Translating Biomarker Discovery to Clinical Application

1. Translating Biomarker Discovery to Clinical Application Sudhir Srivastava, Ph.D., M.P.H. Cancer Biomarkers Research Group 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. 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.

2. 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.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.

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

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

5. 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.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.

6. 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

7. 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.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.

8. MANAGEMENT OVERSIGHT

9. 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 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.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.

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

11. Systematic Approach To Biomarker Discovery: An Engineering Approach 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).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).

12. 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.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.

13. 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.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.

14. 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.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.

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

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

17. 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.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.

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

19. Example: Sample Reference Libraries

20. 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.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.

21. 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.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.

28. 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.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.

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

30. 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

31. 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

32. 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 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.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.

33. 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

34. 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.

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

36. 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) 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.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.

37. COLLABORATION WITH caBIG

38. 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

39. 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.�

40. SUCCESSFUL INFRASTRUCTURE BIOMARKER DISCOVERY BIOMARKER VALIDATION COLLABORATIONS AND PARTNERSHIPS BIOMARKERS AND BIOINFORMATICS