Pharmacogenomics: The Basics

8/9/2019 Pharmacogenomics: The Basics

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Pharmacogenomics

andPrecision Medicine

• ntroduction• Pharmacogenomic

mplementation• PharmacogenomicDisco!ery

• Pharmacogenomic


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Evolution of Particle Physics

Chad#ic$%s&pparatus to Disco!er

the Neutron

"he 'arge(adron Collider


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• Large “omics” datasets• Expensive technologies , NextGen DN

se!uencing, meta"olomics, etc#• $e!uirement for overlapping

complementary expertise, especially

computational expertise• Need for constant cross%disciplinary

dialog

Evolution of

&iomedical 'cience


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(he )uman Genome*e"ruary + -


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Goal(o "ring genomic

scienceto the "edside#

Mayo .linic

.enter for /ndividuali0edMedicine


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Mayo .enter for /ndividuali0ed Medicine

Clin Pharmacol Ther. 94:204-6, 2013


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Pharmacogenomics



mplementation• Pharmacogenomic

Disco!ery

• Pharmacogenomic


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Pharmacogenomics


Pharmacogenomic

mplementati

on Pharmacogenomic

"ranslation

Pharmacogenomic

Disco!ery


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Pharmacogenomics


)oundations*Pharmacogenomics

Research Net#or$ * +PGRNGrant +N GM-

*eM RG / Grant +N(GR


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Pharmacogenomics• .ritical component of

“personali0ed” or “individuali0ed”medicine#

• (he study of the role of inheritancein individual variation in drugresponse phenotypes#


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Pharmacogenomics

.linical Goals• void adverse drug reactions•

Maximi0e drug efficacy• 'elect responsive patients


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"he "herapeuticRe!olution

Goodman and Gilman%s*"he Pharmacological 0asis of


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Childhood &'' -ur!i!al-t. 1ude 2perience

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


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Metabolism of 34Mercaptopurine

N

N

N

NH

SH

N

N

N

NH

SCH3

N

N

N

NH

SH

HO

OH

N

N

N

NH

SCH 3

OH

OH

5anthine 62idase+56

"hiopurineMethyltransferase

+"PM"

56 "PM"

7,84Dihydro2y434Methylmercaptopurine

&do(cy

&do(cy

&doMet

&doMet


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(uman R0C "PM"

10

5

00 5 10 15 20

TPMT Activity, Units/ml RBC

298 Unrelated Adults

TPMT H /TPMT H

TPMT L /TPMT H

TPMT L /TPMT L

% O

f S u b j e c t s P e r

0 . 5

U n i t s o f A c t i v i t y 798 :nrelated

&dults


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(PM(

Genetic Polymorphism.linical .onse!uences

•Lo1 (PM( – /ncreased thiopurine toxicity

– /ncreased ris2 for secondary neoplasm

• )igh (PM( – Decreased therapeutic effect


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lert at point of care in EM$$educe side effects/ncrease effectiveness$educe costs

EducationPrescri"ersPharmacistsPatients

"acavir .ar"ama0epine(hiopurines.odeine(ramadol(amoxifen

'tatins.lopidogrel3arfarin

Drug%Gene $ules


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Drug%Gene EM$ /mplementation Process

Electronic Medical ecord!EM " #$%le$entation and

$aintenance

-top&lino$ics

oversi'(t 'rou%

Ma)o &linical *ecision+u%%ort +u co$$ittee

%%roval

P(ar$aco'eno$ic

s .as/ orce

13 e istin'disease-oriented

.as/ orces

Ma)o &linic P(ar$ac)and or$ular)&o$$ittee

ocal P . and ot(erlocal 'rou%s

%%rovedru'-'eno$e

rule

;es

No


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Pharmacogenomics


Mayo R G(" Pro?ectMayo40aylor Collaboration

@== Patient Pilot


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Pharmacogenomics


• ntroduction• Pharmacogenomicmplementation

• PharmacogenomicDisco!ery

•Pharmacogenomic


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.ancer Pharmacogenomics

(1o Genomes• Germline Genomes

• 'omatic 4(umor5 Genome


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.ancer Pharmacogenomics

0reast Cancer

• Number one in!asi!e cancerof #omen #orld#ide

• B7 ,=== ne# cases in the:- in 7=<• B =,=== deaths in the :- in


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&reast .ancer

Molecular .lassificationand (herapy

$eceptor Positive

Endocrine $x4'E$Ms and /s5

(argeted $x

)E$+ Positive

(rastu0ama"4)erceptin5

(argeted $x

(N&.

.hemotherapy4taxanes%

anthracyclines5

(argeted $x


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0reast Cancerndocrine "herapy

R+E"herapeutic -trategies• 0loc$ estrogen synthesis –

aromatase inhibitors• 0loc$ R – tamo2ifen


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strogen -ynthesis by &romatase

&ndrostenedione

&romatase

stronestrone

Con?ugates

-:'"

"estosterone stradiolstradiol

Con?ugates&romatase -:'"


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M&.7F Collaboration

NC C4NC

Cooperati!eGroups

R > N

Center for GenomicMedicine

PGRN• "ranslational -cience• -tatistical Genomics• )unctional Genomics


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M&.7F NC C4NC&d?u!ant & -tudy

• F@F3 patients enrolled – F7 pro!ided DN&

• Musculos$eletal &d!erse !ents –ma?or ad!erse e!ent leading todiscontinuation of & therapy

• Case4Control GW&- – all patients#ith grade 4 M-4& or #ent oHof therapy for M-4&

– 79 Cases and @8@ controls


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M #+6 G3 ' Manhattan Plot7

J &lin ncol 28!31":4674-82, 2010


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romosome < M&.7F Manhattan Plot Pe

J &lin ncol 28!31":4674-82, 2010


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Pharmacogenomic GW&-

Challenges-NPs

)unction

Genes

DrugHects

ClinicalPhenotypes


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*(uman Iariation Panel/== Cell 'ines

•


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E$E 'e!uence Motif

Nature, 481:38 -3 3,

)uman Genome 8 6, to - , E$E motifs


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Chr< rs


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"C'


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N 1M &ugust 7F, 7==9

M #+6


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M #+6M'% E G3 '

(.L- expression is strongly correlated 1ith cyto2ineexpression in “)uman 9ariation Panel”

Gene Name 'pearman = Pro">?=?

in erle%&in 13 rece' or, al'ha 1 -0.4282 3.16"-14

in erle%&in 18 rece' or 1 -0.4048 9.59"-13

in erle%&in 1 rece' or, ('e )) -0.3835 1.*3"-11

in erle%&in 1* rece' or + 0.3645 1.92"-10in erle%&in 13 rece' or, al'ha 1 -0.358* 3.85"-10

in erle%&in 12 rece' or, e a 2 -0.3368 4.84"-09

in erle%&in 8 0.3462 1.6*"-09

in erle%&in * 0.304 1.50"-0*in erle%&in 13 -0.2922 4.69"-0*

n%clear ac or, in erle%&in 3 reg%la e 0.2881 6.84"-0*

in erle%&in * rece' or -0.2613 *.30"-06

in erle%&in 6 rece' or -0.2313 *.68"-05

)n erle%&in 23 + -0.2451 2.68"-05


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Mohan'iu < ,


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Pharmacogenomics



mplementation• PharmacogenomicDisco!ery

• Pharmacogenomic


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0 &:"; +0reast Cancer

GenomeGuided "herapyGenome -eAuence

Guided &dapti!e"rial

0 &:";


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P sK Matthe# GoetL, 1udy 0oughey'ab P K 'ie#ei Wang

'ab teamK ric Wieben, Dic$ Weinshilboum, 1ames ngle0o#en Gao, 1ia ;u, Minetta 'iu, Michael 0arrett

Pathology teamK Dan Iisscher, &nn Moyer

Radiology teamK &my Conners, >atie 1onesGenetic counselorK Marissa llingson-tats teamK 1eanette c$el Passo#, Iera -uman, "ra!is Doc$ter,

>rishna >alari, -te!e (art, (ugues -icottes, 1ason -inn#ell&riLona teamK Don Northfelt, Ric$ Gray, Michael 0arrett

)lorida teamK &l!aro Moreno, -arah Mc'aughlin

0 &: ; 0reast Cancer

GenomeGuided "herapy-tudy


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3omen 1ithinvasive "reastcancer

(umor "iopsy

M$/'estami"i M&/

@enograft

)E$+ /

)E$+%

Paclitaxel : (rastu0ama"

Paclitaxel

A.4B cycles5

A.4B cycles5

(umor "iopsy

Mammogram&reast C'

&reast M$/

'estami"i M&/

'urgery

Mammogram

&reast and axilla C'&reast M$/

'estami"i M&/

@enograft

(umortissue

yearfollo1%

ad uvanttherapy

0 &:"; +Phase

Neoad?u!ant "herapy


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(umor $N %'e!

(umor DN Exome

'e!uence

Germline'NP rray

(umor Methylation

B F /lumina

Germline

DN Exome'e!uence0aseline

0reast"umor

0iopsies @enograftsDetermination of functionalimplications of genetic

alterations .ompare response in

patient to response in miceDetermine response to novel

drugs

0 &:"; "umor 0iopsies


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Mayo ./M &E C(H

&reast .ancer (rialPhase /

• -B patients recruited• @enograft “ta2e rate” IB <• Novel "iomar2ers identified


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+c in

T3+

+ er Trea men

e oreTrea men

&E C(H Patient$apid $elapse


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@enograftDrug (esting

18

12

6

0

400

200

2 4 6 8 10

3 o

. ( 4 e

i g h , g

T % m o r s i 5 e

i n a 6 a

a r

7 % ( a(s

9e(icle

*ecita ine


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Pharmacogenomics



mplementation• Pharmacogenomic

Disco!ery

• Pharmacogenomic


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Mayo .enter for /ndividuali0ed Medicine

Clin Pharmacol Ther. 94:204-6, 2013


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Pharmacogenomics

Clinical Goals

• &!oid ad!erse drug

reactions

• Ma2imiLe drug e cacy

• -elect responsi!e


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Pharmacogenomics"he )uture

:ltimate Goal

"he right drug, at theright dose for e!ery patient.


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Mayo Pharmacogenomics

'aboratories 44 7=

Pharmacogenomics: The Basics

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