging biomarkers, and refined nasal gene expression biomarkers. We will additionally determine if
longitudinal biomarker assessment improves lung cancer detection over cross-sectional measurements.
Promising assays will be refined, standardized, and validated by the BU-UCLA Lung Cancer Biomarker
Reference Lab embedded within the BCC to advance them toward clinical adoption. These studies are enabled
by biospecimens and imaging data that are being prospectively collected from diverse populations of patients
undergoing workup for intermediate risk IPN in several large-scale ongoing clinical studies including VA LPOP,
DECAMP 1-Plus, and UCLA IDx; lung cancer research programs at UCLA and Lahey; and our EDRN
collaborators at Nashville VA and Vanderbilt. The BU-UCLA Lung Cancer BCC Team has the required multidisciplinary
expertise in lung cancer, translational and clinical pulmonary medicine, biomarker discovery, clinical
assay development, biostatistics, clinical epidemiology, pathology, imaging, artificial intelligence, biological
sciences, bioinformatics, genomics, and complex scientific program management to accomplish these goals. An
Administrative Core embedded within the BCC will ensure that the BCC delivers on its aim to substantially
advance novel lung cancer biomarkers from discovery to clinical application and make significant contributions
to the Early Detection Research Network.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1049 | Segal, Leopoldo, M.D. | New York University Grossman School of Medicine | Contact PI | BCC, BDL, BRL |
176 | Pass, Harvey Ira, M.D. | New York University School of Medicine | MPI | BCC, BRL |
Lung and Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
523 | LaBaer, Joshua, M.D., Ph.D. | Arizona State University | Contact PI | BCC |
1032 | Stengelin, Martin, Ph.D. | Meso Scale Diagnostics | Co-Investigator | BCC, BRL |
the development of biologically-relevant circulating immune biomarkers. The scientific approach of our Center is
based on several fundamental principles. First, that altered cancer protein expression, structure, and posttranslational
modifications induce host autoantibodies to create circulating biomarkers. Second, that alterations
in microbial antigen expression (such as respiratory pathogens) also induce immunity, often detected in benign
rather than malignant disease. Third, that the protein modifications, as well as the immune response to these
neoantigenic structures, are heterogeneous between people, and that serologic biomarkers may complement
circulating protein biomarkers. We will take a systems immunology approach to discover three types of
antibodies, anti-microbial antibodies, autoantibodies and anti-aberrant glycoprotein antibodies. Our proposal
builds on our extensive experiences with cancer biomarker discovery and immunoproteomics technology
development. Our previous results on autoantibody biomarkers have been confirmed in blinded phase 2
multicenter validation studies and led to a CLIA-certified commercial blood test. Our results have shown that
multiplexed panels of autoantibodies are required for adequate predictive value. With prior EDRN support, we
have developed a set of innovative immunoproteomics technologies, namely high-density nucleic acid
programmable protein array (HD-NAPPA), contra-capture protein array (CCPA) and multiplexed in solution
protein array (MISPA), that, together with the largest full-length human and microbial gene collection at our
DNASU plasmid repository, enable us to study antibodies against the full human proteome, microbial proteomes
and the human O-glycoproteome for antibody biomarker signatures in cancer. Our Meso Scale Diagnostics
(MSD) team has fielded over 3,000 instruments worldwide, and over 700 commercially available biomarker assay
kits. Our expertise at serologic assay development was selected by Operation Warp Speed to use the V-PLEX®
serology panels as the basis of its standard binding assays for immunogenicity assessments in all funded Phase
III clinical trials of COVID vaccines. We will use our MSD MultiArray platform to migrate the top serologic and
protein markers for their utility in our target clinical applications. We will collaborate with experts on lung and
ovarian cancer screening at Vanderbilt University Medical Center, Boston University, MD Anderson Cancer
Center, and German Cancer Research Center, who will also provide access to high-quality well-characterized
samples to develop circulating biomarkers to enhance ovarian cancer screening or to distinguish benign from
malignant pulmonary nodules. Adhering to the principles of PRoBE design, we will perform Phase I discovery by
screening protein arrays with cancer patient and control sera for cancer or control-specific antibodies. Candidate
biomarkers for both lung and ovarian cancers will undergo Phase 2 validation.
Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
800 | Zhang, Zhen, Ph.D. | Johns Hopkins University | Contact PI | BCC |
200 | Chan, Daniel, Ph.D. | Johns Hopkins Medical Institutions | Co-Investigator | BCC, BRL |
cancer. The overarching goal of the proposed Biomarker Characterization Center (BCC) is to apply a bydesign
approach based on biology of HGSOC pathogenesis and unmet clinical needs to identify, verify and
prioritize, and validate biomarkers, and to develop them into an in vitro diagnostic multivariate index assay
(IVDMIA) with the intended use to capture HGSOC in high-risk women at the early stages including i)
precursors, ii) confinement to the ovary/fallopian tube or iii) low-volume diseases in high-risk women (BRCA1/2
carriers). The biomarkers that we propose to discover and validate in this proposal are intended for early
detection but not necessarily for screening in general population. The BCC’s capability in advanced data
generation technologies, multiplexed target assay development, and bioinformatics/data science will serve as
resources for the EDRN. Based on the success of our current EDRN projects, this BCC will continue our ongoing
biomarker development studies including the validation of candidate biomarkers that we have identified
through the current BDL. We propose the following specific aims:
1. To optimize and use novel specimen collection and processing technologies, and an iterative and
cumulative process that takes advantage of our newly gained knowledge of the biology in ovarian cancer
pathogenesis. BDL
2. To optimize and apply innovative bioinformatics, data sciences, and AI/ML tools that incorporate existing
knowledge and data to improve discovery of low frequency biomarkers that with their functionally shared
pathways/networks could collectively deliver an improved sensitivity while retaining a high specificity. BDL
3. To further develop and optimize the process for efficient multiplex targeted assay development with respect
to analytical performance, throughput, and specimen volume requirement for a broad spectrum of
candidate biomarkers using a “fit for purpose” approach. BRL
4. To optimize and apply a by-design approach to translating discoveries into clinical tests. Its application had
been critical in the development of two FDA cleared tests by JHU team members for the preoperative
assessment of ovarian malignancy risk. BDL/BRL
5. To provide expertise and analytical and data science capabilities to the entire EDRN community.
The multi-disciplinary team that we have assembled (molecular cancer biology, pathology, clinical chemistry,
mass spectrometry, biostatistics, data science, bioengineering), the unique, novel yet biologically and
statistically sound approaches, and our long-standing experience in biomarker research and translating
discoveries to FDA cleared clinical tests all together ensure the success of this proposed BCC.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
610 | Skates, Steven, Ph.D. | Massachusetts General Hospital | Contact PI | BCC |
1031 | Kulasingam, Vathany, Ph.D. | University Health Network | Co-Investigator | BCC, BRL |
detection of ovarian cancer in normal risk postmenopausal women failed to show a cancer-specific mortality
reduction. The likely fundamental reason for the failure is the short window of opportunity provided by a
blood-based signal. The proposed BCC will seek to identify an alternative biospecimen for the source of signal
which has a much greater window of time for detection in early-stage disease so that an annual testing
frequency will have a high likelihood of detecting ovarian cancer during its curable stages. Due to the direct
connection of the uterus to the fallopian tube, where the cell of origin resides, a uterine lavage will likely
contain the earliest biological signals of the presence of ovarian cancer. Identifying a minimal ovarian cancer
signal amongst a much greater background of uterine epithelium cells and cellular material requires a very
sensitive test. Our BCC will build on a recently developed innovative genome-wide methylation test and
combine it with a sensitive antibody based proteomic test. Having optimized the combined test to detect a
signal in uterine lavage, the BCC will determine its sensitivity in Pap smears. The BCC will optimize the
combined test on training uterine lavage samples, validate the test on independent validation cohort of
uterine lavage samples, and assess its performance in Pap smear samples. If the optimized test is sensitive in
Pap smears, then the overall goal of a clinically acceptable and readily performed test (Pap smear) conducted
at a feasible frequency of every 12 months will be a crucial step towards an annual test for the early detection
of ovarian cancer in normal risk postmenopausal women, the population in which 80% of ovarian cancers
occur. The long-term goal is an early detection program resulting in a significant reduction in ovarian cancer
mortality. The intended use of the test developed by the BCC will be as a clinical decision-support tool for
screening normal risk postmenopausal women for early detection of ovarian cancer. Such a test will fill an
unmet health gap since there is currently no early detection test for ovarian cancer.
Prostate
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
188 | Chinnaiyan, Arul M., M.D., Ph.D. | University of Michigan | Contact PI | BCC |
1030 | Kitchen, John, Ph.D. | LynxDx | Co-Investigator | BCC, BRL |
1011 | Tosoian, Jeffrey, M.D. | Vanderbilt University Medical Center | MPI | BCC, BRL |
1029 | Xiao, Lanbo, Ph.D. | University of Michigan | Co-Investigator | BCC, BRL |
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.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
92 | Semmes, John, Ph.D. | Eastern Virginia Medical School | Contact PI | BCC |
823 | Boutros, Paul, Ph.D. | The University of California, Los Angeles | MPI | BCC, BRL |
distinguishing indolent from aggressive and life-threatening cancers. Biomarkers are urgently needed to
identify those patients who harbor aggressive disease and will derive benefit from definitive treatment. We
therefore, propose to apply complimentary proteogenomic-based discovery approaches to identify and then
validate molecular features in prostate proximal fluids and tumor tissues that will be utilized in accurate early
detection of aggressive forms of prostate cancer and improve disease risk stratification. The intended use of
these biomarkers will be the early identification of men at risk for grade progression and improved riskstratification
for them.
We have three biomarker development laboratory aims: 1) Validate our existing urine-based biomarkers for
grade progression in a ProBE-compliant study selected from our own cohorts and the EDRN GU upgrading
study. 2) Develop and validate urine and tissue-based biomarkers for the risk-stratification of MRI “invisible”
high-grade lesions. 3) Develop and validate biomarkers to sub-stratify risk associated with deleterious
germline BRCA2 variants.
Our biomarker reference laboratory will develop and validate targeted clinically robust assays for multi-protein
biomarkers panels. We will also develop decision algorithms that are cross-referenced for statistical rigor and
benchmarked for optimal clinical performance. In addition to these BCC activities, we will develop robust
PRM-MS assays and statistically rigorous decision tools for other EDRN BCCs and CVCs.
Taken together, our EDRN biomarker characterization center will be a core part of the the EDRN ecosystem.
We will continue to actively participate in trans-Network activities, and to share patient cohorts, protocols,
datasets and analysis approaches and expertise. We will supplement these activities by focusing on
promoting the growth of new and diverse talent in biomarker development through fostering junior investigator
involvement across the full spectrum of biomarker development.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1047 | Chan, Daniel, Ph.D. | The Johns Hopkins University | Contact PI | BCC, BRL |
108 | Chesnut, Gregory, M.D. | Center for Prostate Disease Research Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center | Contact PI | BRL |
Clinical Validation Centers
Clinical Validation Centers (CVCs) conduct validation trials on biomarkers discovered/developed by both EDRN and non-EDRN investigators. CVCs also provide high-quality, well-annotated biospecimens to the BDLs for biomarker discovery, development and pre-validation studies. The use of biospecimens collected using rigorous standard operating procedures helps minimize false discoveries.
Breast
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
593 | Li, Christopher, M.D., Ph.D. | Fred Hutchinson Cancer Center | Contact PI | CVC |
1021 | Partridge, Savannah, Ph.D. | University of Washington SOM | MPI | CVC |
mammography is an effective tool, there are issues with respect to optimizing its use and performance, and
despite widespread screening breast cancer remains the 2nd most common cause of cancer related death
among U.S. women. Through the current EDRN Clinical Validation Center (CVC) led by Dr. Li we have
validated 15 candidate biomarkers through a series of Phase 2 and Phase 3 validation studies that involved
successive series of three independent sets of preclinical samples. Outside of EDRN funding, Dr. Partridge
has led the development of novel strategies to improve breast cancer detection based on quantitative markers
derived from screening MRIs in high-risk women and application of artificial intelligence (AI) approaches in
collaboration with Microsoft. Our overarching goal is to conduct Phase 2 and 3 validation studies of bloodbased
biomarkers and imaging strategies that will be integrated and jointly assessed in a Phase 4 validation
study. Supporting this goal we propose the following 4 projects: Project 1: Phase 3 validation of early detection
biomarkers for ER+ breast cancer; Project 2: Phase 2 and 3 validation of protein biomarkers for the early
detection of breast cancer discovered using a mass spectrometry-based platform; Project 3: Phase 3 validation
of quantitative markers and AI algorithms applied to MRI screening exams for the early detection of breast
cancer in women at high risk; and Project 4: Phase 4 validation of blood-based biomarkers and imaging
algorithms for the early detection of breast cancer. Additionally, we will provide biospecimens and expertise to
support high quality PRoBE compliant EDRN discovery and validation studies across several cancer types.
With the combined expertise of our multidisciplinary team of investigators and our engagement with key
commercial partners, this CVC will both lead well-justified, rigorously designed validation studies and provide
abundant resources to EDRN. Given the strength of our biomarker candidates, the sets of biospecimens that
will be used, the study designs employed, and the clearly delineated clinical applications proposed, we
anticipate that this work will yield near-term clinical impact.
Colon
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
664 | Bresalier, Bob, M.D. | The University of Texas MD Anderson Cancer Center | Contact PI | CVC |
662 | Syngal, Sapna, M.D. | Dana Farber Cancer Institute-BWH | MPI | CVC |
component of the Early Detection Research Network (EDRN) is a highly collaborative group of investigators
whose aims to validate biomarkers for the early detection and risk assessment of cancers of the gastrointestinal
tract. In this fifth competitive application, the GLNE continues to test the overall hypothesis that a panel of
circulating and stool based biomarkers will increase the adherence to colorectal screening and in doing so reduce
mortality caused by colorectal cancers. Based on the rising incidence of colorectal cancer (CRC) among adults
age <50 in the US, and the low compliance and high mortality in underserved populations, increased emphasis
is placed on these populations. The GLNE also proposes to continue its ongoing support of EDRN discovery
priorities. We propose to address the following aims: (1) Primary Aim To expand and renew the archive of
appropriately preserved stool, serum, plasma, urine, tissue and DNA biospecimens to be used by EDRN
investigators for current and future validation and biomarker discovery research with expanded inclusion of
subjects with early-onset CRC and underserved populations. This will allow assessment of the utility of individual
stool-based, and serum-based biomarkers and biomarker panels for discriminating between individuals without
neoplasia (subjects both at average and higher risk for developing colon cancer), and those with colon cancer
or screen-relevant neoplasia (cancer plus advanced adenoma), and construction of panels of markers to
discriminate between these groups. (2) To perform validation trials of promising biomarkers discovered by EDRN
investigators, external collaborating institutions and collaborating EDRN industrial partners for the early detection
of colorectal neoplasia. In this context we propose to (a) to clinically validate (via a methods comparison study)
the performance of a point-of-care blood- based biomarker panel with the testing of serum/plasma samples
obtained in clinics serving low-income and underserved communities and (b) to clinically validate an established
4-plex stool protein panel for early diagnosis of CRC. (3) To follow prospectively subjects enrolled in an
established prospective Phase 2 validation trial to identify pre-diagnostic specimens which may be used to
develop predictive markers.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
609 | Schoen, Robert E., M.D., M.P.H | University of Pittsburgh Cancer Institute | Contact PI | CVC |
1020 | Tomasetti, Cristian, Ph.D. | City of Hope/Tgen | MPI | CVC |
advanced adenoma. Whereas blood-based testing for invasive colorectal cancer is progressing, with multiple
companies pursuing products, the ability of blood-based testing to detect advanced adenomas, the premalignant
lesions closest to invasive cancer, is uncertain. To optimally impact colorectal cancer incidence,
blood-based biomarkers cannot just detect cancer, they should also have sufficient sensitivity to identify
subjects with advanced adenomas. For our CVC, we organized and assembled a network of highly skilled
clinical centers including a focus on minority populations, to prospectively collect well-characterized, highquality
blood specimens from a large number of subjects with advanced adenoma prior to undergoing
polypectomy and serially post-polypectomy. From the same clinical centers, we will collect blood specimens
from control subjects. Specimens will be collected and processed using standard protocols, and relevant
demographic and clinical variables will be captured to facilitate biomarker validation studies. Specifically, we
will use these well-characterized specimens to validate our data on the utility of original, innovative techniques
for molecular detection of advanced adenomas including RealSeqS in combination with custom machine
learning algorithms such as SignaL. We propose two Specific Aims. In Specific Aim 1, we will conduct a phase
2 case-control study to validate our novel methods for advanced adenoma detection. We will prospectively
recruit patients with advanced adenoma (N=400) and site-specific control subjects (N=400) for comparison to
the case subjects. In Specific Aim 2, we will utilize serial blood specimens systematically collected postpolypectomy
from our case subjects to determine whether our novel molecular detection techniques can be
used to predict likelihood of recurrence and potentially guide surveillance colonoscopy exams. Advanced
adenomas are the important, next frontier in non-invasive colorectal cancer screening, and our CVC is
equipped to profoundly advance blood-based detection of advanced adenoma.
Contact PD/PI: Schoen, Robert E
Project Summary/
Esophagus
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
169 | Markowitz, Sanford, M.D., Ph.D. | Case Western Reserve University | Contact PI | CVC |
1027 | Bettegowda, Chetan, B.S., M.D., Ph.D. | Johns Hopkins University | MPI | CVC |
1018 | Chak, Amitabh, M.D. | UH Cleveland Medical Center | MPI | CVC |
347 | Shaheen, Nicholas, B.A., M.D., M.P.H. | University of North Carolina | MPI | CVC |
1028 | Wani, Sachin, M.D. | University of Colorado Anschutz Medical Campus | MPI | CVC |
1017 | Willis, Joseph, M.D. | Case Western Reserve University | MPI | CVC |
risk esophageal neoplasias (Barrett’s esophagus) for the purpose of guiding selection and management of
patients for endoscopic eradication therapy (EET). Two validation studies are proposed: the first, a phase 4
prospective study to identify a patient group at low progression risk who can be spared EET; the second, a phase
3 retrospective study to distinguish individuals who following EET are at low versus high risk of disease
recurrence. Barrett’s esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EAC), a cancer
with 80% lethality whose incidence has increased more than 7-fold in the past three decades. BE progresses to
EAC in a step-wise fashion from non-dysplastic BE, to low grade dysplasia (LGD), to high grade dysplasia (HGD),
and finally cancer. EAC prevention is based on using EET to ablate HGD BE before it can progress to EAC.
However, increasingly, EET is also becoming the default therapy for LGD, a highly imprecise diagnosis about
which expert pathologists frequently disagree, and which is applied to as many as 40% of BE patients at some
point during their course. As EET has a 9% complication rate, the result is an emerging epidemic of overtreatment
of BE with LGD. In a prior EDRN-BDL award, our team developed the “BAD” technology for early detection of
BE progression. In BAD, we used a brushing device to sample a patient’s full BE esophageal segment. We then
analyzed the DNA from this sample using next-generation sequencing technology (developed for liquid biopsy
assays) to instead detect presence of BE clones that had acquired gains or losses on specific driver
chromosomes associated with EAC. Detection of driver chromosome changes (dubbed Very-BAD), typified EAC
and HGD. In contrast, 28% of LGD showed complete absence of any chromosomally aberrant clones (dubbed
Not-BAD). We will now validate Not-BAD as a biomarker that identifies LGD at such low progression risk as to
not require EET. We will do this by partnering with the SURVENT trial, that will be the first U.S. prospective study
to follow LGD patients managed by surveillance, not ablation. A second major challenge with EET is that over
25% of patients recur following ablation (with either high risk BE, HGD, or EAC). These patients face a substantial
burden of post-EET surveillance endoscopies, initially at every 3-month intervals. In our prior EDRN-BDL, our
team identified a panel of methylated DNA biomarkers for sensitive molecular early detection of BE (currently
awarded FDA breakthrough device designation). We have further identified that these markers remain retained
in a subset of patients post-EET. We accordingly now propose a retrospective Phase 3 study to further validate
these DNA markers for molecular assessment of minimal residual disease, whose post-EET elimination identifies
individuals achieving complete molecular eradication of BE, and hence at low risk of disease recurrence and not
in need of intense post-EET surveillance. We do this by partnering with the unique UNC-BEECAB biorepository
of post-EET esophageal biopsies from patients whose disease did or did not recur following ablation.
Head and Neck
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1045 | Anderson, Karen, M.D./Ph.D. | Arizona State University | Contact PI | CVC |
1046 | Sturgis, Erich, M.D., M.P.H | Baylor College of Medicine | MPI | CVC |
Liver
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
726 | Singal, Amit, M.D. | UT Southwestern Medical Center | Contact PI | CVC |
1019 | Kanwal, Fasiha, M.D. | Baylor College of Medicine | MPI | CVC |
992 | Marrero, Jorge, M.D., M.S. | University of Pennsylvania | MPI | CVC |
143 | Parikh, Neehar, M.D. | University of Michigan | MPI | CVC |
projected to be the 3rd leading cause of cancer death in the U.S. by 2040 given the poor effectiveness of current
HCC risk stratification and early detection strategies. Specifically, HCC screening is recommended in all patients
with cirrhosis, despite annual HCC risk varying between 1-4%/year, highlighting a need for risk stratification
biomarkers. HCC screening is performed using abdominal ultrasound and the serum biomarker alpha fetoprotein
(AFP); however, this strategy misses over one-third of HCCs at an early stage and results in screening harms in
many patients. The goal of our Clinical Validation Center for HCC (CVC-HCC) is to validate novel blood and
imaging biomarkers in phase I-III studies to improve HCC risk stratification and early detection.
Translation of HCC biomarkers to practice has been hampered by a dearth of high-quality sample sets including
both stored blood and imaging. Existing sample sets also primarily include patients with cirrhosis from active
viral hepatitis, with limited applicability to contemporary populations who primarily have cured viral hepatitis or
non-viral causes of liver disease. Our CVC will create a contemporary resource with blood and imaging data to
allow for rapid validation of promising biomarkers for HCC risk-stratification and early detection in phase I-III
studies. A specific population in need of better biomarkers is patients with indeterminate liver nodules (ILNs) on
diagnostic CT or MRI, which are observed in over one-fourth of patients undergoing HCC screening and have a
high, yet variable, risk for developing into HCC (annual risk ~6-10%/year). Our group has validated a novel bloodbased
biomarker, PLSec, for risk stratification and a biomarker panel, GALAD, for early HCC detection in patients
with cirrhosis and herein propose to perform a phase II-III biomarker study to evaluate them in patients with ILNs.
Our team includes national leaders in HCC screening, imaging, and biomarker validation. We are leading efforts
to evaluate HCC biomarkers including the EDRN-funded Hepatocellular Early Detection Strategy (HEDS) Study,
NCI-funded Translational Liver Cancer (TLC) Consortium, and CPRIT-funded Texas HCC Consortium. We will
leverage existing infrastructure across five health systems to create two novel resources not offered by the
current sample sets including (1) a biorepository with both blood and imaging data from patients, with and without
HCC, representing contemporary etiologies of liver disease for Phase II studies and (2) a prospective cohort of
patients with ILNs to evaluate HCC risk stratification and early detection biomarkers in Phase III studies using a
prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. We will work with the BCCs
and DMCC to evaluate novel biomarkers, facilitating contributions to trans-network projects. Overall, our CVCHCC
will lead to significant advances in phase I-III validation of novel biomarkers for HCC risk stratification and
early detection, areas of need that will facilitate development of well-designed phase IV clinical utility trials.
Lung
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
240 | Grogan, Eric, M.D. | Vanderbilt -Ingram Cancer Center | Contact PI | CVC |
863 | Deppen, Stephen, Ph.D. | Vanderbilt University Medical Center | MPI | CVC |
needed to improve early detection and diagnosis. The objectives of this proposal for our continuing Clinical
Validation Center are to push early lung cancer detection biomarkers into clinical practice while continuing to
serve as a core resource to the EDRN, as well as to our academic and industry partners. Our overall objective
is to demonstrate that biospecimen and imaging biomarkers will provide clinical utility to diagnose lung cancer
by reducing the number of invasive procedures performed for benign disease and the time to diagnosis for
cancer. Aim 1 will seek to demonstrate clinical utility of a combined biomarker and radiomic approach for
providing Indeterminate Pulmonary Nodule (IPN) diagnoses. We will expand the existing lung specimen and
imaging biorepository available to the scientific community, demonstrate the clinical utility of combination
biospecimen and radiomic biomarkers, and validate additional candidate lung cancer risk biomarkers. We will
diversify the population and enhance statistical power by recruiting from existing partnerships funded by prior
EDRN funding: Meharry Medical College and Washington University in St. Louis. We seek to accomplish three
objectives in this aim: 1) to validate the combined approach of hsCYFRA 21-1 cancer biomarker, radiomic
(HealthMyne) biomarker and a Histoplasmosis benign biomarker (MiraVista) in the EDRN Lung Team Project 2
and National Lung Screening Trial reference cohorts, 2) to determine the clinical utility of the Histoplasmosis test
followed by a Combined Biomarker Model (hsCYFRA21-1, radiomics, and Mayo Model) in a Phase 4 randomized
clinical trial and 3) to validate new candidate blood and epithelial biomarkers in Phase 2 and 3 prospectivespecimen-
collection and retrospective-blinded-evaluation (PRoBE) design studies for the early diagnosis of lung
cancer. In Aim 2 we will validate radiomic risk assessment platforms in IPNs and conduct a pilot clinical
implementation trial in screening discovered IPNs. We will leverage the robust bioinformatics infrastructure at
Vanderbilt University Medical Center to capture and deidentify 800 thoracic CT scans in patients with IPNs. A
Lung Cancer Prediction Convolutional Neural Network (LCP-CNN) and the HealthMyne radiomic model will be
compared to each other and against the Lung-RADS categories. We will perform a prospective pilot evaluation
of the best performing model in Lung-RADS category 3 and 4 IPNs. To accomplish Aim 2 we will: 1) compare
the accuracy of LCP-CNN and HealthMyne radiomics 2) determine the LCP-CCN’s ability to reclassify nodules
in screening patients in a prospective clinical implementation pilot study. At the completion of this proposal, we
will have 1) evaluated clinical utility of combining lung cancer biospecimen and imaging biomarkers, 2) developed
a platform within current practice to present an imaging biomarker approach to improve IPN risk assessment,
and 3) enhanced the biorepository resource for the EDRN and collaborative use.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
151 | Hanash, Samir, M.D., Ph.D. | The University of Texas MD Anderson Cancer Center | Contact PI | CVC |
biomarker panel for personalized risk assessment, modeled for its cost effectiveness. To
this effect, substantial validation work in phase 3 studies has been done using retrospective
longitudinal cohorts to test the performance of a four-marker protein panel (4MP) as a means to
determine lung cancer risk and need for CT screening. The goal moving forward is to test the
4MP alone and in combinations with other types of markers in the screening setting, using lung
cancer screening cohorts available to the CVC. The resulting marker panel, in combination with
subject characteristics, would identify subjects who are currently not eligible based on USPSTF
criteria that would benefit from CT screening based on their risk, ultimately leading to a utility trial
for which a concept has been presented at a recent EDRN scientific meeting. The utility trial
concept also includes as an objective to test the value of biomarkers in informing subjects who
are currently eligible but not decided to undergo CT screening, about their risk through a decision
sharing process. Specific Aim 2 will test the use of biomarkers and AI for interpretation of CT
images and to personalize the screening frequency and duration. Sub Aim 1 is intended to validate
the macrovasculature surrounding a nodule (vessel number) previously developed as a
biomarker, in an independent screening cohort. Sub Aim 2 is intended to develop a validated
integrative computational model for improved early lung cancer detection that includes bloodbased
biomarkers, CT features such as emphysema, presence or absence of a nodule, small
airways and subject characteristics for interpretation of CT images and to determine screening
frequency. The model will be subjected to a cost effectiveness analysis compared to current lung
cancer screening guidelines.
The CVC represents a multi-institution, multi-investigator effort with expertise in cancer
biomarkers and statistics; pulmonology and lung cancer; epidemiology; radiomics, bioinformatics
and artificial intelligence; and clinical trial design, simulation modeling and cost-effectiveness
analysis. The CVC brings in substantial accomplishments in biomarker discovery and validation
related to lung cancer screening and in CT image analysis. In pursuit of its aims, the CVC has
access to samples from a multitude of cohorts for validation studies.
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
1044 | Velculescu, Victor, M.D., Ph.D. | Johns Hopkins University | Contact PI | CVC |
86 | Sidransky, David, M.D. | Johns Hopkins University | MPI | CVC |
Multiple
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
816 | Heine, John, Ph.D. | H. Lee Moffitt Cancer Center & Research Institute, Inc. | Contact PI | CVC |
815 | Schabath, Matthew, Ph.D. | H. Lee Moffitt Cancer Center & Research Institute, Inc. | MPI | CVC |
Ovary
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
236 | Bast, Robert C, M.D. | The University of Texas MD Anderson Cancer Center | Contact PI | CVC |
Pancreas
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
797 | Maitra, Anirban, M.B.B.S. | The University of Texas M D Anderson Cancer Center | Contact PI | CVC |
for advancing public health in the United States. Certain sub-groups of patients, such as those with germline
mutations, mucinous pancreatic cysts and new-onset diabetes (NOD) are at higher than average risk for PDAC.
In the immediate prior cycle, our EDRN Clinical Validation Center (CVC) at MD Anderson Cancer Center
(MDACC): (a) facilitated the conduct of the first ever, multi-institutional, blinded “biomarker bakeoff” in PDAC by
providing annotated biospecimens, (b) completed one of the first EDRN-defined Phase 3 biomarker studies in
PDAC using pre-diagnostic samples (Fahrmann et al, Gastroenterology 2021), and (c) served as a conduit for
the implementation of additional EDRN collaborative research initiatives, including a pre-diagnostic PDAC
imaging consortium. Our renewal application represents a Gulf Coast-Great Lakes EDRN Clinical Validation
Center (GCGLEC) in Pancreatic Cancer is comprised of UTMDACC/Lyndon B Johnson Hospital (Harris Health,
TX), Henry Ford Health System (HFHS, Detroit, MI) and Ochsner Health System (OHS, New Orleans, LA) and
has three major objectives: First, to implement a multi-institutional framework for collecting the highest quality
biospecimens from patients with a variety of well-defined pancreatic pathologies (including early stage PDAC,
pancreatic cystic lesions, and other benign pancreatic diseases, such as chronic pancreatitis, benign cysts, and
endocrine tumors of low malignant potential), in order to conduct biomarker validation studies for early detection
of PDAC that conform to EDRN-defined Phase 2 and Phase 3 study design. Current PDAC biomarker studies
typically have sparse representation from racial and ethnic minorities, and therefore a major impetus of the
GCGLEC will be to address the “disparity gap” in biomarker research by obtaining biospecimens from
underrepresented minorities. Second, the GCGLEC will build upon our published Phase 3 study utilizing the
“anchor panel” of CA19-9, LRG1 and TIMP-1, by conducting four additional PRoBE-compliant studies that
incorporate autoantibodies, metabolites and additional protein biomarkers for improving the sensitivity of
diagnosing asymptomatic PDAC without compromising the 99% or greater specificity threshold. These EDRNdefined
Phase 3 studies will be conducted in pre-diagnostic cases and controls obtained from existing cohorts,
including the PLCO, WHI, and the so-called “Harvard cohorts” (NHS, PHS, WHS and HPFS), as well as ongoing
prospective cohorts undergoing accrual, such as the NCI-funded New Onset Hyperglcyemia and Diabetes (NOD)
cohort, and the Early detection Initiation (EDI) in PDAC, a collaboration between PanCAN and the NCI. Third,
the GCGLEC will serve as a “hub” for collaborative activities within and outside the EDRN, including
collaborations with investigators funded by the Pancreatic Cancer Detection Consortium (PCDC), and laying the
foundations for conducting an EDRN-approved multi-institutional “clinical utility” (Phase 4 study) for PDAC early
detection, within a CAP/CLIA environment.
Contact PD/PI: Maitra, Anirban
Project Summary/
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
156 | Brand, Randall E., M.D. | University of Pittsburgh | Contact PI | CVC |
607 | Batra, Surinder, Ph.D. | University of Nebraska Medical Center | MPI | CVC |
Prostate
Group
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
742 | Sanda, Martin, M.D. | Emory University | Contact PI | CVC |
Data Management and Coordinating Center
The Data Management and Coordinating Center (DMCC) works with the CVCs to conduct biomarker validation trials. The DMCC assists with protocol design, monitors the trial, and maintains the data and biospecimen tracking system. The DMCC is responsible for analyzing the results of the trials, thereby reducing bias as they are independent from the laboratories that discovered the biomarkers. The DMCC provides statistical advice to the BDLs, develops theoretical and applied approaches for simultaneous analysis of multiple markers, and collaborates with the EDRN Informatics Center.
DMCC
Site ID | Investigator | Site Name | PI Type | Member Type |
---|---|---|---|---|
5 | Feng, Ziding, Ph.D. | Fred Hutchinson Cancer Center | Contact PI | DMCC |
782 | Etzioni, Ruth, Ph.D. | Fred Hutchinson Cancer Center | MPI | DMCC |
1012 | Zheng, Yingye, Ph.D. | Fred Hutchinson Cancer Center | MPI | DMCC |
Informatics Center
The Informatics Center, provided by the Jet Propulsion Laboratory, pioneers data science software, systems, tools, and data-driven methodologies, serving the data capture, management, sharing, and analysis needs to enable a national biomarker data ecosystem.
Site ID | Investigator | Site |
---|---|---|
128 | Crichton, Dan | NASA Jet Propulsion Laboratory |
National Cancer Institute
The National Cancer Institute is the hub of the Early Detection Research Network.
Site ID | Investigator | Site |
---|---|---|
87 | Srivastava, Sudhir | National Cancer Institute |
Associate Members
This section lists associate EDRN members.