Preclinical Models for Developing Therapy for Pediatric Solid Tumors uses and limitations

1
Preclinical Models for Developing Therapy for
Pediatric Solid Tumors uses and limitations

• Peter J. Houghton, Ph.D.
• Solid Malignancies Program
• St. Jude Childrens Research Hospital

2
Problems in using Preclinical Data

• Early drug discovery is conducted under
  defined/standardized environment.
• Pediatric cancer models are not part of this
  process either in industry or NCI.
• Preclinical data using pediatric models are
  generated in an uncontrolled or regulated
  environment.
• Such data are derived from experimental systems
  that are not validated using experimental design
  and interpretation that lacks consistency or
  rigor.

3
(No Transcript)
4
Informative Non-Clinical Data

• Pharmacology and pharmacokinetics
• Safety
• Efficacy
• Behaviour
• Long term effects
• Developmental aspects
• Other? Pharmacodynamics

5
UsesWhere Do Animal Models Fit in Drug
Development for Childhood Cancer?
Drug acquired NCI/Industry/Academia

• Identification of active agents/analogs

• Optimization of administration schedules
• and drug combinations.

• Prioritization of agents for phase I

Phase I

• Rational decisions to advance/stop development

• Potential to focus phase II trials

Phase II

• Potential to relate target inhibition to
• biological response

6
Models Identify Clinically Active Agents
Prospectively
RHABDOMYOSARCOMA

COLON CARCINOMA
7
SENSITIVITY OF WILMS TUMOR XENOGRAFTS
8
Topotecan Lactone AUC Associated with Response
in Neuroblastoma Xenografts
290
150
125
100
75
AUC (ng-hr/mL)
50
25
0
NB1382.2
NB1643
NBEB
NB1771
NB1691
PR
CR
9
Targeted Topotecan Neuroblastoma Protocol NB97

• Results
• 28 evaluable patients
• TPT median dose 3.0 mg/m2
• 17 partial responses (60)
• 11 stable disease
• no tumor progressions

Dose Adjustment Schema (100 20
nghr/ml)
Day 1 2 3 4 5 6 7 8
9 10 11 12
TPT TPT TPT TPT TPT X X TPT
TPT TPT TPT TPT
PK Studies
Dose Adjust
113 Courses 92 Targeting Success
Santana et al.(submitted)
10
Retrospective Analysis of Response-Exposure
Relationships for Pediatric Tumors Xenografts
Drugs that failed
Drugs that worked
11
Evaluation of MGI-114(Phase II in COG?)
Systemic exposure is still gt 10-fold higher than
in children _at_MTD
12
Schedule-dependent antitumor activity of
topotecan
Control
TPT (daily x 5)every 21 daysTotal dose 22.5
mg/kg
TPT (daily x 5) x 2 every 21 daysTotal dose
22.5 mg/kg
10
Tumor volume (cm3)
1
0.1
0
2
4
6
8
10
12
4
6
8
0
2
12
10
0
2
4
6
8
10
12
Week
Week
Week
13
Discriminating Between Analogs Osteosarcoma
Models
14
The Challenge of Molecularly-Targeted Drugs

• Tumor models must accurately recapitulate
  activity of signal transduction
  pathways. -orthotopic or subcutaneous? -
  expression profiling - proteomics profiling

15
WT6 vs parent
XENOGRAFT
PRIMARY TUMOR
WT8 vs parent
XENOGRAFT
PRIMARY TUMOR
16
P. Hedge et al. ASCO 535A
GSK/Cytokinetics
17
Evaluation of SB713489


S
t
ud
y


T
um
or
15

mg
/k
g
10

mg
/k
g
5

mg
/k
g
CR
/P
R
Tox
_at_
15
d
ea
t
h
s
m
g
/
kg
1998
SK
NE
P

-
-
0
/
5
0
/
5
1999
SK
NE
P



-
-
2
/
5
1
/
5
2005
S
J-W
T
7









5
/
5
0
/
5
2009
S
J-W
T
7






CR

w
i
t
h

regrow
th





a
ll

tum
ors

hav
e

p
ar
ti
a
l
reg
r
es
si
on
(
PR

gt

50 vo
lum
e
r
e
d
u
c
t
i
o
n)







s
t
a
b
l
e di
sea
s
e






grow
th

d
e
l
ay

2

t
um
or

vol
um
e

do
ublin
g
ti
m
e
s








grow
t
h
d
e
l
ay

1
tu
mo
r
vo
lu
m
e d
o
ub
l
in
g

t
im
e






-

n
o grow
th

inhib
i
ti
o
n
18
Study 2026 SJ-WT10
19
Informative Non-Clinical Data

• Pharmacology and pharmacokinetics
• Safety
• Efficacy
• Behaviour
• Long term effects
• Developmental aspects
• Other? Pharmacodynamics

20
PHARMACOKINETICS
IGF-II
IRS-1
PI-3K
Akt
PTEN
PDK1/2
Low Amino Acid Pools
TSC1
TSC2
mLST8
AMP
Low Energy (High AMP)
AMPK
mTOR
Rapamycin (CCI-779) TARGET INHIBITION
GTP
GDP
Raptor
LKB1
GTP
p70S6K
?
Increased translation
TOP Dependent Translation
IGF-II
Targets of Cap Dependent Translation Cyclin
D1 ODC1 MYC HIF1a
BIOLOGICAL READOUT
21
Developing Initiatives for a National Consortium
to Identify and Prioritize New Agents

• RFA to systematically characterize models through
  genomic/proteomic screens to identify potential
  molecular targets (POPP-TAP).
• RFP to establish preclinical screening program
  that will identify agents having high priority
  for pediatric Phase I testing through the
  Childrens Oncology Group.

22
Effective use of Non-clinical Data

• Standardization of experimental procedures
  difficult, but a realistic goal.
• Standardization of acceptable criteria for
  assessing drug activity.
• GLP compliance very expensive, most academic
  centers would be excluded.

23
(No Transcript)