# Presentation: 196868

## Translating Biomarker Discovery to Clinical Application

**Sudhir Srivastava, Ph.D., M.P.H.**
**Cancer Biomarkers Research Group**

**Notes:**
Good Afternoon!
Thank you for giving the opportunity to update on the EDRN Activities over six years. EDRN has made tremendous progress in translating biomarker discovery to clinical application.

## Goal: Establish a Comprehensive

**Conduct correlative studies/trials to validate biomarkers as indicators of early cancer, pre-invasive cancer, risk, or as surrogate endpoints**
**Develop quality assurance programs for biomarker testing and evaluation**
**Forge public-private partnerships**

**Goal: Establish a Comprehensive**
**Approach to Biomarker Development**

**Notes:**
EDRN became fully functional in April 2000. It was established to help discover and validate clinically useful biomarkers for cancer detection, diagnosis and risk assessment in collaboration with public and private institutions.

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## INVESTIGATOR-DRIVEN CONSORTIUM

***An “infrastructure”    for supporting collaborative research on molecular, genetic and other biomarkers in human cancer detection and risk assessment.***

**INVESTIGATOR-DRIVEN CONSORTIUM**

**Notes:**
EDRN is a investigator-driven consortium of more than 200 investigators and 40 laboratories. It is structured around four major scientific components: BDL, BRL, CEVC, and DMCC. The Steering Committee is the major oversight committee, comprised of the Principal Investigators. DMCC provides logistics support and conduct research in statistical methodologies and manage and analyze data for the consortium. In collaboration the JPL, our Informatics Center, they help develop informatics infrastructures.

## PARTNERING WITH  FEDERAL AGENCIES

**National Institute of Standards and Technology as a **
**     ****Reference Laboratory**
**NASA’s Jet Propulsion Laboratory (JPL) as an Informatics **
**     ****Center**
**Centers for Disease Control and Prevention as a Clinical**
**     ****Epidemiology and Validation Center**
**DOE’s Pacific Northwest National Laboratory as a **
**     ****Reference Laboratory for Antibody and MS**
**NIEHS Genes-Environment Initiative**

## MANAGEMENT STRUCTURE

- Executive
- Committee

- Colon and Other
-  GI Cancers

- Breast & Ob/Gyn
- Cancers

- Lung and Upper
- Respiratory
-  Cancers

- Policy Making
- Subcommittees

- Prostate &
- Other Urologic
- Cancers

- Steering Committee

**MANAGEMENT STRUCTURE**

- Prioritization
- Technology Sharing
- Collaboration
- Communication and Workshop
- Data sharing and Informatics

**Notes:**
The EDRN Steering Committee is assisted by organ-based collaborative groups and policy making subcommittees. The EDRN Executive Committee, a subset of the SC is responsible for making decisions on validation projects, collaborative studies, release of set-aside funds and on approval of Associate Members.

## MANAGEMENT OVERSIGHT 

- NCI Staff: The Partner

- Steering Committee:  The “Housekeeper” Main governing body of the Network that meets three times annually. Subcommittees develop EDRN management policies.

- EDRN Executive Committee: Subgroup of the Steering Committee that meets monthly to consider routine EDRN issues.

- Network Consulting Team: The “Spell Checker” provides independent scientific oversight team.

## ORGANIZATIONAL SUCCESS

**Instilled a sense of urgency among investigators for collaborative needs on biomarker research**
**Rewards collaboration**
**EDRN-like structures have been emulated NIH-wide and internationally**

**Notes:**
EDRN has successfully instilled a sense of urgency among investigators to move discover from bench to the bedside. EDRN uses a novel funding approach to reward collaboration. The EDRN structure has been emulated by many programs with NCI, NIH and internationally.

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## Systematic Approach To Biomarker Discovery: An Engineering Approach

**Source: JPL/NASA**

- BRL: Biomarkers Readiness Level

**Notes:**
As our leader have said: Cancer is an engineering problems and must be dealt with adopting engineering approaches and concepts. EDRN has adapted NASA’s approach to measuring the technology readiness level to biomarker readiness level (BRL).

## BIOMARKER DISCOVERY (2000-2006)

**BIOMARKER DISCOVERY (2000-2006)**

**   ****More than 400 papers published on new **
**     ****biomarkers**
**   ****Seminal discoveries and study foundations**

**Notes:**
EDRN investigators have published more than 300 papers, more than 25% are in journals with impact factors 30 or greater. On the next slide I have listed some of the seminal discoveries that EDRN has made in the past six years.

## BIOMARKER DISCOVERY: Seminal Discoveries

**BIOMARKER DISCOVERY: Seminal Discoveries**

**   ****Gene Fusion in Prostate Cancer; first ever report for      **
**    ****a major epithelial tumor  (Chinnaiyan); Translocation **
**    ****in Bladder Cancer (Sidransky)**
**   ****Auto-antibodies as Biomarkers for Lung and  **
**    ****Prostate cancers (Hanash, Chinnaiyan, Tainsky)**
**  ** **Pioneering Work in Protein Patterns as  Diagnostic **
**    ****Biomarkers (Semmes, Liotta)**
**   ****Mitochondrial Mutations as Cancer Biomarkers **
**    ****(Sidransky)**

**Notes:**
I would like to emphasize the study on findings of gene fusion in prostate and bladder cancer. This is the first major report of gene fusion of EGR, ETV1 and TMPRSS genes. ERG and ETV1 fusion has been reported in Ewing Sarcoma. Our partner NIST is nor evaluating this finding and trying to develop Q-dot based staining for fusion detection.

## DISCOVERY IN CONJUCTION  WITH VALIDATION IS CRITICAL

**DISCOVERY IN CONJUCTION  WITH VALIDATION IS CRITICAL**

**   ****EDRN-supported discoveries are:**
** ****Linked to clinical needs**
** ****Verifiable**
** ****Triaged to minimize bias, chance and **
**  ****confounders**
**  **

**Notes:**
Man claimed discoveries have not yielded reproducible results in the past. However, EDRN-supported discoveries are verifiable in BRL and other laboratories. Since most discoveries are linked to clinical questions, they are easily translatable.

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## OUT OF DISCOVERY, GET INTO CLINICS... BIOMARKER VALIDATION

**OUT OF DISCOVERY, GET INTO CLINICS... BIOMARKER VALIDATION**

**   ****Systematic Approach to Biomarker Validation**
**  ****Phases of Biomarker Validation**
**  ****Two-stage Validation Design**
**  ****Sample Reference Libraries**
**   ****EDRN Validation Studies in Progress**
**   ****EDRN Validation Studies in the Pipeline**
**    **

**Notes:**
A good quality has been possible because of our systematic approach to biomarker discovery and validation supported by statistically-designed phase of biomarker development.

## PHASES OF BIOMARKER VALIDATION

**PHASES OF BIOMARKER VALIDATION**

**Notes:**
Each phase is statistically tested for its progression to the next phase. As we move further along these phases, the evidence for clinical usability of the biomarker increases.

## Sample Reference Libraries

**  ****Reference Libraries are sets of samples with cases **
**  ****and controls statistically powered to allow rapid **
**  ****assessment of technologies and biomarkers **
**  ****discovered through a wide variety of technology **
**  ****platforms.**

-   **First-ever concept originated and implemented within**
**  ****EDRN for rapid evaluation of technologies and **
**  ****biomarkers**

**Notes:**
In our effort to move faster, any biomarker or a panel  is first test in Reference Sets.

## Example: Sample Reference Libraries

|  |  Reference Set A | Reference Set B |
| --- | --- | --- |
| Clinical context | Diagnosis of lung cancer | Early diagnosis of lung cancer  |
| Study design | Case-control study | Case-control study |
| Study population | All suspicious lung lesions on CXR or on CT | CT screening |
| Cases | Lung cancers, ≥50% Stage I | Detected by CT- lung cancer >0.5cm and <3cm |
| Controls | Clinically free of lung cancer at 1year after enrollment
75 patients with other cancers (25 breast, 25 colon,25 prostate) | Detected by CT with a lung nodule >0.5cm and <3cm
Detected by CT without a lung nodule 
All free of disease at the 1 year F/U CT
75 patients with other cancers (25 breast, 25 colon, 25 prostate) |
| Matching criteria | Age, sex, smoking status, PKYs | Age, sex, smoking status, PKYs |
| Sample size
Rapid pre-validation (1)

Combined pre-validation (2) | (1) 50 cases 100 controls, 25 other cancer controls

(2) 475 (200 cases and 200 controls, 75 other cancer controls) | (1) 50 cases 100 controls, 25 other cancer controls

(2) 675 (200 cases, 400 controls, 75 other cancer controls) |
| Pulmonary diseases | Enriched across whole population | Enriched in controls with CT detected lung nodules |
| Institution provider candidates | Pittsburgh, Vanderbilt, MDACC, Moffitt, NYU, UCLA, Mayo, Lovelace | Pittsburgh, Moffitt, NYU, UCLA, Mayo  |

## VALIDATION STUDIES IN PROGRESS: MICROSATELLITE ALTERATIONS (MSA) IN URINE SEDIMENT

**VALIDATION STUDIES IN PROGRESS: MICROSATELLITE ALTERATIONS (MSA) IN URINE SEDIMENT**

**    **

**Determine the sensitivity and specificity of a panel of 15 MSA markers in urine sediment to detect bladder cancer, both for first malignancy and for recurrence.**
**	**
**2.****	****D****etermine the temporal performance characteristics of MSA in urine sediment****. **
**Determine which markers or combination of markers are most predictive of the presence of bladder cancer.**
_**Design:**_** Case-control study**
_**Status:**_
**	****Cases: 200 enrolled out of 300**
**	****Control: 130 enrolled out of 200**
**	**** **

**Notes:**
We have a number of validation studies in progress and in planning. I have listed tow of them here. EDRN validation studies were selected as Case Studies by TRWG.

## MSA in Urine Sediment: Participants

**MSA in Urine Sediment: Participants**

**    **

| Name | Institution |
| --- | --- |
| Joseph W. Basler, M.D., Ph.D. | University of Texas |
| Guido Dalbagni, M.D. | Memorial Sloan-Kettering |
| Colin P. Dinney, M.D. | M.D. Anderson Cancer Center |
| Margaret F. Fay, PhD, RN, MA, CCRC | LURN (Linked Urology Research Network) |
| Adam Kibel, M.D. | Washington University |
| Laurence Klotz, M.D., FRCSC  | University of Toronto |
| Cheryl T. Lee, M.D. | University of Michigan |
| Seth P Lerner, M.D., F.A.C.S | Baylor College of Medicine |
| Edward Messing, M.D.,F.A.C.S. | University of Rochester Medical Center |
| Joseph C. Presti, Jr., M.D. | Stanford University |
| Mark P. Schoenberg, M.D. (PI) | Johns Hopkins University |
| Neal Shore, M.D. | Carolina Urologic Research Center |
| Gary D. Steinberg, M.D., F.A.C.S. | University of Chicago Urology Center |
| Donald Urban, M.D. | University of Alabama, Birmingham |

**Notes:**
Many of the participants are non-EDRN investigators and this has only been possible through the openness of EDRN Consortium and a unique funding mechanism that EDRN uses.

## VALIDATION STUDIES IN PROGRESS: AFP versus DCP for Hepatocellular Carcinoma

**VALIDATION STUDIES IN PROGRESS: AFP versus DCP for Hepatocellular Carcinoma**

**    **

**Determine the sensitivity and specificity of des-gamma carboxyprothrombin (DCP) for the diagnosis of early hepatocellular carcinoma (HCC).**
**	**
**2.****	****Compare performance characteristics of DCP and Alpha-fetoprotein (AFP) in the diagnosis of early HCC. **
**3.****	****Determine whether demographic or etiology of underlying liver disease alter the expression of DCP or AFP.**
_**Design:**_** Case-control study**
**	****cases: modified TNM stage I and II HCC (eligible for liver transplant), **
**	****prior to any cancer therapy**
**	****controls: cirrhosis without tumor**

## VALIDATION STUDIES IN PROGRESS: AFP versus DCP for Hepatocellular Carcinoma

**VALIDATION STUDIES IN PROGRESS: AFP versus DCP for Hepatocellular Carcinoma**

**    **

| Name | Institution |
| --- | --- |
| Jorge Marrero, MD   PI | University of Michigan |
| Myron Schwartz, MD & Josep Llovet, MD | Mount Sinai University Hospital |
| Rajender Reddy, MD | University of Pennsylvania |
| Lewis Roberts, MB, ChB, PHD | Mayo Clinic, Rochester |
| Alex Befeler, MD | Saint Louis University |
| Mindie H. Nguyen, M.D | Stanford University |
| David Chia, PhD | University of California Los Angles |

_**Status:**_
**  ****Cases: 250 enrolled out of 450 **
**  ****Controls: 200 enrolled out of 450**

## VALIDATION STUDIES IN PROGRESS: EDRN-PLCO-SPORE Ovarian Markers

**VALIDATION STUDIES IN PROGRESS: EDRN-PLCO-SPORE Ovarian Markers**

**    **

**Identify a consensus panel comprised of biomarkers that are most informative in detecting early ovarian cancers (CA 72-4, CA 15-3, CEA, CA 19-9, SMRP-1, OV-1.10, HE-4, Osteopontin, HK-11, HK -10, Spondin-2, Prolactin and CA-125).**
**2.****	****Establish and estimate the lead time of each individual marker in the panel and estimate a marker combination rule.**
**3.****	****Evaluate the performance of final biomarker panel in PLCO preclinical samples.**

## VALIDATION STUDIES IN PROGRESS: EDRN-PLCO-SPORE Ovarian Markers

**    **

| NAME | Institution |
| --- | --- |
| Daniel Cramer, M.D. | Brigham and Women’s Hospital (BWH) |
| Nicole Urban, ScD. | Fred Hutchinson Cancer Research Center (FHCRC) |
| Robert C. Bast, M.D. | MD Anderson (MDA) |
| Andrew Godwin, Ph.D | Fox Chase Cancer Center (FCCC) |
| Anna Lokshin, Ph.D | Univ. of Pittsburgh Cancer Institute (UP) |
| Martin McIntosh, Ph.D | Fred Hutchinson Cancer Research Center (FHCRC) |
| Edward Partridge, M.D. | Univ. of Alabama at Birmingham (UAB) |
| Steven Skates, Ph.D | Mass General Hospital (MGH) |

**VALIDATION STUDIES IN PROGRESS: EDRN-PLCO-SPORE Ovarian Markers**

## VALIDATION STUDIES IN PIPELINE

**VALIDATION STUDIES IN PIPELINE**

**    **

_**Samir Hanash**_
**Validation of Protein Markers of Lung Cancer (autoantibodies to **
**annexins I & II and PGP9.5., includes acute phase reactants CRP**
**and serum amyloid A)**
_**Harvey Pass**_
**Serum Protein Biomarkers for Early Detection of Mesothelioma**
**(serum mesothelin related-protein and osteopontin)**
_**David Sidransky**_** **
**Circulating DNA Methylation Markers of Lung Cancer**
**(6 gene panel)**
_**Alan Partin**_
**GSTP1 Methylation Markers in Screen-Detected Prostate Biopsy as reflex markers**
**	****	****	****	****	****	****	****continues...**

## VALIDATION STUDIES IN PIPELINE, continued...

**VALIDATION STUDIES IN PIPELINE, continued...**

**    **

_**Stephen Meltzer **_
**A panel of methylation markers (p16, HPP1, RUNX3) to determine the risk of progression from Barrett’s esophagus to esophageal adenocarcinoma**
_**Robert Getzenberg and Robert Schoen**_
**Novel serum based markers, Colon Cancer Specific Antigen-3 and -4 (CCSA-3 and CCSA-4), for detection of colorectal cancer.**
_**Brian B. Haab**_** **
**Discrimination of benign from malignant prostatic disease in men with elevated PSA using serum TSP-1.**
_**Eleftherios Diamandis**_
**Human Kallikreins, biomarkers for early detection and progression of prostate cancer.**
_**Robert Getzenberg**_
**EPCA (Early Prostate Cancer Antigen) as a markers for earlier detection of prostate cancer (sensitivity 92%,  specificity is 94%).**

**Continues..**

## Have Biomarkers, Will Validate...

**Have Biomarkers, Will Validate...**
**Request for Biomarkers (RFB)**

**    **

-   **R01 Investigators (David Beer, Ed Hirschowitz, Avi Spira) have joined with****   EDRN Investigators on Lung Cancer Biomarkers **
**  ****R01 Investigator (David Wong) Biomarkers for oral cancer in saliva are****   being tested in an EDRN Reference Laboratory**
**  ****NCI Intramural Investigator (Thomas Ried) has  requested  help from the****   EDRN on cervical cancer biomarkers**
**  ****SPORE Investigator (Robert Coffey in collaboration with EDRN PI Dean****   Brenner) Urinary PGE-M as a biomarker for the detection of large polyps or****   colorectal cancers**
**  ****R01 Investigators (David Ward and Gil Mor) ****Ovarian cancer biomarkers are****   being verified by EDRN**

**Notes:**
Now that EDRN has mature organizationally, we issued a Request for Biomarkers (RFB) to major programs and sent the announcement to Cancer Center Directors. In response to our request, a number of investigators have approached us. I have listed some of the R01 and NCI investigator who are working with us.

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## COLLABORATIONS

**More than 100 collaborative efforts within EDRN**
**Active collaborations with major programs, such as:**
**	****MMHC, SPORE, WHI, CARET, ****PCPT****, PLCO and**
**	****Consortium for Functional Glycomics (NIGMS)**
**	****- ****EDRN and PCPT Investigators have developed Prostate Cancer**
**       ****Risk Calculator**
**Much sought-after EDRN Associate Memberships**
**	****expanding; many industrial/biotech companies**
**	****joining EDRN**
** **
**On-going collaborations with HUPO, AACR and Gordon**
**	****Conference**

**Continues...**

## Collaborations, continued

**Validation Studies/Trials Sponsored by**
**Biotech/Pharmaceutical firms:**
**Cangen: MSA Study (non-exclusive license for MSA test)**
**Eisai and Wako: DCP Study (provide free test kits)**
**Ciphergen: Protein Profiling for Prostate Cancer**

## EDRN’S RAID-Like Program For Rapid Independent Diagnostic Evaluation (PRIDE)

**EDRN encourages extramural investigators to seek assistance from EDRN in cross-laboratory validation of their biomarker assays**
**PRIDE develops and institutes quality assurance programs for biomarker testing and evaluation**
**PRIDE announcement will be made through NIH Guide**

**Notes:**
EDRN has been using a RAID- and RAPID-like mechanism to assist nonEDRN investigators to validate their biomarkers. We are now planning to publish this opportunity in the NIH Guide. EDRN’s biomarker measurement standards are being modeled on NIST’s standards for chemical reagents.

## PARTNERSHIPS

**Ontario Cancer Biomarkers Research Network**
**    ****(Dr. Elefitherios Diamandis)**
**Irish Cancer Biomarkers Research Network**
**    ****(Dr. Mark Lawler)**
**Canary Foundation for Early Detection Research**
**    ****(Donald Listwin)**
**Human Proteome Project, HUPO**

## OUTREACH ACTIVITIES

**AACR-Sponsored Sunrise Program on NCI Early **
**    ****Detection Research Network**
**EDRN Investigators and Program Officers Invited to **
**    “****Meet-the-Expert” sessions by AACR and ASCO**
**EDRN-Sponsored Sessions in HUPO, AACR Special **
**     ****Meetings, ASMP, RSNI, Am. Urol. Soc.**

## ACCOMPLISHMENTS (2000-2006)

**ACCOMPLISHMENTS (2000-2006)**

-   **SUCCESSFUL INFRASTRUCTURE**
**  ****BIOMARKER DISCOVERY**
**  ****BIOMARKER VALIDATION**
**  ****COLLABORATIONS AND PARTNERSHIPS**
**  ****BIOMARKERS AND BIOINFORMATICS**

**Notes:**
I will discuss its accomplished using the following outlines. First: EDRN as a Successful Infrastructure.

## BIOMARKERS AND BIOINFROMATICS IN SUPPORT OF EDRN-SPECIFIC NEEDS

**Support multi-institutional Validation Studies **
**Establish Virtual Specimen Bank**
**Support secure data transfer, data analysis and communication**
**Support EDRN-wide data storage, curation and **
**     ****retrieval of multidimensional, multi-format data**
**Details on EDRN Informatics Infrastructure published in**
**     ****Informatics in Proteomics, ed. Srivastava 2005, Marcel Dekker) **

- _[EDRN has Created a Biomarker Knowledge Environment](file:///../Local%20Settings/Temporary%20Internet%20Files/OLK118/edrn.mov)_

**EDRN Informatics Infrastructure Blueprint was established in 2001 to:**

**Notes:**
Biomarker research generates a lot of data and requires information technology to assist in  biomarker validation and information dissemination. Also, it is important to store data for future use. Therefore, EDRN has created a Biomarker Knowledge Environment. The conceptual designs have been published in Informatics In Proteomics.

## COLLABORATION WITH caBIG

**  ****EDRN Common Data Elements (CDE) posted on**
**   ****caBIG portal**
** ****Integration of ERNE and caTISSUE is underway**
** ****Request for Bioinformatics Biomarkers Interest Group **
**  ****is pending with caBIG leadership**

## SUMMARY

**EDRN is a dynamic infrastructure meeting the challenge of rapidly evolving technologies and translational biology**
**EDRN empowers investigators and challenges them to meet scientific expectations**
**EDRN rewards collaborations and teamwork**

## Ransohoff, Nature Rev Cancer 2004; 4:309-314

**“****The most successful and efficient research about molecular markers will require effective interdisciplinary communication and collaboration involving fields of molecular biology, observational epidemiology and biostatistics.”**

**Team Science**

##  	 SUCCESSFUL INFRASTRUCTURE 	 BIOMARKER DISCOVERY 	 BIOMARKER VALIDATION 	 COLLABORATIONS AND PARTNERSHIPS 	 BIOMARKERS AND BIOINFORMATICS