Session 4: Developing New

Therapeutics Sharpless, Roberts (Duncan presentation unavailable)

May 25, 2011

Overview Ned Sharpless

May 25, 2011

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

Patrick Roberts, PharmD, PhD

5/25/2011

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.

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.

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 (

%)

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%

RTK (EGFR, KIT, MET)

RAS

B-RAF

AKT

ERK

PTEN

PI3K

MEK

Mutated in 30% of

all human cancer BEZ235

AZD6244

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 (

%)

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% ???

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

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.

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).

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.

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!

David Darr

Jerry Usary

Patrick Dillon

Kat Bendt

Kelly Clark

Jamie Jordan

Lorraine Balletta

Austin Combest

Suzan Hanna

Norman Sharpless

Chuck Perou

Bill Zamboni