pharmacogenomics: the basics
TRANSCRIPT
-
8/9/2019 Pharmacogenomics: The Basics
1/53
-
8/9/2019 Pharmacogenomics: The Basics
2/53
Pharmacogenomics
andPrecision Medicine
• ntroduction• Pharmacogenomic
mplementation• PharmacogenomicDisco!ery
• Pharmacogenomic
-
8/9/2019 Pharmacogenomics: The Basics
3/53
Evolution of Particle Physics
Chad#ic$%s&pparatus to Disco!er
the Neutron
"he 'arge(adron Collider
-
8/9/2019 Pharmacogenomics: The Basics
4/53
• Large “omics” datasets• Expensive technologies , NextGen DN
se!uencing, meta"olomics, etc#• $e!uirement for overlapping
complementary expertise, especially
computational expertise• Need for constant cross%disciplinary
dialog
Evolution of
&iomedical 'cience
-
8/9/2019 Pharmacogenomics: The Basics
5/53
(he )uman Genome*e"ruary + -
-
8/9/2019 Pharmacogenomics: The Basics
6/53
Goal(o "ring genomic
scienceto the "edside#
Mayo .linic
.enter for /ndividuali0edMedicine
-
8/9/2019 Pharmacogenomics: The Basics
7/53
Mayo .enter for /ndividuali0ed Medicine
Clin Pharmacol Ther. 94:204-6, 2013
-
8/9/2019 Pharmacogenomics: The Basics
8/53
Pharmacogenomics
andPrecision Medicine
• ntroduction• Pharmacogenomic
mplementation• Pharmacogenomic
Disco!ery
• Pharmacogenomic
-
8/9/2019 Pharmacogenomics: The Basics
9/53
Pharmacogenomics
andPrecision Medicine
Pharmacogenomic
mplementati
on Pharmacogenomic
"ranslation
Pharmacogenomic
Disco!ery
-
8/9/2019 Pharmacogenomics: The Basics
10/53
Pharmacogenomics
andPrecision Medicine
)oundations*Pharmacogenomics
Research Net#or$ * +PGRNGrant +N GM-
*eM RG / Grant +N(GR
-
8/9/2019 Pharmacogenomics: The Basics
11/53
Pharmacogenomics• .ritical component of
“personali0ed” or “individuali0ed”medicine#
• (he study of the role of inheritancein individual variation in drugresponse phenotypes#
-
8/9/2019 Pharmacogenomics: The Basics
12/53
Pharmacogenomics
.linical Goals• void adverse drug reactions•
Maximi0e drug efficacy• 'elect responsive patients
-
8/9/2019 Pharmacogenomics: The Basics
13/53
"he "herapeuticRe!olution
Goodman and Gilman%s*"he Pharmacological 0asis of
-
8/9/2019 Pharmacogenomics: The Basics
14/53
Childhood &'' -ur!i!al-t. 1ude 2perience
Pui and Evans, NEJM 354:166-78, 2006
-
8/9/2019 Pharmacogenomics: The Basics
15/53
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
-
8/9/2019 Pharmacogenomics: The Basics
16/53
(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
-
8/9/2019 Pharmacogenomics: The Basics
17/53
(PM(
Genetic Polymorphism.linical .onse!uences
•Lo1 (PM( – /ncreased thiopurine toxicity
– /ncreased ris2 for secondary neoplasm
• )igh (PM( – Decreased therapeutic effect
-
8/9/2019 Pharmacogenomics: The Basics
18/53
lert at point of care in EM$$educe side effects/ncrease effectiveness$educe costs
EducationPrescri"ersPharmacistsPatients
"acavir .ar"ama0epine(hiopurines.odeine(ramadol(amoxifen
'tatins.lopidogrel3arfarin
Drug%Gene $ules
-
8/9/2019 Pharmacogenomics: The Basics
19/53
Drug%Gene EM$ /mplementation Process
Electronic Medical ecord!EM " #$%le$entation and
$aintenance
-top&lino$ics
oversi'(t 'rou%
Ma)o &linical *ecision+u%%ort +u co$$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
-
8/9/2019 Pharmacogenomics: The Basics
20/53
Pharmacogenomics
andPrecision Medicine
Mayo R G(" Pro?ectMayo40aylor Collaboration
@== Patient Pilot
-
8/9/2019 Pharmacogenomics: The Basics
21/53
Pharmacogenomics
andPrecision Medicine
• ntroduction• Pharmacogenomicmplementation
• PharmacogenomicDisco!ery
•Pharmacogenomic
-
8/9/2019 Pharmacogenomics: The Basics
22/53
.ancer Pharmacogenomics
(1o Genomes• Germline Genomes
• 'omatic 4(umor5 Genome
-
8/9/2019 Pharmacogenomics: The Basics
23/53
.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
-
8/9/2019 Pharmacogenomics: The Basics
24/53
&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 $x
-
8/9/2019 Pharmacogenomics: The Basics
25/53
0reast Cancerndocrine "herapy
R+E"herapeutic -trategies• 0loc$ estrogen synthesis –
aromatase inhibitors• 0loc$ R – tamo2ifen
-
8/9/2019 Pharmacogenomics: The Basics
26/53
strogen -ynthesis by &romatase
&ndrostenedione
&romatase
stronestrone
Con?ugates
-:'"
"estosterone stradiolstradiol
Con?ugates&romatase -:'"
-
8/9/2019 Pharmacogenomics: The Basics
27/53
M&.7F Collaboration
NC C4NC
Cooperati!eGroups
R > N
Center for GenomicMedicine
PGRN• "ranslational -cience• -tatistical Genomics• )unctional Genomics
-
8/9/2019 Pharmacogenomics: The Basics
28/53
M&.7F NC C4NC&d?u!ant & -tudy
• F@F3 patients enrolled – F7 pro!ided DN&
• Musculos$eletal &d!erse !ents –ma?or ad!erse e!ent leading todiscontinuation of & therapy
• Case4Control GW&- – all patients#ith grade 4 M-4& or #ent oHof therapy for M-4&
– 79 Cases and @8@ controls
-
8/9/2019 Pharmacogenomics: The Basics
29/53
M #+6 G3 ' Manhattan Plot7
J &lin ncol 28!31":4674-82, 2010
-
8/9/2019 Pharmacogenomics: The Basics
30/53
romosome < M&.7F Manhattan Plot Pe
J &lin ncol 28!31":4674-82, 2010
-
8/9/2019 Pharmacogenomics: The Basics
31/53
-
8/9/2019 Pharmacogenomics: The Basics
32/53
Pharmacogenomic GW&-
Challenges-NPs
)unction
Genes
DrugHects
ClinicalPhenotypes
-
8/9/2019 Pharmacogenomics: The Basics
33/53
*(uman Iariation Panel/== Cell 'ines
•
-
8/9/2019 Pharmacogenomics: The Basics
34/53
E$E 'e!uence Motif
Nature, 481:38 -3 3,
)uman Genome 8 6, to - , E$E motifs
-
8/9/2019 Pharmacogenomics: The Basics
35/53
Chr< rs
-
8/9/2019 Pharmacogenomics: The Basics
36/53
"C'
-
8/9/2019 Pharmacogenomics: The Basics
37/53
N 1M &ugust 7F, 7==9
M #+6
-
8/9/2019 Pharmacogenomics: The Basics
38/53
M #+6M'% E G3 '
(.L- expression is strongly correlated 1ith cyto2ineexpression in “)uman 9ariation Panel”
Gene Name 'pearman = Pro">?=?
in erle%&in 13 rece' or, al'ha 1 -0.4282 3.16"-14
in erle%&in 18 rece' or 1 -0.4048 9.59"-13
in erle%&in 1 rece' or, ('e )) -0.3835 1.*3"-11
in erle%&in 1* rece' or + 0.3645 1.92"-10in erle%&in 13 rece' or, al'ha 1 -0.358* 3.85"-10
in erle%&in 12 rece' or, e a 2 -0.3368 4.84"-09
in erle%&in 8 0.3462 1.6*"-09
in erle%&in * 0.304 1.50"-0*in erle%&in 13 -0.2922 4.69"-0*
n%clear ac or, in erle%&in 3 reg%la e 0.2881 6.84"-0*
in erle%&in * rece' or -0.2613 *.30"-06
in erle%&in 6 rece' or -0.2313 *.68"-05
)n erle%&in 23 + -0.2451 2.68"-05
-
8/9/2019 Pharmacogenomics: The Basics
39/53
-
8/9/2019 Pharmacogenomics: The Basics
40/53
Mohan'iu < ,
-
8/9/2019 Pharmacogenomics: The Basics
41/53
Pharmacogenomics
andPrecision Medicine
• ntroduction• Pharmacogenomic
mplementation• PharmacogenomicDisco!ery
• Pharmacogenomic
-
8/9/2019 Pharmacogenomics: The Basics
42/53
0 &:"; +0reast Cancer
GenomeGuided "herapyGenome -eAuence
Guided &dapti!e"rial
0 &:";
-
8/9/2019 Pharmacogenomics: The Basics
43/53
P sK Matthe# GoetL, 1udy 0oughey'ab P K 'ie#ei Wang
'ab teamK ric Wieben, Dic$ 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
-
8/9/2019 Pharmacogenomics: The Basics
44/53
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
-
8/9/2019 Pharmacogenomics: The Basics
45/53
(umor $N %'e!
(umor DN Exome
'e!uence
Germline'NP rray
(umor Methylation
B F /lumina
Germline
DN Exome'e!uence0aseline
0reast"umor
0iopsies @enograftsDetermination of functionalimplications of genetic
alterations .ompare response in
patient to response in miceDetermine response to novel
drugs
0 &:"; "umor 0iopsies
-
8/9/2019 Pharmacogenomics: The Basics
46/53
Mayo ./M &E C(H
&reast .ancer (rialPhase /
• -B patients recruited• @enograft “ta2e rate” IB <• Novel "iomar2ers identified
-
8/9/2019 Pharmacogenomics: The Basics
47/53
+c in
T3+
+ er Trea men
e oreTrea men
&E C(H Patient$apid $elapse
-
8/9/2019 Pharmacogenomics: The Basics
48/53
@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
-
8/9/2019 Pharmacogenomics: The Basics
49/53
Pharmacogenomics
andPrecision Medicine
• ntroduction• Pharmacogenomic
mplementation• Pharmacogenomic
Disco!ery
• Pharmacogenomic
-
8/9/2019 Pharmacogenomics: The Basics
50/53
Mayo .enter for /ndividuali0ed Medicine
Clin Pharmacol Ther. 94:204-6, 2013
-
8/9/2019 Pharmacogenomics: The Basics
51/53
Pharmacogenomics
Clinical Goals
• &!oid ad!erse drug
reactions
• Ma2imiLe drug e cacy
• -elect responsi!e
-
8/9/2019 Pharmacogenomics: The Basics
52/53
Pharmacogenomics"he )uture
:ltimate Goal
"he right drug, at theright dose for e!ery patient.
-
8/9/2019 Pharmacogenomics: The Basics
53/53
Mayo Pharmacogenomics
'aboratories 44 7=