Transcript New Directions in the Prevention and Treatment of Tobacco

A Team Science
Approach to
Nicotine
Dependence
Treatment
Caryn Lerman, Ph.D.
Center for Interdisciplinary
Research on Nicotine Addiction
Continuum of Research Teams
Level of Interaction and Integration
Low
High
Individual
Collaboration
• Investigator
• Each group member
works largely
brings expertise to
independently on
address research
research problem
problems
in own lab
Team Science
• Each team member
brings expertise to
address common
research problem
• Group members work •
on separate parts of
research problem which
later become
integrated
• Data sharing or
brainstorming varies
from limited to
frequent
Teams meet regularly
to discuss team goals,
individuals’ objectives
and next steps
• Team shares
leadership
responsibility,
decision authority,
data and credit
Team Science
1. Get the right people “on the bus”.
2. Develop a collective vision to address an important scientific,
clinical, and or public health problem.
3. Identify a unifying theme that can/must be addressed from a
multi-disciplinary perspective.
4. Generate a common conceptual model that links individual
scientific projects to address the problem.
5. Develop a common vocabulary through cross-education of team
members.
6. Meet often to facilitate synergy across projects and
communicate goals and interests.
7. Support junior investigators in all aspects of career development.
Who to get on the bus?
Team Science Essentials
(smart is not sufficient)
•
•
•
•
Creative
Open (cognitive flexibility)
Dependable
Accessible
team science takes extra time
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
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
*
Exon1
A Translational Research Example
Opioid genetic mechanisms in
nicotine reward and relapse
Opioid Mechanisms in Nicotine Reward
Nestler
Mouse Model of Nicotine Reward
Preconditioning Day
C
A
B
A
B
A
B
A
B
Day 1
S
C
Pairing
Days 2-8
S
C
S
C
S
Blendy Lab
Test Day
??
Naloxone on Test Day Blocks Conditioned Rewarding
Effects of Nicotine in 129/C57 B16 Mice
Treatment on Test Day
*
500.00
Time on paired minus time on
unpaired
400.00
Saline
300.00
Naloxone
200.00
100.00
0.00
-100.00
-200.00
-300.00
-400.00
-500.00
*p<.05
Saline
Nicotine
(1.0mg/kg)
Nicotine
(2.0mg/kg)
Nicotine on Pairing Days
Walters et al, Neuron, 2005
The Human OPRM1 Gene
PROMOTOR
3’UTR
EXON 1
EXON 2
EXON 3
EXON 4
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
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)
OPRM1 Asn40Asp Variant is Associated with
Response to Nicotine Replacement Therapy
% quit
60
Treatment Phase
Follow-up Phase
50
AA n=238
Normal
GA GG n=82
Reduced
activity
40
30
20
10
0
All
Patch
OR= 1.9, p=.01
Spray
All
Patch
Spray
Lerman et al., Pharmacogenomics , 2004
What is the Mechanism of Enhanced Therapeutic
Response in Smokers with the OPRM1 Asp40 (G) allele?
1. 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?
3. Are females more sensitive to opioid
system effects on nicotine reward?
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 Day 2 Day 3 Day 4
Day 1 Day 2 Day 3 Day 4
12.5mg*
12.5mg* 25mg*
25mg*
50mg*
Observation
Period
• CO, medication
compliance, side
effects assessed inperson daily.
50mg*
5-7 day Washout
Test Day
Nicotine choice paradigm
50mg*
Observation
Period
• CO, medication
compliance, side
effects assessed inperson daily.
50mg*
Test Day
Nicotine choice paradigm
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
Reduced Activity OPRM1 Allele is
Associated with Reduced Nicotine Reward
Subjective Ratings (nicotine minus denicotinized cigarette)
2
AA (n=30) Normal
activity
1.8
1.6
G* (n=30)
1.4
1.2
Reduced
activity
1
0.8
0.6
0.4
0.2
0
Satisfaction
p=.05
Strength
p=.03
Ray et al. Psychopharmacology, 2006
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
20
15
AA n=30
19.65
50%
GA GG n=30
18
18
13.58
10
5
0
Males
Females
P (genotype by gender interaction)=.036
Ray et al. Psychopharmacology, 2006
Naltrexone Does Not Reduce Nicotine
Reward or Interact with OPRM1 Genotype
number of nicotine puffs in 24
24
AA
20
AG/GG
18.83
15
10
18.23
15.55
16.38
5
0
Naltrexone
Placebo
Using Targeted Genetic Mutations in the Mouse
to Understand Human OPRM1 SNP
(Blendy Lab)
*
Exon1
Molecular
Cellular
Imaging
Behavioral
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
MOR Binding Availability as Mechanism for
OPRM1 Association with Nicotine Reward
2x2 factorial design in 24 smokers,
11C [carfentanil PET imaging]:
(1) Nicotine: (nicotine vs. placebo)
within subject (n=24)
(2) OPRM1 genotype (AA vs. AG/GG)
between subject
(3) Healthy non-smoking controls
(AA vs. AG/GG) (n=20)
Collaboration with Andy Newberg,
Chaitan Divgi and Gur Lab
MOR Binding Potential by OPRM1 A118G
Ray et al., PNAS, 2011
Summary: OPRM1
Pharmacogenetic Clinical Trial
OPRM1 G allele is
protective for
smoking
Preclinical pharmacology
MOR antagonist
decreases nicotine
reward
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
CIRNA Team
Riju Ray
Mary Falcone
Rebecca Ashare
Allison Gold
Janet AudrainMcGovern
Angela Pinto
Susan Ware
Paul Wileyto
Freda Patterson
Andrew Strasser
Christopher
Jepson
Leah LaPrate
Dan Heitjan
Steve Siegel
https://www.cancer.gov/
Julie Blendy
Ruben Gur
James Loughead
Kosha Ruparel
Greg O’Donnel
Jill Turner
Monica Hilario
Steve Mague
M Casetllano
Carrie Walters
Heath Schmidt
Robbie Schnoll
Don Baldwin
David Asch
Ken Perkins
Ze Wang
John Detre
Thank you
Funding
Primary: NCI and NIDA
Secondary: Pfizer, AstraZeneca