Combination Therapy with a Liver Selective Acetyl CoA Carboxylase Inhibitor ND-654 and Sorafenib Improves Efficacy in the Treatment of Cirrhotic Rats with Hepatocellular Carcinoma Lan Wei 1 , Omeed Moaven 1 , Geraldine Harriman 2 , Sarani Ghoshal 1 , Wenyan Miao 2 , Jennifer Rocnik 2 , Jeremy Greenwood 3 , Sathesh Bhat 3 , William F. Westlin 2 , H. James Harwood 2 , Rosana Kapeller 2 , Kenneth K. Tanabe 1 , Bryan C. Fuchs 1 1 Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 2 Nimbus Therapeutics, Cambridge, MA, 3 Schrodinger, New York, NY, Abstract #3781 1. ND-654 Targets Allosteric Site in Biotin Carboxylase Domain ACC: An Emerging Tumor Metabolism Target 2. ND-654 is Well-Tolerated in the DEN Rat Model OVERVIEW CONCLUSION 3. ND-654 Results in Marked Reduction of Tumor Nodules 4. ND-654 Decreases Tumor Proliferation and Increases Tumor Necrosis 5. ND-654 Significantly Improves Survival in the Aggressive DEN Model 6. ND-654 Decreases Markers of Fibrosis and Inflammation 7. ND-654 Decreases Markers of Fibrosis and Inflammation in Primary Human Stellate Cells in vitro 8. ND-654 Improves the Efficacy of Sorafenib • Current treatment options for HCC are limited, and as such, prognosis is extremely poor with a 5-year survival less than 12% • Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Hepatospecific ND-654 is a potent allosteric inhibitor of the lipid master regulator Acetyl CoA Car - boxylase (ACC) • ND-654 demonstrates excellent PK/ PD relationships in the target tis- sue, the liver (exposure vs Malonyl CoA reduction), and is effective at modifying cirrhotic and HCC rele- vant endpoints in the DEN model • ND-654 demonstrates the ability for tissue targeted ACC inhibition to decrease tumor burden, liver fibrosis and prolong survival in the highly aggressive rat DEN model of HCC DEN DEN + ND-654 10 PBS Alpha-Smooth Muscle Actin CD68 Inflammation Marker Collagen 1A1 Marker (Fibrosis) DEN + ND-654 30 a-SMA Trichrome • Only potent BC domain inhibitor: Soraphen A • Industry efforts on analoging Soraphen proved unsuccessful • Allosteric binding site implicated in dimerization of ACC • Highly lipophilic binding site • Inhibitors bind to active site • Past programs exhibited poor drug-like properties Challenges in Drugging ACC Target potency • ACC1 IC 50 = 3 nM • ACC2 IC 50 = 8 nM • HepG2 EC 50 = 4 nM (serum free) = 14 nM (10% serum) Pharmacology • Rat FASyn ED 50 = 0.3 mg/kg PO • Rat Malonyl-CoA ED 50 = 0.3 mg/kg (liver) PO • Rat DEN HCC MED = 10 mg/kg PO ADME • Moderate multispecies intrinsic clearance (human, mouse, rat, dog, monkey) • P450 inhib >50 μM • Highly selective across broad panel (>1000x) Exposure at 10 mg/kg Hep-G2 Cell FASyn Inhibition [ 14 C]acetate incorporation into FA Liver p < 0.01 Muscle (Gastrocnemius) n.s. 784 Memorial Dr, Cambridge, MA 02139, USA • www.nimbustx.com • Tel: 857.999.2009 • [email protected] ND-654 • ND-654 preferentially biodistributes to the liver where it inhibits ACC activity without generating liver toxicity • ND-654 inhibits HCC development by decreasing tumor proliferation and causing tumor necrosis • ND-654 reduces markers of fibrosis and inflammation in the liver of DEN rat in vivo efficacy model and in primary human stellate cells in vitro • ND-654 improves overall survival and the efficacy of sorafenib in the DEN rat model • Our results therefore provide further evidence that de novo fatty acid synthesis is an important mediator of hepatic carcinogenesis • Selective inhibition of hepatic ACC is a potential therapeutic strategy for hepatocel- lular carcinoma a-SMA TIMP1 DEN + ND-654 DEN + Sorafenib DEN DEN + Combination Study Design OTHERS COO - Acetyl CoA Malonyl CoA BC CT Acetyl -CoA Acetyl -CoA Acetyl -CoA Malonyl -CoA Citrate Very long chain fatty acids ACC1 ACC2 Fatty Acids Fatty Acids FAO Pyruvate Oxaloacetate Krebs Cycle ETC NADH NADH + FADH 2 FAO MITOCHONDRION PEROXISOME Phosphoinositides Eicosanoids Sphingolipids Phosphoglycerides CELL GROWTH SIGNALING MEMBRANE BIOGENESIS AMPK LKB1 CPT1 0.000001 0.0001 0.01 1 0 5000 10000 15000 cpm ND-654 (µM) 0.01 0.1 1 10 100 Plasma Liver Muscle Tissue Concentration (µM) 0 2 3 6 Vehicle 0.3 3 30 mg/kg 1 5 4 Malonyl-CoA (nmol/g tissue) 0 4 5 Vehicle 0.3 3 30 mg/kg 1 2 3 Malonyl-CoA (nmol/g tissue) 0 1 2 3 4 5 9 Liver Weight (% Body) PBS DEN DEN + ND-654 0 10 15 20 25 Tumor Nodules PBS DEN DEN + ND-654 5 # * 6 7 8 # ** PBS DEN DEN + ND-654 PCNA Actin DEN DEN + ND-654 Tumor PBS DEN DEN + ND-654 Liver PCNA Actin DEN DEN + ND654 H&E PCNA Cleaved Caspase-3 ND-654 10 mg/kg qd po 50mg/kg DEN 13 18 50mg/kg DEN Weeks 0 8 Cirrhosis HCC 50mg/kg DEN Fibrosis Vehicle qd po ND-654 30 mg/kg qd po 0 10 20 30 40 50 60 70 80 90 100 90 95 100 105 110 115 120 125 130 135 140 145 150 155 Percent Survival Time (Days) Vehicle ND-654 10 ND-654 30 Vehicle/ DEN ND-654 10 mg/kg ND-654 30 mg/kg MEDIAN SURVIVAL 114 days 126 days 129 days P VALUE 0.02 0.009 # DEN + ND-654 # # # ** # ND-654 10 mg/kg qd po Control (PBS) 13 18 Sacrifice 50mg/kg DEN Weeks 0 8 Cirrhosis HCC 50mg/kg DEN X Fibrosis 0 100 200 300 400 500 600 Body Weight (g) PBS DEN 0 20 40 60 80 100 140 ALT (IU/L) PBS DEN DEN + ND-654 0 100 150 200 250 300 350 AST (IU/L) PBS DEN DEN + ND-654 120 50 0 1.5 2 2.5 3 3.5 4.5 Alb (g/dL) PBS DEN DEN + ND-654 4 1 .5 0 0.2 0.3 0.4 0.5 0.6 0.7 Spleen Weight (% Body) PBS DEN DEN + ND-654 0.1 0 1 2 3 4 5 6 TBIL (mg/dL) PBS DEN DEN + ND-654 0 20 40 60 80 100 160 TG (mg/dL) PBS DEN DEN + ND-654 120 140 # ** * DEN DEN + ND-654 DEN + Sorafenib DEN + Combination # * DEN DEN + ND-654 DEN + Sorafenib DEN + Combination 0 5 25 Tumor Nodules 0 400 500 600 700 Total Body Weight (g) 300 10 15 20 200 100 0 0.40 0.80 1.20 RQ TKL4.1 Control 10 µM ND-654 30 µM ND-654 0 0.40 0.80 1.20 RQ TKL4.1 Control 10 µM ND-654 30 µM ND-654 0 0.00005 0.0001 0.0003 PBS DEN DEN + 10 ND-654 DEN+ 30 ND-654 mg/kg 0.0002 0.00025 0.00015 0 0.00005 0.0001 0.0003 PBS DEN DEN + 10 ND-654 DEN+ 30 ND-654 mg/kg 0.0002 0.00025 0.00015 0 0.0004 0.0005 0.0009 PBS DEN DEN + 10 ND-654 DEN+ 30 ND-654 mg/kg 0.0007 0.0008 0.0006 0.0001 0.0002 0.0003 * * * * * * Gene Expression (AU) Gene Expression (AU) Gene Expression (AU)
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Combination Therapy with a Liver Selective Acetyl CoA Carboxylase Inhibitor ND-654 and Sorafenib Improves Efficacy in the Treatment of Cirrhotic Rats with Hepatocellular Carcinoma
Lan Wei1, Omeed Moaven1, Geraldine Harriman2, Sarani Ghoshal1, Wenyan Miao2, Jennifer Rocnik2, Jeremy Greenwood3, Sathesh Bhat3, William F. Westlin2, H. James Harwood2, Rosana Kapeller2, Kenneth K. Tanabe1, Bryan C. Fuchs1
1Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 2Nimbus Therapeutics, Cambridge, MA, 3Schrodinger, New York, NY,
Abstract#3781
1. ND-654 Targets Allosteric Site in Biotin Carboxylase Domain
ACC: An Emerging Tumor Metabolism Target
2. ND-654 is Well-Tolerated in the DEN Rat ModelOVERVIEW
CONCLUSION3. ND-654 Results in Marked Reduction of Tumor Nodules
4. ND-654 Decreases Tumor Proliferation and Increases Tumor Necrosis
5. ND-654 Significantly Improves Survival in the Aggressive DEN Model
6. ND-654 Decreases Markers of Fibrosis and Inflammation
7. ND-654 Decreases Markers of Fibrosis and Inflammation in Primary Human Stellate Cells in vitro
8. ND-654 Improves the Efficacy of Sorafenib
• Current treatment options for HCC are limited, and as such, prognosis is extremely poor with a 5-year survival less than 12%
• Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. Hepatospecific ND-654 is a potent allosteric inhibitor of the lipid master regulator Acetyl CoA Car-boxylase (ACC)
• ND-654 demonstrates excellent PK/PD relationships in the target tis-sue, the liver (exposure vs Malonyl CoA reduction), and is effective at modifying cirrhotic and HCC rele-vant endpoints in the DEN model
• ND-654 demonstrates the ability for tissue targeted ACC inhibition to decrease tumor burden, liver fibrosis and prolong survival in the highly aggressive rat DEN model of HCC
DEN DEN + ND-654 10PBS
Alpha-Smooth Muscle Actin
CD68 InflammationMarker
Collagen 1A1 Marker(Fibrosis)
DEN + ND-654 30
a-S
MA
Tric
hrom
e
• Only potent BC domain inhibitor: Soraphen A
• Industry efforts on analoging Soraphen proved unsuccessful
• Allosteric binding site implicated in dimerization of ACC
• Highly lipophilic binding site• Inhibitors bind to active site• Past programs exhibited poor
drug-like properties
Challenges in Drugging ACCTarget potency• ACC1 IC50 = 3 nM• ACC2 IC50 = 8 nM• HepG2 EC50 = 4 nM (serum free) = 14 nM (10% serum) Pharmacology• Rat FASyn ED50 = 0.3 mg/kg PO• Rat Malonyl-CoA ED50 = 0.3 mg/kg (liver) PO• Rat DEN HCC MED = 10 mg/kg PO
ADME• Moderate multispecies intrinsic clearance
(human, mouse, rat, dog, monkey)• P450 inhib >50 μM• Highly selective across broad panel (>1000x)
Exposure at 10 mg/kgHep-G2 Cell FASyn Inhibition[14C]acetate incorporation into FA
Liverp < 0.01
Muscle(Gastrocnemius)
n.s.
784 Memorial Dr, Cambridge, MA 02139, USA • www.nimbustx.com • Tel: 857.999.2009 • [email protected]
ND-654
• ND-654 preferentially biodistributes to the liver where it inhibits ACC activity without generating liver toxicity
• ND-654 inhibits HCC development by decreasing tumor proliferation and causing tumor necrosis
• ND-654 reduces markers of fibrosis and inflammation in the liver of DEN rat in vivo efficacy model and in primary human stellate cells in vitro
• ND-654 improves overall survival and the efficacy of sorafenib in the DEN rat model
• Our results therefore provide further evidence that de novo fatty acid synthesis is an important mediator of hepatic carcinogenesis
• Selective inhibition of hepatic ACC is a potential therapeutic strategy for hepatocel-lular carcinoma
a-SMA TIMP1
DEN + ND-654 DEN + SorafenibDEN DEN + Combination
Study Design
OTHERS
COO-
Acetyl CoA Malonyl CoA
BC CT
Acetyl-CoA
Acetyl-CoA
Acetyl-CoA
Malonyl-CoA
Citrate
Very long chain fatty
acids
ACC1
ACC2
Fatty Acids
Fatty Acids
FAO
Pyruvate
Oxaloacetate
Krebs Cycle
ETC NADH
NADH +
FADH2
FAO
MITOCHONDRION
PEROXISOME
Phosphoinositides
Eicosanoids
Sphingolipids
Phosphoglycerides
CELL GROWTH SIGNALING MEMBRANE BIOGENESIS
AMPK
LKB1
CPT1
0.000001 0.0001 0.01 10
5000
10000
15000
cpm
ND-654 (µM)
0.01
0.1
1
10
100
Plasma Liver Muscle Tiss
ue C
once
ntra
tion
(µM
)
0
2
3
6
Vehicle 0.3 3 30
mg/kg
1
5
4
Mal
onyl
-CoA
(n
mol
/g ti
ssue
)
0
4
5
Vehicle 0.3 3 30
mg/kg
1
2
3
Mal
onyl
-CoA
(n
mol
/g ti
ssue
)
012345
9
Live
r Wei
ght
(% B
ody)
PBS DEN DEN +ND-654
0
10
15
20
25
Tum
or N
odul
es
PBS DEN DEN +ND-654
5
#
*678#
**
PBS DEN DEN + ND-654
PCNA
Actin
DEN DEN + ND-654
Tumor
PBS DEN DEN + ND-654
Liver
PCNA
Actin
DEN DEN + ND654
H&
EPC
NA
Cle
aved
C
aspa
se-3
ND-65410 mg/kg qd po
50mg/kg DEN
13 18
50mg/kg DEN
Weeks 0 8
Cirrhosis HCC
50mg/kg DEN
Fibrosis
Vehicle qd po
ND-65430 mg/kg qd po
0
10
20
30
40
50
60
70
80
90
100
90 95 100 105 110 115 120 125 130 135 140 145 150 155
Perc
ent S
urvi
val
Time (Days)
Vehicle
ND-654 10
ND-654 30
Vehicle/
DEN ND-654
10 mg/kgND-654
30 mg/kg
MEDIAN SURVIVAL 114 days 126 days 129 days
P VALUE 0.02 0.009
#
DEN +ND-654
#
#
#
**
#
ND-65410 mg/kg qd po
Control (PBS)
13 18
Sacrifice
50mg/kg DEN
Weeks 0 8Cirrhosis HCC
50mg/kg DEN
X
Fibrosis
0
100
200
300
400
500
600
Bod
y W
eigh
t (g)
PBS DEN
0
20
40
60
80
100
140
ALT
(IU
/L)
PBS DEN DEN +ND-654
0
100
150
200
250
300
350
AST
(IU
/L)
PBS DEN DEN +ND-654
120
50
0
1.52
2.53
3.5
4.5
Alb
(g/d
L)
PBS DEN DEN +ND-654
4
1.5
0
0.2
0.3
0.4
0.5
0.6
0.7Sp
leen
Wei
ght
(% B
ody)
PBS DEN DEN +ND-654
0.1
0
1
2
3
4
5
6
TBIL
(mg/
dL)
PBS DEN DEN +ND-654
020406080
100
160
TG (m
g/dL
)
PBS DEN DEN +ND-654
120140
#
** *
DEN DEN +ND-654
DEN +Sorafenib
DEN +Combination
#
*
DEN DEN +ND-654
DEN +Sorafenib
DEN +Combination
0
5
25
Tum
or N
odul
es
0
400
500
600
700
Tota
l Bod
y W
eigh
t (g)
300 10
15
20
200
100
0
0.40
0.80
1.20
RQ
TKL4.1Control
10 µMND-654
30 µMND-654
0
0.40
0.80
1.20
RQ
TKL4.1Control
10 µMND-654
30 µMND-654
0
0.00005
0.0001
0.0003
PBS DEN DEN + 10ND-654
DEN+ 30ND-654
mg/kg
0.0002
0.00025
0.00015
0
0.00005
0.0001
0.0003
PBS DEN DEN + 10ND-654
DEN+ 30ND-654
mg/kg
0.0002
0.00025
0.00015
0
0.00040.0005
0.0009
PBS DEN DEN + 10ND-654
DEN+ 30ND-654
mg/kg
0.00070.0008
0.0006
0.00010.00020.0003
*
*
**
* *
Gen
e Ex
pres
sion
(AU
)
Gen
e Ex
pres
sion
(AU
)
Gen
e Ex
pres
sion
(AU
)
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