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Heinrich & Corless Laboratories
GIST Research Updates: May 2011
Genotyping for Clinical Trials
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Regorafenib (Bayer) – phase II trial
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Tyrosine kinase inhibitor
3rd/4th line therapy for resistant GISTs
Initial results will be reported at ASCO
FDA has put the drug on fast-track for review
Phase III trial is getting underway
Synta
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HSP90 inhibitor (intravenous)
Phase II trial ongoing
Genotyping for Clinical Trials
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PERSIST trial
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ImClone
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Ron DeMatteo’s trial of 5 years of adjuvant
imatinib
More than 50% enrolled
Antibody against PDGFRA
Phase II trial for KIT-mutant or PDGFRA-mutant
tumors resistant to imatinib & sunitinib
Phase I/II trial for a new drug that Mike will
talk about
‘Next Generation’ DNA Sequencing
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Traditional DNA sequencing is limited to
just one part of one gene at a time
Second-generation DNA sequencers are
now available and have begun to
revolutionize cancer research by
generating information on thousands of
genes simultaneously
Starting last summer, we have been using
this new technology to study GISTs
Sequencing Data
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Human genome consists of 3.2
billion letters (A, C, T, G)
Genes comprise only ~2% of our
DNA (about 64 million letters)
We ‘pre-select’ the genes, so that
only the 64 million letters of
interest get sequenced
Cost: $3,000 per sample
Sequencing Data
First experiment: 8/2010
• Illumina GAIIX
~1,000,000,000 letters per
experiment
• Most recent experiment: 4/2011
• Illumina HiSeq
~10,000,000,000 letters per
experiment
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Sequencing GIST Tumors
Source
Status
Genotypes
Source
OHSU
Completed
3 tumors; 1 KIT & 2 PDGFRA D842V
Primary
Debiec-
Completed
6 tumors; KIT exon 9 or 11; some with
Primary &
resistance mutations
Metastatic
Rychter
Fletcher
Bauer
Data analysis in 5 tumors; KIT exon 9 with varying
Metastatic
progress
resistance mutations
Pending
9 tumors; KIT exon 9 or 11; some with
Primary &
resistance mutations
Metastatic
Confirmed Mutations
Sequence
Patient
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2
3
Gene
AA Change
# exons
Exon affected
Chr
confirmed?
PDGFRA
D842V
23
18
4q11-q13
yes
HNRNPA2B1
S36G
12
3
7p15
yes
PDGFRA
D842V
23
18
4q11-q13
yes
TP53
C135G
11
5
17p13.1
yes
MDN1
E661K
102
14
6q15
yes
KEL
T421M
19
11
7q33
yes
TACR3
S435N
5
5
4q25
yes
CTNND2
N1211S
21
21
5p15.2
yes
INSR
S995A
22
16
19p13.3-p13.2
yes
KIT
V559D
21
11
4q11-q12
yes
LAS1L
Q634L
14
12
Xq12-q13
yes
ODZ1
R1519C
31
24
Xq25
yes
TP53
L348S
11
10
17p13.1
yes
COL1A2
G430E
52
23
7q22.1
yes
TP53
G245C
11
7
17p13.1
yes
Sequence
Patient
Gene
BAZ2B
AA Change
# exons
Exon affected
Chr
confirmed?
S554F
37
9
2q23-q24
pending
Gene function
bromodomain adjacent to zinc finger
domain
Possible relationship with lung
FAM134A
V296M
9
8
2q35
pending
ca metastasis?
osteoblast-secreted decoy receptor that
functions as a negative regulator of bone
resorption. This protein specifically binds to
4
TNFRSF11B
I312T
5
5
8q24
pending
its ligand, osteoprotegerin ligand
SERINC2
T245N
10
6
1p35.1
pending
Nothing known
SHBG
A210V
8
5
17p13-p12
pending
Steroid binding globulin
C10orf82
L149M
4
5
10q25.3
pending
Nothing known
IFNGR1
N433Y
7
7
6q23-q24
pending
interferon gamma receptor 1
PCDHB16
P390H
1
1
5q31
pending
Ca++ Cell adhesion
KIT
D816G
21
17
4q11-q12
yes
Growth regulation; sphingolipid
7(A)
LASS2
L45M
11
2
1q21.2
pending
synthesis
FAM176A
V12M
4
3
2p12
pending
Apoptosis/autophagy
AAAS
A167T
16
6
12q13
pending
COL1A2
A683D
52
34
7q22.1
pending
KIT
Y823D
21
17
4q11-q12
yes
Growth regulation; sphingolipid
7(B)
8
10(A)
LASS2
L45M
11
2
12q13
pending
synthesis
FAM176A
V12M
4
3
2p12
pending
Apoptosis/autophagy
GIPC2
L206P
6
4
1p31.1
pending
PDZ-containing protein
PRAMEF2
E83K
4
2
1p36.21
pending
Nothing known
Knight Diagnostic Laboratories
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The Corless laboratory has recently been
integrated into the new Knight Diagnostic
Laboratories
These Labs are now operating independent
from OHSU Hospital
Mandate from Dr. Druker:
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Offer the most advanced genotyping in the
country
Expand outreach to serve as many cancer patients
as possible