A Team Science Approach to Nicotine Dependence Treatment

1. A Team Science Approach to Nicotine Dependence Treatment Caryn Lerman, Ph.D. Center for Interdisciplinary Research on Nicotine Addiction

2. Continuum of Research Teams Level of Interaction and Integration High Low Individual Collaboration Team Science • Each team member brings expertise to address common research problem • Teams meet regularly to discuss team goals, individuals’ objectives and next steps • Team shares leadership responsibility, decision authority, data and credit • Each group member brings expertise to address research problems • Group members work on separate parts of research problem which later become integrated • Data sharing or brainstorming varies from limited to frequent • Investigator works largely independently on research problem in own lab

3. Team Science • Get the right people “on the bus”. • Develop a collectivevision to address an important scientific, clinical, and or public health problem. • Identify a unifying theme that can/must be addressed from a multi-disciplinary perspective. • Generate a common conceptual model that links individual scientific projects to address the problem. • Develop a common vocabulary through cross-education of team members. • Meet often to facilitate synergy across projects and communicate goals and interests. • Support junior investigators in all aspects of career development.

4. Who to get on the bus? • Team Science Essentials • (smart is not sufficient) • Creative • Open (cognitive flexibility) • Dependable • Accessible • team science takes extra time

5. Center for Interdisciplinary Research on Nicotine Addiction (1999- ) Common vision: Elucidate the cellular, molecular and neural regulation of cognitive and affective responses that promote relapse, and translate findings to improve therapy for nicotine dependence (2009-2014) Julie Blendy multi-PI CIRNA

6. Common Conceptual Model Cognitive, neurobiological markers of medication effects Screening of novel compounds and repurposed meds A focus on the key clinical endpoint: relapse • Cellular and genomic studies to identify potential targets

7. * Exon1 A Translational Research Example Opioid genetic mechanisms in nicotine reward and relapse

8. Opioid Mechanisms in Nicotine Reward Nestler

9. A B Preconditioning Day C S A B DRUG C S A B C SALINE S C A B S Mouse Model of Nicotine Reward Day 1 Pairing Days 2-8 ?? Test Day Blendy Lab

10. Naloxone on Test Day Blocks Conditioned Rewarding Effects of Nicotine in 129/C57 B16 Mice * Treatment on Test Day Time on paired minus time on unpaired Nicotine (1.0mg/kg) Nicotine (2.0mg/kg) Saline Nicotine on Pairing Days *p<.05 Walters et al, Neuron, 2005

11. The Human OPRM1 Gene PROMOTOR EXON 1 EXON 2 EXON 3 EXON 4 3’UTR A118G • The human OPRM1 gene includes a common Exon 1 Asn40Asp (A118G) mis-sense single nucleotide polymorphism (SNP). • G allele associated with reduced mRNA expression and protein levels and is present in 25-30% of persons of European ancestry • Hypothesis: Smokers with G allele will have a lower liability to relapse in smoking cessation treatment

12. Open Label Pharmacogenetic Trial of NRT (n=600*) Pre-treatment Assessment & Genotyping Transdermal nicotine x 8 wks Nicotine nasal spray x 8 wks 95% retention rate Follow-Up: EOT, 6-months, and 12-months *European ancestry only (n=420)

13. OPRM1 Asn40Asp Variant is Associated with Response to Nicotine Replacement Therapy % quit Treatment Phase Follow-up Phase Normal Reduced activity OR= 1.9, p=.01 Lerman et al.,Pharmacogenomics , 2004

14. What is the Mechanism of Enhanced Therapeutic Response in Smokers with the OPRM1 Asp40 (G) allele? • Do carriers of the OPRM1 G allele (loss of function) exhibit reduced nicotine reinforcement? 2. Does naltrexone reduce nicotine reinforcement—particularly in smokers with OPRM1 G allele? • Are females more sensitive to opioid system effects on nicotine reward?

15. Within Subject Design N=60, genotype pre-screening, OPRM1 rare allele oversampled Study Phase 1 Study Phase 2 *NTX or PLACEBO *NTX or PLACEBO Day 1 12.5mg* Day 2 25mg* Day 3 50mg* Day 4 50mg* Day 1 12.5mg* Day 2 25mg* Day 3 50mg* Day 4 50mg* 5-7 day Washout Observation Period Observation Period Test Day Test Day • CO, medication compliance, side effects assessed in-person daily. • CO, medication compliance, side effects assessed in-person daily. Nicotine choice paradigm Nicotine choice paradigm

16. Human Model of Nicotine Reward • 2 hour deprivation period (to standardize exposure without inducing serious withdrawal symptoms) • Initial (blinded) exposure to 4 puffs of Quest cigarettes: denic. (.05 mg) vs nic. (.6 mg) • Assess subjective effects • Self-administer 4 puffs from either cigarette at 30 minute intervals in 6 trials over a 3-hour period • Outcome measure is number of nicotine puffs chosen out of 24 = relative reinforcing value of nicotine

17. Reduced Activity OPRM1 Allele is Associated with Reduced Nicotine Reward Subjective Ratings (nicotine minus denicotinized cigarette) Normal activity Reduced activity p=.05 p=.03 Ray et al. Psychopharmacology, 2006

18. OPRM1 Genotype Predicts Nicotine Reinforcement in Females but not in Males number of nicotine puffs in 24 (across treatments) 24 75% of Puffs from Nicotine 50% P (genotype by gender interaction)=.036 Ray et al. Psychopharmacology, 2006

19. Naltrexone Does Not Reduce Nicotine Reward or Interact with OPRM1 Genotype number of nicotine puffs in 24 24

20. * Exon1 Using Targeted Genetic Mutations in the Mouse to Understand Human OPRM1 SNP (Blendy Lab) Molecular Cellular Imaging Behavioral

21. MOPR expression is decreased in A112G knock-in mice Female G/G mice failed to show a conditioned place preference to morphine-paired environments (10 mg/kg) Mague et al, PNAS, 2009 (Blendy Lab) ©2009 by National Academy of Sciences

22. MOR Binding Availability as Mechanism for OPRM1 Association with Nicotine Reward 2x2 factorial design in 24 smokers, 11C [carfentanil PET imaging]: Nicotine: (nicotine vs. placebo) within subject (n=24) OPRM1 genotype (AA vs. AG/GG) between subject (3) Healthy non-smoking controls (AA vs. AG/GG) (n=20) Collaboration with Andy Newberg, ChaitanDivgi and Gur Lab

23. MOR Binding Potential by OPRM1 A118G Ray et al., PNAS, 2011

24. Summary: OPRM1 Pharmacogenetic Clinical Trial Preclinical pharmacology MOR antagonist decreases nicotine reward OPRM1 G allele is protective for smoking Human behavioral pharmacology OPRM1 G allele linked to reduced nicotine reward Preclinical and clinical receptor studies G allele linked with reduced MOR mRNA and protein in mice; reduced MOR binding in humans Transgenic, molecular pharmacology Human genetic, PET imaging Cross-species MOR binding studies provide a platform for screening mu opioid receptor modulators

25. CIRNA Team Julie Blendy Ruben Gur James Loughead KoshaRuparel Greg O’Donnel Riju Ray Mary Falcone Rebecca Ashare Allison Gold Janet Audrain-McGovern Angela Pinto Susan Ware Paul Wileyto Freda Patterson Andrew Strasser Christopher Jepson Leah LaPrate Dan Heitjan Steve Siegel Jill Turner Monica Hilario Steve Mague M Casetllano Carrie Walters Heath Schmidt Robbie Schnoll Don Baldwin David Asch Ken Perkins Ze Wang John Detre https://www.cancer.gov/

26. Thank you Funding Primary: NCI and NIDA Secondary: Pfizer, AstraZeneca