Pharmacogenomics

and
Precision Medicine
Richard Weinshilboum, M.D.
Dasburg Professor of Cancer Genomics
Research
Departments of Pharmacology and Medicine
Mayo Clinic Mayo Clinic College of Medicine
Rochester, MN

Pharmacogenomics
and
Precision Medicine

Introduction
Pharmacogenomic
Implementation
Pharmacogenomic
Discovery
Pharmacogenomic

Evolution of
Particle Physics

Chadwicks
Apparatus to Discover
the Neutron

The Large
Hadron Collider

Evolution of
Biomedical Science

Large omics datasets

Expensive technologies, NextGen DNA

sequencing, metabolomics, etc.

Requirement for overlapping
complementary expertise, especially
computational expertise
Need for constant cross-disciplinary
dialog

The Human Genome

February 2001

Mayo Clinic
Center for Individualized
Medicine
Goal
To bring genomic
science
to the bedside.

Mayo Center for Individualized Medicine

Clin Pharmacol Ther. 94:204-6, 2013

Pharmacogenomics
and
Precision Medicine

Introduction
Pharmacogenomic
Implementation
Pharmacogenomic
Discovery
Pharmacogenomic

Pharmacogenomics
and
Precision Medicine
Pharmacogen
omic
Implementati
on
Pharmacogen
Pharmacogen
omic
omic
Discovery
Translation

Pharmacogenomics
and
Precision Medicine
Foundations
Pharmacogenomics
Research Network (PGRN)
Grant (NIGMS)
eMERGE Grant (NHGRI)

Pharmacogenomics

Critical component of
personalized or individualized
medicine.

The study of the role of inheritance

in individual variation in drug
response phenotypes.

Pharmacogenomics

Clinical Goals

Avoid adverse drug reactions

Maximize drug efficacy
Select responsive patients

The Therapeutic
Revolution

Goodman and Gilmans

The Pharmacological Basis of

Childhood ALL Survival

St. Jude Experience

Pui and Evans, NEJM 354:166-78, 2006

Metabolism of 6-Mercaptopurine
SH
N

Thiopurine
Methyltransferase
(TPMT)

N
H

Xanthine Oxidase
(XO)

AdoMet
AdoHcy

SH

SCH 3
N

N
N

N
H

HO

AdoMet

OH
N

N
H

AdoHcy

XO

TPMT

SCH3
N

N
OH

OH
N

N
H

2,8-Dihydroxy-6-Methylmercaptopurine

% Of Subjects Per
0.5 Units of Activity

Human RBC TPMT

298
Adults
298Unrelated
Unrelated
Adults

10

TPMTH/TPMTH

TPMTL/TPMTH

TPMTL/TPMTL

10

15

TPMT Activity, Units/ml RBC

20

TPMT
Genetic Polymorphism
Clinical Consequences

Low TPMT

Increased thiopurine toxicity

Increased risk for secondary neoplasm

High TPMT

Decreased therapeutic effect

Drug-Gene Rules
Alert at point of care in EMR

Reduce side effects

Increase effectiveness
Reduce costs
Education
Prescribers
Pharmacists
Patients

Abacavir
Carbamazepine
Thiopurines
Codeine
Tramadol
Tamoxifen
Statins
Clopidogrel
Warfarin

Drug-Gene EMR Implementation Process

Mayo
Mayo Clinic
Clinic Pharmacy
Pharmacy
and
and Formulary
Formulary
Committee
Committee

Clinomics
Clinomics
oversight
oversight group
group

Pharmacogenomic
Pharmacogenomic
ss Task
Task Force*
Force*

13
13 existing
existing
disease-oriented
disease-oriented
Task
Task Forces
Forces

No
Approve
No
drug-genome
rule?

Yes
Yes
Electronic
Electronic Medical
Medical Record
Record
(EMR)
Implementation
(EMR) Implementation and
and
maintenance
maintenance

Mayo
Mayo Clinical
Clinical Decision
Decision
Support
Subcommittee
Support Subcommittee
Approval
Approval

Local
Local P&T
P&T and
and other
other
local
local groups
groups

Stop
Stop

Pharmacogenomics
and
Precision Medicine
Mayo RIGHT 10K Project
Mayo-Baylor Collaboration
500 Patient Pilot
10,000 Patients Pharmacogenes
Sequenced Pre-emptively and
Placed in EHR

Pharmacogenomics
and
Precision Medicine

Introduction
Pharmacogenomic
Implementation
Pharmacogenomic
Discovery
Pharmacogenomic

Cancer Pharmacogenomics

Two Genomes

Germline Genomes
Somatic (Tumor) Genome

Cancer Pharmacogenomics
Breast Cancer

Number one invasive cancer

of women worldwide

~233,000 new cases in the

US in 2014

~40,000 deaths in the US in

Breast Cancer
Molecular Classification
and Therapy
Receptor Positive

HER2 Positive

TNBC

Endocrine Rx
(SERMs and AIs)

Trastuzamab
(Herceptin)

Chemotherapy
(taxanesanthracyclines)

Targeted Rx

Targeted Rx

Targeted Rx

Breast Cancer
Endocrine Therapy
ER(+)
Therapeutic Strategies
Block estrogen synthesis
aromatase inhibitors
Block ER tamoxifen

Estrogen Synthesis by Aromatase

Aromatase
Androstenedione

SULT
Estrone
Conjugates

Estrone
17-HSD

17-HSD
Testosterone

Estradiol
Conjugates

Estradiol

Aromatase

SULT

MA.27 Collaboration
NCIC-NCI
Cooperative
Groups

RIKEN
Center for Genomic
Medicine

PGRN
Translational Science
Statistical Genomics
Functional Genomics

MA.27 NCIC-NCI
Adjuvant AI Study

7576 patients enrolled

72% provided DNA

Musculoskeletal Adverse Events

major adverse event leading to
discontinuation of AI therapy
Case-Control GWAS all patients
with grade 3-4 MS-AE or went off
of therapy for MS-AE

293 Cases and 585 controls

MA.27 GWAS Manhattan Plot*

J. Clin. Oncol. 28(31):4674-82, 2010

hromosome 14 MA.27 Manhattan Plot Pea

J. Clin. Oncol. 28(31):4674-82, 2010

Chromosome 14 MA.27 GWAS SNP Signals

J. Clin. Oncol. 28(31):4674-82, 2010

Pharmacogenomic GWAS
Challenges
SNPs
Function
Genes
Drug
Effects

Clinical
Phenotypes

Pharmacogenomics
Human Variation Panel
300 Cell Lines

100 EA, 100 AA, 100 HCA

1.3 million SNPs/cell line
1.4 million exon probes/cell line
54,000 expression array

probes/cell line
Genome-wide CpG methylation
Liewei Wang,

ERE Sequence Motif

Human Genome 7,000 to 10,000 ERE motifs

Nature, 481:389-393,

Chr14 rs11849538 SNP ERE

Chromatin Immunoprecipitation (ChIP)
Assay
DNA (+)ER Ab ( - )ER Ab
Ladder
V WT
V WT
rs11849538
WT

ggggcctgagtggtcagggacagcttca

ggggcctgagtggtcagggagagcttca
=== ERE ===

J. Clin. Oncol. 28(31):4674-82, 2010

input
V

WT

TCL1A Expression Estrogen Response

Human Variation Panel Cells
TCL1A expression relative
to ER (%)

Chr 14 SNPs

0.00001 0.0001

0.001

0.01

0.1

Concentration of E2 (nM)
J. Clin. Oncol. 28(31):4674-82, 2010

10

NEJM August 27, 2009

MA.27
MS-AE GWAS
TCL1A expression is strongly correlated with cytokine
expression in Human Variation Panel
Gene Name

Spearman

Prob>||

interleukin 13 receptor, alpha 1

-0.4282

3.16E-14

interleukin 18 receptor 1

-0.4048

9.59E-13

interleukin 1 receptor, type II

-0.3835

1.73E-11

interleukin 17 receptor A

0.3645

1.92E-10

interleukin 13 receptor, alpha 1

-0.3587

3.85E-10

interleukin 12 receptor, beta 2

-0.3368

4.84E-09

interleukin 8

0.3462

1.67E-09

interleukin 7

0.304

1.50E-07

interleukin 13

-0.2922

4.69E-07

nuclear factor, interleukin 3 regulated

0.2881

6.84E-07

interleukin 7 receptor

-0.2613

7.30E-06

interleukin 6 receptor

-0.2313

7.68E-05

Interleukin 23 A

-0.2451

2.68E-05

Mohan
Liu1,

Pharmacogenomics
and
Precision Medicine

Introduction
Pharmacogenomic
Implementation
Pharmacogenomic
Discovery
Pharmacogenomic

BEAUTY
(Breast Cancer
Genome
Guided Therapy)
Genome Sequence
Guided Adaptive
Trial

BEAUTY
Breast Cancer
Genome
Guided Therapy
Study
PIs: Matthew Goetz, Judy Boughey
Lab PI: Liewei Wang
Lab team: Eric Wieben, Dick Weinshilboum, James Ingle
Bowen Gao, Jia Yu, Minetta Liu, Michael Barrett
Pathology team: Dan Visscher, Ann Moyer
Radiology team: Amy Conners, Katie Jones
Genetic counselor: Marissa Ellingson
Stats team: Jeanette Eckel Passow, Vera Suman, Travis Dockter,
Krishna Kalari, Steve Hart, Hugues Sicottes, Jason Sinnwell
Arizona team: Don Northfelt, Rick Gray, Michael Barrett
Florida team: Alvaro Moreno, Sarah McLaughlin

BEAUTY
(Phase I)
Neoadjuvant Therapy
A/C
(4 cycles)

Paclitaxel + Trastuzamab
HER2+
Women with
invasive breast
cancer
HER2-

Paclitaxel

A/C
(4 cycles)

Surgery

5 year
followadjuvant
therapy

Tumor biopsy

Tumor biopsy

Tumor
tissue
Mammogram

MRI

Mammogram

Breast and axilla US

Sestamibi MBI

Breast US

Breast MRI

Xenograft

Breast MRI

Sestamibi MBI

Sestamibi MBI

Xenograft

BEAUTY Tumor Biopsies

Baseline
Breast
Tumor
Biopsies

Tumor
DNA Exome
Sequence

Tumor
RNA-Seq

Germline
DNA Exome
Sequence

Germline
SNP Array

Xenografts
Determination of functional
implications of genetic
alterations:
Compare response in
patient to response in mice:
Determine response to novel
drugs

Tumor
Methylation
450K Ilumina

Mayo CIM BEAUTY

Breast Cancer Trial

Phase I

140 patients recruited

Xenograft take rate ~40%
Novel biomarkers identified

BEAUTY Patient
Rapid Relapse

DNMT3A

Actin
Before
After
Treatment Treatment

Tumor size in avatar

Body weight, g

Xenograft
Drug Testing
18
12

Vehicle
Decitabine

6
0

400

200

Study days

10

Pharmacogenomics
and
Precision Medicine

Introduction
Pharmacogenomic
Implementation
Pharmacogenomic
Discovery
Pharmacogenomic

Mayo Center for Individualized Medicine

Clin Pharmacol Ther. 94:204-6, 2013

Pharmacogenomic
s
Clinical Goals

Avoid adverse drug

reactions

Maximize drug efficacy

Select responsive

Pharmacogenomics
The Future
Ultimate Goal
The right drug, at the
right dose for every
patient.

Mayo Pharmacogenomics
Laboratories -- 2014