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Session 4: Developing New
Therapeutics Sharpless, Roberts (Duncan presentation unavailable)
May 25, 2011
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Overview Ned Sharpless
May 25, 2011
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Therapeutics Theme Team
Target Identification and Validation
• Structural Biology • RNAi Screening • Proteomics
Drug delivery innovation • Nanoparticles • Theranostics • Novel delivery systems
NOVEL THERAPIES
Small molecules • High Throughput Screening
• Computational Approaches
• Medicinal Chemistry
Novel drug discovery
Preclinical Cancer Models • Predict efficacy • Test UNC compounds • Analyze PK/PD
Human clinical trials
MP1U
CCNE Pharm/ TOND2I / IPIT
CICBDD
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Patrick Roberts, PharmD, PhD
5/25/2011
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Credential the GEM model Primary Endpoints: 21 day response and survival “Success” requires tumor regression and
prolonged survival Routine PK and/or PD Use large cohorts (n>15) Test old drugs Get best new drugs any way you can.
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Genetics faithful to the human disease (Ras activation and Ink4a/Arf loss)
Simple genetics assures large colonies of tumor-bearing mice with minimal genotyping.
Although B-Raf mutations are more common, we
choose Ras mutant model given the importance of this target in a wide spectrum of cancers, as well as the difficulty of drugging Ras as opposed to kinases like Raf.
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No
Treat
men
t (17
)
7.5
Gy (1
5)
Car
boplat
in (1
7)
Pac
litax
el (2
4)
Car
boplat
in/P
aclitax
el (2
1)
ABT-8
88 (1
7)
Temoz
olom
ide
(10)
Temoz
olom
ide/
ABT-8
88 (1
5)
Erlo
tinib (1
6)
Lapa
tinib (1
2)
Sun
itinib
(23)
FTS (1
1)
AZD
6244
(6)
BEZ23
5 (1
1)
0
500
1000
-100
Day 2
1 P
erc
ent
Change
in T
um
or
Volu
me (
%)
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Drug Mean day 0 tumor volume (mm3)
Mean day 21 tumor volume (mm3)
Response Rate by RECIST at 21 Days (CR+PR+SD)
Reported Human response rates for melanoma
Untreated 83 322 0% 0
Carboplatin 89 217 21% 14-23%
Paclitaxel 62 182 21% 14-18%
Carboplatin/Paclitaxel 41 97 38% 19-47%
Temozolomide 88 266 10% 15% (10-17%)
Sunitinib 63 115 32% 33%
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RTK (EGFR, KIT, MET)
RAS
B-RAF
AKT
ERK
PTEN
PI3K
MEK
Mutated in 30% of
all human cancer BEZ235
AZD6244
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No
Treat
men
t (17
)
7.5
Gy (1
5)
Car
boplat
in (1
7)
Pac
litax
el (2
4)
Car
boplat
in/P
aclitax
el (2
1)
ABT-8
88 (1
7)
Temoz
olom
ide
(10)
Temoz
olom
ide/
ABT-8
88 (1
5)
Erlo
tinib (1
6)
Lapa
tinib (1
2)
Sun
itinib
(23)
FTS (1
1)
AZD
6244
(6)
BEZ23
5 (1
1)
AZD
6244
/BEZ23
5 (1
5)
0
500
1000
Day 2
1 P
erc
ent
Change
in T
um
or
Volu
me (
%)
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Drug Mean day 0 tumor volume (mm3)
Mean day 21 tumor volume (mm3)
Response Rate by RECIST at 21 Days (CR+PR+SD)
Reported Human response rates for melanoma
Untreated 83 322 0% 0
Carboplatin 89 217 21% 14-23%
Paclitaxel 62 182 21% 14-18%
Carboplatin/Paclitaxel 41 97 38% 19-47%
Temozolomide 88 266 10% 15% (10-17%)
Sunitinib 63 115 32% 33%
AZD6244/BEZ235 57 82 56% ???
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Median Survival (Days)
Control Sunitinib AZD BEZ Carbo/Tax AZD/BEZ
21 22 31 36 39.5 61
0 50 100 1500
20
40
60
80
100 Controls (9)
Carboplatin/Paclitaxel (12)
AZD6244 (12)
Sunitinib (12)
AZD6244/BEZ235 (10)
BEZ235 (11)
Days
Perc
ent
surv
ival
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0 20 40 60 80 1000
20
40
60
80
100
AZD/BEZ (14)
AZD (10)
BEZ (11)
No Treatment (25)
Carbo/Taxol (8)
Sunitinib (9)
Days
Perc
ent S
urv
ival
(%)
No Tre
atment (
16)
Carboplatin
/Pacli
taxe
l (31)
Sunitinib (8
)
AZD6244 (7)
BEZ235 (7)
AZD/BEZ (1
7)
0
500
1000
1200
-100
Day 2
1 P
erc
ent
Change
in T
um
or
Volu
me (
%)
Expresses SV40 large T antigen shown to inactivate both p53 and RB.
Shown to have frequent K-Ras amplification and infrequent Ras mutations.
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0 100 200 3000
20
40
60
80
100
No Treatment (21)
Carboplatin/Paclitaxel (11)
Lapatinib (14)
AZD6244 (9)
BEZ235 (6)
AZD/BEZ (10)
Days
Perc
ent
surv
ival
No Tre
atment (
44)
Carboplatin
/Pacli
taxe
l (22)
Lapatinib (2
9)
AZD6244 (10)
BEZ235 (7)
AZD6244/BEZ235 (9
)
0
500
1000
-100
Day 2
1 P
erc
ent
Change
in T
um
or
Volu
me (
%)
Expresses c-neu (the mouse ortholog of human HER2).
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No Tre
atment (
9)
Carboplatin
/Pacli
taxe
l (7)
Sunitinib (8
)
AZD6244 (7)
BEZ235 (8)
AZD/BEZ (1
0)
0
1000
20003000
6000
Day 2
1 P
erc
ent
Change
in T
um
or
Volu
me (
%)
0 20 40 600
20
40
60
80
100
No Treatment (30)
AZD6244 (11)
BEZ235 (10)
AZD6244/BEZ235 (15)
Sunitinib (12)
Days
Perc
en
t su
rviv
al
An orthotopic P53 null Breast Cancer model which has a similar gene
expression profile to the human claudin-low breast cancer subtype.
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GEMM testing at UNC is highly advanced We have identified dual MEK/PI3K inhibition as a
promising treatment approach for Ras-mutant and non-mutant cancer.
We have initiated industry collaborations to test other MEK and PI3K inhibitors with varying isoform selectivity.
We are always looking for new collaborators!
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David Darr
Jerry Usary
Patrick Dillon
Kat Bendt
Kelly Clark
Jamie Jordan
Lorraine Balletta
Austin Combest
Suzan Hanna
Norman Sharpless
Chuck Perou
Bill Zamboni