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The Clinical and Translational Science Award Program:
                  Transdisciplinary Teams
              in Cancer Prevention Research


   11th Annual International
   Conference on Frontiers in
   Cancer Prevention Research
   October 16, 2012




Steven Dubinett, MD
Director, Clinical and Translational Science Institute
Senior Associate Dean and Associate Vice Chancellor for Research, UCLA
www.ctsi.ucla.edu
Disclosure Information
11th Annual International Conference on Frontiers in Cancer Prevention Research

            The Clinical and Translational Science Award Program:
            Transdisciplinary Teams in Cancer Prevention Research
                                Steven Dubinett

                  I have no financial relationships to disclose.

                                     – and –

  I will not discuss off label use and/or investigational use in my presentation.
National, regional and institutional teams



National CTSA
Program


CTSA Constoria


Team Science
Purpose of the
         National CTSA Program
   Providing an infrastructure for clinical and
             translational research
     OLD                          NEW

   Inpatient
     GCRC         Outpatient & community based research

    Individual
  investigators      Transdisciplinary team science

  Traditional      Training in clinical and translational
   training
                               team science
  Individual
  academic
                     Regional and national consortia
medical centers          linked for collaboration
NIH CTSA Consortium
UCLA CTSI
Clinical and Translational Science Institute

                Team Science-
                How do we get there?
                • Facilitate - infrastructure
                • Reward - funding
                • Recognize - promotions
                • Training - in the team environment




                            www.ctsi.ucla.edu
CTSI Research Funding

• Pilot Program: 53 awards totaling $1.8 million
• Team Science Awards: up to $200K for team science
  proposals

• Core Services Vouchers: awards of up to $10K each

• Business of Science Center collaborations: fellowships
  and team awards

• CTSI Scholars: mentored research program for new
  faculty; $30K each annually

• Shared Resources Consortium: support for
  instrumentation and existing and proposed cores     7
Current Team Science Award
            Partners

• AIDS Institute
• Jonsson Comprehensive Cancer Center
• Broad Stem Cell Research Center
• Cardiovascular
• Neuroscience
• Patient Safety Institute (PSI)
• Center for AIDS Research (CFAR)
                                        8
Current Seed Grant Partners

• Center for Autism Research & Treatment (CART)
• Cousins Center for Psychoneuroimmunology
• Women’s Health Center
• Resource Centers for Minority Aging Research /
  Center for Health Improvement for Minority
  Elders (RCMAR/CHIME)
• Pepper Center

                                                   9
Examples of Team Science Awards
Barbara Vickrey, MD, MPH

   Stroke/cardiovascular disease in underserved minority
   populations:
       • working with community partners, design and test
         interventions to reduce risk of disease
Joel Braslow, MD, PhD

   DMH-UCLA-USC Public Mental Health Translational
   Research Consortium:
       • in partnership with LA County and USC, implement best
         practices within the public mental health system

Antoni Ribas, MD
   Overcoming acquired resistance to B-Raf targeting in
   melanoma using phospho-proteomics and microfluidics:
       • Building a comprehensive program for signaling
         discovery and diagnostics to guide kinase inhibitor     10
         clinical trials in melanoma
Clinical and Translational Research
           Center (CTRC)
Ambulatory Clinical Research Facilities
• 7 private rooms, infusion rooms, 2 procedure rooms
• >20,000 sq ft outpatient area
• Clinical and Research Sleep Center
• Interview and conference rooms
• A service center including
  pharmacy and sample processing
• 23 hour capacity

First Year accomplishments
 400 ongoing research projects
 80 new protocols
 4800 out-patient
  & 210 in-patient stays
What is translational research?

  UCLA translational investigation extends
         from molecules to society
Translating knowledge gained from laboratory
science into clinical practice to improve health.
The aim of translational research is to produce
new:
• therapeutics
• medical devices
• tools for diagnosing disease
• community engagement research/ implementation 12
CTSA Regional Consortia




University of California,
           Los Angeles
UC BRAID
University of California - Biomedical Research,
   Acceleration, Integration & Development




    a new initiative…
                building on success of 5 CTSAs

             http://www.ucbraid.org/
UC Biomedical Research Acceleration
Integration and Development (UC-BRAID)

• A committee of the CTSA PIs at UC Davis,
  San Diego, San Francisco, Irvine and Los
  Angeles
• contracting, informatics and IRBs

• Drug discovery and development
• Biobanking and global consent

• Future inclusion of other partner institutions
                                            15
UC Biomedical Research Acceleration
Integration and Development (UC-BRAID)




                                         16
UC Biomedical Research Acceleration
Integration and Development (UC-BRAID)




                                         17
UC-ReX




http://www.ucbraid.org/i
  nformaticsmdashuc-
        rex.html
UC-ReX User Interface
Science of Team Science

• growing interest and investment in large-
scale, team-based research initiatives to
address complex and multi-faceted
problems that require cross-disciplinary
collaboration

•The science-of-team-science field -
concerned especially with understanding
and managing circumstances that facilitate
or hinder the effectiveness of team science
initiatives.            Stokols, Am J Prev Med 2008
Science of Team Science




       Clin Transl Sci. 2010 Oct
Training in Team Science



Starting early

Creating new
  mechanisms
Changes in Bronchial Epithelium in Relation to Cigarette
Smoking and in Relation to Lung Cancer
Oscar Auerbach, A. P. Stout, E. Cuyler Hammond, and Lawrence Garfinkel
NEJM August 10, 1961




     Rui Li     Paul Pagano     Jeannette Grant    Kostyantyn Krysan    Elvira Liclican   Tonya Walser   Felicita Baratelli




   Gina Lee   Stacy Park      Brian Gardner       Puja Kachroo         Ying Lin           Wen Mao        Zhe Jing             23
Two Models of Cancer Development and Progression
       Model 1                             Model 2
  normal                                normal
  tissue                                tissue
                                 (e.g., a stem cell
                                expressing Snail)         metastasis

  in situ
  cancer                            dissemination
                       DNA damage




disseminated                            in situ
   cancer                               cancer
                       DNA damage




                                                         aggressive
aggressive                          disseminated         metastasis
metastasis                             cancer

                                    Adapted from Sánchez-García NEJM 2009
Snail drives programs of inflammation, migration/invasion,
  angiogenesis and stem cell phenotype expansion in HBEC


 Snail in Premalignancy



               Squamous
    AAH        Metaplasia




  Air-Liquid Interface 3D Model
HBEC-
Vector                                          Q-RT-PCR
         H&E   Snail   E-cad   Ki67             Validation

HBEC-
 Snail
Inflammation-mediated promotion of EMT

                                                                         IL-1b, PGE2, TGF-b
                        Snail
 mRNA expression




                                                                                   ++Snail
                       ZEB 1



                                PGE2                                 •   apoptosis resistance
                                                                     •   angiogenesis
                   1                                                 •   decreased E-cadherin
mRNA expression




                                                                     •   enhanced inflammation



                       E-cadherin                                    • stem cell phenotypes
                                                                     • drug resistance
                                       E-cadherin red; COX-2 brown   • metastases
Which features of pulmonary premalignancy
   portend transformation and progression?


             Squamous
   AAH       Metaplasia

What proteins/genes are evident
  in situ in premalignancy?

                                                  …and which are critical for
                                                  driving transformation and
                                                         progression?
                         Air-Liquid Interface 3D Model
                HBEC-
                Vector
                         H&E    Snail    E-cad    Ki67
                HBEC-
                 Snail
Team Science
Tonya Walser           Maie St. John          Avi Spira (Boston University)
Kostyantyn Krysan      Xiaoyan Cui            Marc Lenburg (Boston University)
David Elashoff         Saswati Hazra          Ignacio Wistuba (MD Anderson)
Leonard Rome           Elvira Liclican        Pierre Massion (Vanderbilt)
Jay Lee                Eileen Heinrich        Jerry Shay (UT Southwestern)
Edward Garon           Jie Luo                John Minna (UT Southwestern)
Gina Lee               Wen Mao                Patient advocates &
Fran Rosen             Ying Lin               foundations
Sherven Sharma         Zhe Jing
Minu Srivastava        Li Zhu
Felicita Baratelli     Yuan Lin
Ying Lin               Stacy Park
Mi-Heon Lee            Jeanette Grant
Michael Fishbein       Nicole Rodriguez
Dean Wallace           Paul Pagano
Denise Aberle          Rui Li
Fereidoun Abtin        Sahil Patel
Robert Suh             Puja Kachroo
Brian Gardner          Aik Ooi
Brigitte Gomperts      Dorthe Shaue
Min Huang              Grigoriy Shekhtman

                           Supported by:
  NCI EDRN · Lung Cancer SPORE · VA · DOD · LungEVITY · UCLA CTSI ·
   Tobacco Related Disease Res Program · Broad Foundation · LCMC
29
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10/16 AACR Team Science Presentation

  • 1. The Clinical and Translational Science Award Program: Transdisciplinary Teams in Cancer Prevention Research 11th Annual International Conference on Frontiers in Cancer Prevention Research October 16, 2012 Steven Dubinett, MD Director, Clinical and Translational Science Institute Senior Associate Dean and Associate Vice Chancellor for Research, UCLA www.ctsi.ucla.edu
  • 2. Disclosure Information 11th Annual International Conference on Frontiers in Cancer Prevention Research The Clinical and Translational Science Award Program: Transdisciplinary Teams in Cancer Prevention Research Steven Dubinett I have no financial relationships to disclose. – and – I will not discuss off label use and/or investigational use in my presentation.
  • 3. National, regional and institutional teams National CTSA Program CTSA Constoria Team Science
  • 4. Purpose of the National CTSA Program Providing an infrastructure for clinical and translational research OLD NEW Inpatient GCRC Outpatient & community based research Individual investigators Transdisciplinary team science Traditional Training in clinical and translational training team science Individual academic Regional and national consortia medical centers linked for collaboration
  • 6. UCLA CTSI Clinical and Translational Science Institute Team Science- How do we get there? • Facilitate - infrastructure • Reward - funding • Recognize - promotions • Training - in the team environment www.ctsi.ucla.edu
  • 7. CTSI Research Funding • Pilot Program: 53 awards totaling $1.8 million • Team Science Awards: up to $200K for team science proposals • Core Services Vouchers: awards of up to $10K each • Business of Science Center collaborations: fellowships and team awards • CTSI Scholars: mentored research program for new faculty; $30K each annually • Shared Resources Consortium: support for instrumentation and existing and proposed cores 7
  • 8. Current Team Science Award Partners • AIDS Institute • Jonsson Comprehensive Cancer Center • Broad Stem Cell Research Center • Cardiovascular • Neuroscience • Patient Safety Institute (PSI) • Center for AIDS Research (CFAR) 8
  • 9. Current Seed Grant Partners • Center for Autism Research & Treatment (CART) • Cousins Center for Psychoneuroimmunology • Women’s Health Center • Resource Centers for Minority Aging Research / Center for Health Improvement for Minority Elders (RCMAR/CHIME) • Pepper Center 9
  • 10. Examples of Team Science Awards Barbara Vickrey, MD, MPH Stroke/cardiovascular disease in underserved minority populations: • working with community partners, design and test interventions to reduce risk of disease Joel Braslow, MD, PhD DMH-UCLA-USC Public Mental Health Translational Research Consortium: • in partnership with LA County and USC, implement best practices within the public mental health system Antoni Ribas, MD Overcoming acquired resistance to B-Raf targeting in melanoma using phospho-proteomics and microfluidics: • Building a comprehensive program for signaling discovery and diagnostics to guide kinase inhibitor 10 clinical trials in melanoma
  • 11. Clinical and Translational Research Center (CTRC) Ambulatory Clinical Research Facilities • 7 private rooms, infusion rooms, 2 procedure rooms • >20,000 sq ft outpatient area • Clinical and Research Sleep Center • Interview and conference rooms • A service center including pharmacy and sample processing • 23 hour capacity First Year accomplishments  400 ongoing research projects  80 new protocols  4800 out-patient & 210 in-patient stays
  • 12. What is translational research? UCLA translational investigation extends from molecules to society Translating knowledge gained from laboratory science into clinical practice to improve health. The aim of translational research is to produce new: • therapeutics • medical devices • tools for diagnosing disease • community engagement research/ implementation 12
  • 13. CTSA Regional Consortia University of California, Los Angeles
  • 14. UC BRAID University of California - Biomedical Research, Acceleration, Integration & Development a new initiative… building on success of 5 CTSAs http://www.ucbraid.org/
  • 15. UC Biomedical Research Acceleration Integration and Development (UC-BRAID) • A committee of the CTSA PIs at UC Davis, San Diego, San Francisco, Irvine and Los Angeles • contracting, informatics and IRBs • Drug discovery and development • Biobanking and global consent • Future inclusion of other partner institutions 15
  • 16. UC Biomedical Research Acceleration Integration and Development (UC-BRAID) 16
  • 17. UC Biomedical Research Acceleration Integration and Development (UC-BRAID) 17
  • 20. Science of Team Science • growing interest and investment in large- scale, team-based research initiatives to address complex and multi-faceted problems that require cross-disciplinary collaboration •The science-of-team-science field - concerned especially with understanding and managing circumstances that facilitate or hinder the effectiveness of team science initiatives. Stokols, Am J Prev Med 2008
  • 21. Science of Team Science Clin Transl Sci. 2010 Oct
  • 22. Training in Team Science Starting early Creating new mechanisms
  • 23. Changes in Bronchial Epithelium in Relation to Cigarette Smoking and in Relation to Lung Cancer Oscar Auerbach, A. P. Stout, E. Cuyler Hammond, and Lawrence Garfinkel NEJM August 10, 1961 Rui Li Paul Pagano Jeannette Grant Kostyantyn Krysan Elvira Liclican Tonya Walser Felicita Baratelli Gina Lee Stacy Park Brian Gardner Puja Kachroo Ying Lin Wen Mao Zhe Jing 23
  • 24. Two Models of Cancer Development and Progression Model 1 Model 2 normal normal tissue tissue (e.g., a stem cell expressing Snail) metastasis in situ cancer dissemination DNA damage disseminated in situ cancer cancer DNA damage aggressive aggressive disseminated metastasis metastasis cancer Adapted from Sánchez-García NEJM 2009
  • 25. Snail drives programs of inflammation, migration/invasion, angiogenesis and stem cell phenotype expansion in HBEC Snail in Premalignancy Squamous AAH Metaplasia Air-Liquid Interface 3D Model HBEC- Vector Q-RT-PCR H&E Snail E-cad Ki67 Validation HBEC- Snail
  • 26. Inflammation-mediated promotion of EMT IL-1b, PGE2, TGF-b Snail mRNA expression ++Snail ZEB 1 PGE2 • apoptosis resistance • angiogenesis 1 • decreased E-cadherin mRNA expression • enhanced inflammation E-cadherin • stem cell phenotypes • drug resistance E-cadherin red; COX-2 brown • metastases
  • 27. Which features of pulmonary premalignancy portend transformation and progression? Squamous AAH Metaplasia What proteins/genes are evident in situ in premalignancy? …and which are critical for driving transformation and progression? Air-Liquid Interface 3D Model HBEC- Vector H&E Snail E-cad Ki67 HBEC- Snail
  • 28. Team Science Tonya Walser Maie St. John Avi Spira (Boston University) Kostyantyn Krysan Xiaoyan Cui Marc Lenburg (Boston University) David Elashoff Saswati Hazra Ignacio Wistuba (MD Anderson) Leonard Rome Elvira Liclican Pierre Massion (Vanderbilt) Jay Lee Eileen Heinrich Jerry Shay (UT Southwestern) Edward Garon Jie Luo John Minna (UT Southwestern) Gina Lee Wen Mao Patient advocates & Fran Rosen Ying Lin foundations Sherven Sharma Zhe Jing Minu Srivastava Li Zhu Felicita Baratelli Yuan Lin Ying Lin Stacy Park Mi-Heon Lee Jeanette Grant Michael Fishbein Nicole Rodriguez Dean Wallace Paul Pagano Denise Aberle Rui Li Fereidoun Abtin Sahil Patel Robert Suh Puja Kachroo Brian Gardner Aik Ooi Brigitte Gomperts Dorthe Shaue Min Huang Grigoriy Shekhtman Supported by: NCI EDRN · Lung Cancer SPORE · VA · DOD · LungEVITY · UCLA CTSI · Tobacco Related Disease Res Program · Broad Foundation · LCMC
  • 29. 29

Hinweis der Redaktion

  1. Our CTSI proposes to create a collaborative culture in which practice-changing innovation is not the exception but the rule