Download Full Dose Response/PK

The Role of Preclinical Models to
Identify Novel Therapeutics in
Rare Cancers
Peter J. Houghton, Ph.D.
St. Jude Children’s Research Hospital
How To Select New Agents for Clinical
Trials?
Rationale for the Pediatric Preclinical Testing Program (PPTP)
Drug Development
NCI/Industry/Academia
Phase I
Phase II
400 new drugs in development
• Prioritization of agents for phase I
• Establish relevant models that
encompass clinical heterogeneity
• Rational decisions to advance/stop
development
• Potential to focus phase II trials
• Potential to identify sensitive tumors
Overview of the PPTP Screen
Testing
@ MTD
Drug X
Panel A
Panel B
Panel C
Panel D
Panel E
Stage 1 Report
6 neuroblastomas
Active in Model(s)?
Yes
Full Dose
Response/PK
No
Other Tumor
Models Available?
Yes
Yes
No
Final Report
Houghton et al. Clin Cancer Res. (2002)
Orthotopic
Models
Transgenic
Models
Why Do Preclinical Cancer
Models Fail?
• Tumor models do not recapitulate human cancer at
the molecular level
• Preclinical tumor models do not encompass clinical heterogeneity
• Species Tolerance: Host tolerance leads to high systemic exposure to
drug -overprediction. Low tolerance leads to low systemic exposure, and
underprediction of drug activity.
• Criteria for defining ‘activity’ is more stringent in clinical trials
• Clinical trials design ignores preclinical data
•Tumor models do not recapitulate human cancer at the molecular level
Molecular Characterization of
Xenograft Tumor Models
• Pediatric Preclinical Testing Program (PPTP)
-Affymetrix (U133A)
-SNP analysis (100K)
-CGH
• Pediatric Oncology Preclinical Protein-Tissue
Array Project (POPP-TAP)
-cDNA arrays
-Tissue/Protein arrays
How well do xenograft tumors represent the respective
clinical disease?
Tumors Cluster Along Diagnostic Type
by Unsupervised Clustering
cDNA Array: all 38,789 Good Quality Genes
RH1 ? EWS
RH6
JHAN
AS
KCNR
SC/Orthotopic
Javed Khan -POPP-TAP (subnitted)
Identify Xenografts That Recapitulate the
Tumors of Origin.
MDS 38,789 genes of primary/xeno/cell line: EWS/NB/RMS
ANN trained on tumors predict xenografts
PPTP Lines
-Rh41
-Rh10
-Rh28
-Rh30
-Rh36
-Rh18
PPTP Lines
-SK-N-AS
-NB-1643
-NB-1691
-NB-1771
-NB-EB
-NB-SD
-NB-1382
• Preclinical tumor models do not encompass clinical heterogeneity
Panels of Xenograft Tumors
Accurately Reflect Clinical
Responsiveness
Tumor
Line
Histology
Rh10
Rh12
Rh18
Rh28
Rh30
Rh35
Rh36
Rh39
IRS56
IRS68
Rh65
Rh66
ARMS ERMS ERMS ARMS ARMS ERMS ERMS ARMS ERMS ERMS ARMS ARMS
Vincristine
Cytoxan
Dactinomyc in
Topotecan
MCR
CR
PR
Vincristine 44%
Cyclophosphamide 50%
Actinomycin D 25%
SD
PD
NO
DATA
Topotecan 50% clinical responses
Comparison of Expression Profiles in Kidney
Tumors and Their Derived Xenografts Models
Clustering using 543 best classifiers >1Present (Affymetrix U133A)
CCSK
Fetal kidney
HPLNR
Wilms
Xenograft
Wilm’s Tumor Xenografts Cluster with
Their Clinical Samples
CCSK
Fetal kidney
HPLNR
Wilms
Xenograft
• Criteria for defining ‘activity’ is more stringent in clinical trials
Link Expression Profiles to
Chemosensitivity of Kidney
Chemosensitivity to Identify
TumorofXenografts
Biomarkers
Response
Tumor Line
Tumor Line
Histology
Vincristine
Cytoxan
Dactinomyc in
Topotecan
Temozo lomid e
CPT-11
MG1-114
BCNU
VP-16
CDDP
Doxorubi cin
Taxol
Expt 1
BMS247550
Expt
2
Expt 3
Expt 4
Expt 5
Expt 6
Expt 7
Expt 8
Expt 9
RESPONSE
KEY
WT-1
FH
WT-5
NU
WT-6
FH*
WT-7
FH
WT-8
FH
WT-9
FH
WT-1
RESPONSE
KEY
MCR
CR
WT-5
FH
NU
Histology
Vincristine
Cytoxan
Dactinomyc
WT-10 in WT-11
Topotecan
FH lomid e FH*
Temozo
CPT-11
MG1-114
BCNU
VP-16
CDDP
Doxorubi cin
Taxol
Expt 1
Expt 2
Expt 3
Expt 4
Expt 5
Expt 6
Expt 7
Expt 8
Expt 9
MCR
PR
WT-6
FH*
WT-7
FH
WT-12
Rhabdoid
WT-8
FH
WT-13
DA
WT-9
FH
WT-10
FH
WT-11
FH*
WT-14
Rhabdoid
CR
WT-12
Rhabdoid
WT-16
Rhabdoid
WT-13
DA
WT-16
Rhabdoid
SKNEP
DA
SKNEP
DA
PR
SD
WT-14
Rhabdoid
SD
PD
PD
Non-GBM Brain Tumors
BT-29
BT-34
BT-45
BT-28
BT31
BT-32
BT-36
BT-41
ATRT
ATRT
MED
MED
ANAPL
MED
MED
EPEND
EPEND
Tumor Line
Histology
Vincristine
Topotecan
Temozo lomid e
CPT-11
MG1-114
BCNU
VP-16
CDDP
Cytoxan
Doxorubi cin
PS-341
BMS247550
AR(111)
R-115777
Depsipeptid e
17AAG
RESPONSE
KEY
Linking Chemosensitivty
To Expression Profiling
Tumor Line
Histology
Vincristine
Cytoxan
Dactinomyc in
Topotecan
Temozo lomid e
CPT-11
MG1-114
BCNU
VP-16
CDDP
Doxorubi cin
Taxol
Expt 1
Expt 2
Expt 3
Expt 4
Expt 5
Expt 6
Expt 7
Expt 8
Expt 9
WT-1
FH
RESPONSE
KEY
MC
R
CR
PR
SD
NB-1382
NB-1643
NB-1691
NB-1771
NB-EB
WT-6
FH*
MCR
WT-7
FH
WT-8
FH
WT-9
FH
CR
WT-10
FH
WT-11
FH*
PR
WT-12
Rhabdoid
WT-13
DA
WT-14
Rhabdoid
WT-16
Rhabdoid
SD
mor Line
stology
PD
Rh10 Rh12 Rh18 Rh28 Rh30 Rh35 Rh36 Rh39 IRS56 IRS68 Rh65 Rh66
ARMS ERMS ERMS ARMS ARMS
ERMS
ERMS ERMS ARMS ARMS
ncristine
toxan
ctinomyc in
potecan
mozo lomid e
PT-11
PAM
G1-114
CNU
P-16
DDP
xorubi cin
-341
MS247550
R(111)
115777
psipeptid e
AAG
-713489
HA
xol
BT-751
AD001
D1839
6668
Osteosarcoma
Glioblastoma
BCNU
VP-16
CDDP
TOPOTECAN
CPT-11
TEMOZOLOMIDE
VINCRISTINE
MGI-114
PS341
DOXORUBICIN
CARBOPLATIN
DEPSIPEPTIDE
BMS247550
RII5777
SU6668
SKNEP
DA
Rhabdomyosarcoma
NB-SD
Vincristine
Topotecan
Temozo lomid e
CPT-11
MG1-114
BCNU
VP-16
CDDP
Cytoxan
Doxorubi cin
PS-341
BMS247550
AR(111)
R-115777
Depsipeptid e
17AA G
Taxo l
ABT-751
ZD1839
Drug
WT-5
NU
NO
DATA
PD
Neuroblastoma
Tumo r Line
Kidney Tumors
umor Line OS-1 OS-2 OS-17 OS-21 OS-29 OS-31 OS-32 OS-33
Respons e
SJ-BT39
SJ-GBM2
Identifying Biomarkers
For Predicting DrugResponsive Populations
ncristine
toxan
ctinomyc in
potecan
mozo lomid e
PT-11
G1-114
CNU
P-16
DDP
ARBO
POPLAT
XAL IPLAT
xorubi cin
-341
MS247550
R(111)
115777
psipeptid e
AAG
-713489
HA
xol
BT-751
AD 001
CI-779
RF1042
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
4-11-05
BT-39
SJ-GBM2
D-456
BT-56
D-212
BT-41
BT-36
OS-17
OS-2
OS-21
OS-1
NB-1643
Clustering method: UPGMA (unweighted average)
NB-132 Similarity measure: Euclidean distance
Ordering function: Average value
BT-45
OS-164
OS-166
OS-187
ALL-19
SKNEP
---------------------------------Total no of records: Columns included: log2(dap086u133v2_Signal), Z-scores (1), log2(dap110-u133v2_Signal),
scores (1), log2(dap113-u133v2_2_Signal), Z-scores (1),
log2(dap111-u133v2_Signal), Z-scores (1), log2(dap121u133v2_Signal), Z-scores (1), log2(dap073-u133v2_Signal),
scores (1), log2(dap078-u133v2_Signal), Z-scores (1),
EW-8
log2(dap077-u133v2_Signal), Z-scores (1), log2(dap074u133v2_Signal), Z-scores (1), log2(dap075-u133v2_Signal),
EW-5
WT-12 scores (1), log2(dap071-u133v2_Signal), Z-scores (1),
log2(dap070-u133v2_Signal), Z-scores (1), log2(dap069WT-14 u133v2_Signal), Z-scores (1), log2(dap084-u133v2_Signal),
WT-13 scores (1), log2(dap079-u133v2_Signal), Z-scores (1),
WT-11 log2(dap085-u133v2_Signal), Z-scores (1), log2(dap083WT-10 u133v2_Signal), Z-scores (1), log2(dap081-u133v2_Signal),
scores (1), log2(dap076-u133v2_Signal), Z-scores (1),
Rh36
log2(dap082-u133v2_Signal), Z-scores (1), log2(dap068Rh10
u133v2_Signal), Z-scores (1), log2(dap072-u133v2_Signal),
scores (1), log2(dap080-u133v2_Signal), Z-scores (1),
Rh65
log2(dap092-u133v2_Signal), Z-scores (1), log2(dap093Rh41
u133v2_Signal), Z-scores (1), log2(dap103-u133v2_Signal),
Rh28
scores (1), log2(dap101-u133v2_Signal), Z-scores (1),
EW-1
log2(dap102-u133v2_Signal), Z-scores (1), log2(dap106u133v2_Signal), Z-scores (1), log2(dap100-u133v2_Signal),
Rh30
scores (1), log2(dap099-u133v2_Signal), Z-scores (1),
BT-29
log2(dap104-u133v2_Signal), Z-scores (1), log2(dap105WT-16 u133v2_Signal), Z-scores (1), log2(dap089-u133v2_Signal),
Rh18
scores (1), log2(dap095-u133v2_Signal), Z-scores (1),
log2(dap094-u133v2_Signal), Z-scores (1), log2(dap096BT-46
BT-50
u133v2_Signal), Z-scores (1), log2(dap097-u133v2_Signal),
CHL-79 scores (1), log2(dap098-u133v2_Signal), Z-scores (1),
NB-1691 log2(dap091-u133v2_Signal), Z-scores (1), log2(dap090u133v2_Signal), Z-scores (1), log2(dap109-u133v2_Signal),
NB-EBc1 scores (1), log2(dap108-u133v2_Signal), Z-scores (1),
SK-N-AS log2(dap112-u133v2_Signal), Z-scores (1), log2(dap107NB-1771 u133v2_Signal), Z-scores (1)
NB-SD Empty values replaced by: 0
BT-28
Z-
Z-
Z-
Z-
Z-
Z-
Z-
Z-
Z-
Z-
Z-
Hierarchical Clustering Trusted samples based on LogSignal CV 0.5
Max-Min>=100 at least 3 Present (1113 probesets)
Group 1 versus Group 2 Osteosarcomas
( Probesets >4-fold Ttest FDR<0.01)
keratin 18
keratin 19
cadherin 1, type 1, E-cad
fibronectin 1 /// fibronec
carboxypeptidase E
Integrin-binding sialopro
OS#1
OS#2
0501
Vincristine
Not Determined
0502
0503
0504
0505
0506
0507
0508
Progressive Disease
0
Stable Disease
1
Partial Response
2
Complete Response
3
Maintained Complete Response
4
ALL-10
ALL-11
ALL-19
ALL-16
ALL-17
Osteosarcoma
ALL-8
ALL-4
ALL-7
ALL-3
OS160
ALL-2
OS-21
OS187
OS164
OS166
OS-17
Neuroblastoma
OS-1
OS-2
SK-N-AS
NB-1643
NB-1382
CHLA-79
NB-1691
NB-EBc1
Glioblastoma
NB-1771
NB-SD
SJ-BT56
D212
D456
Non-GBM Brain Tumor
SJ-BT39
D645
SJ-GBM2
BT-46
BT-50
BT-41
BT-45
BT-36
BT-32
Sarcoma
BT-28
BT-31
Rh65
Rh36
Rh30
Rh41
Rh28
Kidney/Rhabdoid
Rh10
Rh18
EW8(Rh1)
EW1
EW5
WT-12
WT-14
WT-10
SKNEP
WT-13
WT-16
WT-11
BT-29
Chemosensitivity of Tumors in the PPTP Panel
ALL
The PPTP
•
•
•
•
•
•
•
•
•
Richard Gorlick (osteosarcoma)
John Maris (neuroblastoma)
Henry Friedman (glioblastoma)
Richard Lock (ALL)
Pat Reynolds (in vitro testing)
Malcolm Smith (CTEP)
Javed Khan (NCI)
Geoff Neale (St. Jude)
Chris Morton (St. Jude; coordinator)
Thanks
Overview of the PPTP Screen
Testing
@ MTD
Drug X
Panel A
Panel B
Panel C
Panel D
Panel E
Stage 1 Report
Active in Model(s)?
Yes
Full Dose
Response/PK
No
Other Tumor
Models Available?
Yes
Yes
No
Final Report
Houghton et al. Clin Cancer Res. (2002)
Orthotopic
Models
Transgenic
Models
Model Systems for Drug Selection
Drug Development
NCI/Industry/Academia
Phase I
Phase II
•Relevant models (panels).
-molecular identity
-encompass clinical heterogeneity
•Rational decisions to advance/stop
development based on PK parameters
•Potential to focus phase II trials
•Potential to identify biomarkers for
patient selection
Tumor Panel: 9-10-05
Brain Tu mor Panel (glioblastoma)
SJ-GBM2
SJ-BT39
D645
D456
SJ-BT56 (extended panel)
D212 (extended panel)
Duke University School of Medicine
Glio blastoma
Glio blastoma
Glio blastoma
Glio blastoma
Glio blastoma
Glio blastoma
Brain Tu mor Panel
(non-glioblastoma)
BT-28
BT-31
BT-32
BT-45
BT-36
BT-41
BT-46 (extended panel)
BT-50 (extended panel)
St. Jude Children’s Research Hospital
Sarcoma Panel
EW1
EW5
EW8
RH10
RH1 8*
RH28
RH3 0*
RH4 1*
RH3 6 (extended panel)
RH6 5 (extended panel)
St. Jude Children’s Research Hospital
Ewing sarcoma (relapse)
Ewing sarcoma (diagnosis)
Ewing sarcoma
Rhabdo myosarcoma , alveolar (relapse)
Rhabdo myosarcoma , embryonal (diagnosis)
Rhabdo myosarcoma , alveolar (diagnosis)
Rhabdo myosarcoma , alveolar (diagnosis)
Rha bdomyosarcoma , alveolar (relapse)
Rhabdo myosarcoma , embryonal (relapse)
Rhabdo myosarcoma , alveolar (relapse)
Osteosarcoma panel
OS-1
OS-2
OS-17
OS-164
OS-166
OS-187
OS-21 (extended panel)
OS-160 (extended panel)
Albert Einstein College of Medicine
Osteosarcoma (primary/untreated)
Osteosarcoma (primary/untreated)
Osteosarcoma (primary/untreated)
Osteosarcoma (primary/previously treated)
Osteosarcoma (osteoblastic primary/relapse)
Osteosarcoma (primary/untreated)
Osteosarcoma (primary/untreated)
Osteosarcoma (lung metastasis/relapse)
Medulloblastoma (diagnosis)
Anaplastic medulloblastoma (diagnosis)
Medulloblastoma (diagnosis)
Medulloblastoma (diagnosis)
Anaplastic Ependymoma (diagnosis)
Ependymom a (relapse)
Medulloblastoma (diagnosis)
Medulloblastoma (diagnosis)
Tumor Panel: 9-10-05 (cont.)
Acute Lymphoblastic Leuke mia
panel
ALL-2
ALL-3
ALL-4
ALL-7
ALL-8
ALL-16
ALL-17
ALL-19
ALL-10 (extended panel)
ALL-11 (extended panel)
Children’s Cancer Institute of A ustralia
Neuroblastoma panel
NB-SD
NB-1771
NB-1691
NB-EBc1*
CHLA -79
NB-1643*
NB-1382 (extended panel)
SK-N-AS (extended panel)
Children’s Hospital of Philadelphia
MYCN amplified (pre viously treated)
MYCN amplified (diagnosis)
MYCN amplified (relapse)
Not MYCN amp lified (relapse)
Not MYCN amp lified (relapse)
MYCN amplified (diagnosis)
MYCN amplified (relapse)
Not MYCN amp lified (diagnosis)
Kid ney/rhabdoid tumor panel
BT-29
WT-14
WT-11
WT-13
WT-16
SKNEP
WT-10 (extended panel)
WT-12 (extended panel)
St. Jude Children’s Research Hospital
Atypical teratoid rhabdoid (CNS) (diagnosis)
Rhabdoid , kidney (relapse)
Wilms favorable histology (diagnosis)
Wilms diffuse anaplastic (diagnosis)
Rhabdoid , kidney (relapse)
Wilms diffuse anaplastic (relapse)
Wilms favorable histology (diagnosis)
Rhabdoid , kidney (diagnosis)
c-ALL /Relapse 3 (CR1 = 30 mos)
Pre-B ALL /Diagnois (CR1 = 38 mos)
Ph+ ALL /Dia gnosis (CR1 = 10 mos)
Bip henotypic /Diag nosis (CR1 = 7 mos)
T-ALL /Relapse 1 (CR1 = 17 mos)
T-ALL /Diagnosis (CR1 = 103+ mos)
c-ALL /Diagnosis (CR1 = 25 mos)
c-ALL /Relapse 1 (CR1 = 4 mos)
c-ALL /Diagnosis (CR1 = 57+ m os)
c-ALL /Diagnosis (CR1 = 120+ mos)
Volcano: Group OS1 vs Group OS2