The Clinical and Translational Science Award Program:

Transdisciplinary Teams in Cancer Prevention Research

11th Annual International

Conference on Frontiers in Cancer Prevention ResearchOctober 16, 2012

Steven Dubinett, MDDirector, Clinical and Translational Science Institute Senior Associate Dean and Associate Vice Chancellor for Research, UCLA www.ctsi.ucla.edu

UC-ReX

Disclosure Information11th 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

Outpatient & community based research

Inpatient GCRC

Training in clinical and translational team science

Regional and national consortia linked for collaboration

Traditional training

Individual academic medical centers

OLD NEW

Purpose of the National CTSA Program

Providing an infrastructure for clinical and translational research

Transdisciplinary team scienceIndividual investigator

s

NIH CTSA Consortium

UCLA CTSI Clinical and Translational Science

Institute

www.ctsi.ucla.edu

Team Science-How do we get there?

• Facilitate - infrastructure • Reward - funding• Recognize - promotions• Training - in the team environment

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

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)

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

10

Examples of Team Science Awards

Stroke/cardiovascular disease in underserved minority populations:

• working with community partners, design and test interventions to reduce risk of disease

Barbara Vickrey, MD, MPH

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

Joel Braslow, MD, PhD

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 clinical trials in melanoma

Antoni Ribas, MD

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

CTSA Regional Consortia

University of California,

Los Angeles

UC-BRAID

UC BRAIDUniversity of California - Biomedical

Research, Acceleration, Integration & Development

http://www.ucbraid.org/

a new initiative…building on success of 5 CTSAs

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

16

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

Investigator

• IRB harmonization• Master contracting

• Integrated Research Data Repository

• Harmonizing biobanking

UCSF

UC Davis

UCLA

UC San Diego

UC Irvine

17

UC Biomedical Research Acceleration Integration and

Development (UC-BRAID)

UCs UCLA CTSI

Partner

InstitutionsLocal

Delivery

Network

PatientLA County

health system

Community-

based clinics

& centers

Harbor /

LA BioMed

Charles Drew

University

UCLA

UCSF

UC Irvine

UC Davis

UC San Diego

Cedars-Sinai

UC-ReX

UC-ReXhttp://

www.ucbraid.org/informaticsmdashu

c-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

23

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

Two Models of Cancer Development and Progression

normaltissue

in situcancer

disseminatedcancer

aggressive metastasis

(e.g., a stem cell expressing Snail)

DNA damage

DNA damage

normaltissue

in situcancer

dissemination

metastasis

aggressive metastasis

Model 1 Model 2

Adapted from Sánchez-García NEJM 2009

disseminated cancer

Snail drives programs of inflammation, migration/invasion, angiogenesis and stem cell phenotype expansion in HBEC

HBEC-Snail

Air-Liquid Interface 3D Model

HBEC-Vector

E-cad Ki67SnailH&E

AAHSquamous Metaplasia

Snail in Premalignancy

Q-RT-PCR Validation

ZEB 1

mR

NA

exp

ress

ion

Snail

1

E-cadherinmR

NA

exp

ress

ion

Inflammation-mediated promotion of EMT

IL-1b, PGE2, TGF-b

++Snail

• apoptosis resistance• angiogenesis• decreased E-cadherin• enhanced inflammation

• stem cell phenotypes • drug resistance• metastasesE-cadherin red; COX-2 brown

PGE2

Which features of pulmonary premalignancy portend transformation and progression?

AAH

Squamous Metaplasia

What proteins/genes are evident in situ in premalignancy?

…and which are critical for driving transformation and

progression?

HBEC-Snail

Air-Liquid Interface 3D Model

HBEC-Vector

E-cad Ki67SnailH&E

Tonya WalserKostyantyn KrysanDavid Elashoff Leonard RomeJay Lee Edward Garon Gina Lee Fran Rosen Sherven SharmaMinu SrivastavaFelicita BaratelliYing LinMi-Heon LeeMichael Fishbein Dean Wallace Denise AberleFereidoun AbtinRobert SuhBrian Gardner Brigitte GompertsMin HuangMaie St. John

Xiaoyan CuiSaswati HazraElvira LiclicanEileen HeinrichJie LuoWen MaoYing LinZhe JingLi ZhuYuan LinStacy ParkJeanette GrantNicole RodriguezPaul PaganoRui LiSahil PatelPuja KachrooAik Ooi Dorthe ShaueGrigoriy ShekhtmanAvi Spira (Boston University)

Marc Lenburg (Boston University)

Ignacio Wistuba (MD Anderson)

Pierre Massion (Vanderbilt)

Jerry Shay (UT Southwestern)

John Minna (UT Southwestern)

Patient advocates & foundations

Supported by: NCI EDRN · Lung Cancer SPORE · VA · DOD · LungEVITY · UCLA

CTSI · Tobacco Related Disease Res Program · Broad Foundation · LCMC

Team Science

29