ACC Inhibitor Research Articles

IL-10 protects against OPC ferroptosis by regulating lipid reactive oxygen species levels post stroke

Accumulation of reactive oxygen species (ROS), especially on lipids, induces massive cell death in neurons and oligodendrocyte progenitor cells (OPCs) and causes severe neurologic deficits post stroke. While small compounds, such as deferoxamine, lipostatin-1, and ferrostatin-1, have been shown to be effective in reducing lipid ROS, the mechanisms by which endogenously protective molecules act against lipid ROS accumulation and subsequent cell death are still unclear, especially in OPCs, which are critical for maintaining white matter integrity and improving long-term outcomes after stroke. Here, using mouse primary OPC cultures, we demonstrate that interleukin-10 (IL-10), a cytokine playing roles in reducing neuroinflammation and promoting hematoma clearance, significantly reduced hemorrhage-induced lipid ROS accumulation and subsequent ferroptosis in OPCs. Mechanistically, IL-10 activated the IL-10R/STAT3 signaling pathway and upregulated the DLK1/AMPK/ACC axis. Subsequently, IL-10 reprogrammed lipid metabolism and reduced lipid ROS accumulation. In addition, in an autologous blood injection intracerebral hemorrhagic stroke (ICH) mouse model, deficiency of the endogenous Il-10, specific knocking out Il10r or Dlk1 in OPCs, or administration of ACC inhibitor was associated with increased OPC cell death, demyelination, axonal sprouting, and the cognitive deficits during the chronic phase of ICH and vice versa. These data suggest that IL-10 protects against OPC loss and white matter injury by reducing lipid ROS, supporting further development of potential clinical applications to benefit patients with stroke and related disorders.

Pharmacokinetics, Mass Balance, Metabolism, and Excretion of the Liver-Targeted Acetyl-CoA Carboxylase Inhibitor PF-05221304 (Clesacostat) in Humans

The disposition of the hepatoselective ACC inhibitor PF-05221304 (Clesacostat) was studied after a single 50-mg oral dose of [14C]-PF-05221304 to healthy human subjects. Mass balance was achieved with 89.9% of the administered dose recovered in urine and faeces, over the 11-day study period. The total administered radioactivity excreted in faeces and urine was 81.7% and 8.2%, respectively. Unchanged PF-05221304 accounted for 35.6% of the radioactive dose in faeces, suggesting ∼64% of the administered dose was absorbed. PF-05221304 was principally metabolized via oxidative and reductive pathways involving: (a) N-dealkylation, (b) isopropyl group monohydroxylation to yield enantiomeric metabolites (M2a and M2b), (c) hydroxylation on the 3-azaspiro[5.5]undecan-8-one moiety to metabolites M5 and 519c, and (d) carbonyl group reduction to enantiomeric alcohol metabolites M3, and M4. Secondary metabolites (521a, 521b, and 533), derived from a combination of oxidation and reduction of the primary metabolites accounted for ∼14.8% of the dose. In plasma, unchanged PF-05221304 represented 96.1% circulating radioactivity. Metabolites M1, M2b, and M2a represented 1.94, 1.76, and 0.18% of circulating radioactivity, respectively. Overall, these data suggest that PF-05221304 is well absorbed in humans and eliminated largely via phase I metabolism.

Efficacy and safety of an orally administered DGAT2 inhibitor alone or coadministered with a liver-targeted ACC inhibitor in adults with non-alcoholic steatohepatitis (NASH): rationale and design of the phase II, dose-ranging, dose-finding, randomised, placebo-controlled MIRNA (Metabolic Interventions to Resolve NASH with fibrosis) study

IntroductionSmall molecule inhibitors of the terminal step in intrahepatic triglyceride synthesis (diacylglycerol acyltransferase 2 inhibitor (DGAT2i, PF-06865571, ervogastat)) and upstream blockade of de novo lipogenesis via acetyl-coenzyme A carboxylase inhibitor...

Abstract P5-17-01: Targeting Acetyl-CoA carboxylase in pre-clinical breast cancer models

Abstract Background: Cancer cells and normal cells of the same lineage differ in their metabolism. We previously described large scale shifts in isoenzyme distribution between matching cancer and normal tissues and identified Acetyl-coA carboxylase (ACC1/ACACA) as a cancer dominant enzyme that is overexpressed in multiple cancer types. ACC1 catalyzes the initial rate-limiting step in de novo fatty acid synthesis, the conversion of acetyl-CoA to malonyl-CoA. Gene knock-out experiments demonstrated that this enzyme is essential for cancer growth. In this study, we evaluated the in vitro and in vivo efficacy of a small molecule ACC inhibitor, PF05175157 as a potential anticancer drug. This drug has been tested in clinical trials for diabetes, but development was discontinued due to grade 2 thrombocytopenia.Methods: We performed in vitro cytotoxicity assays in 15 breast cancer cell lines and in normal mammary epithelial HMEC cells, examined effect on apoptosis and cell cycle progression, and tested for synergy with alpelisib, docetaxel, doxorubicin, everolimus, iniparib, neratinib and TEPP46 (PKM2 and PKLR activator). We next assessed in vivo single agent activity in a triple negative patient derived (PDX) model (J000102184) in NSGTM mice and in MDAMB468 xenografts implanted into Rag2/IL2RG double knockout mice. We performed RNA sequencing and metabolomic profiling of cells treated with PF05175157 to study metabolic and transcriptomic effects of the drug. Results: PF05175157 induced time and dose dependent growth inhibition in all but 1 of the 15 cancer cell lines. The estimated EC50 after 72h exposure ranged from 0.95 to 76 μg/mL in T47D and BT549 cells, respectively (Cmax of 20 μg/mL can be achieved in human serum). There was no significant inhibitory effect on HMEC cells. In cancer cell lines, the % of apoptotic cells increased from 4% to 8% in BT474 and from 7.7% to 17.8% in MDMBA468 cells upon treatment with the compound, and there was a trend towards G2/M cell cycle arrest in both cell lines after 72 hours of exposure (10μg/mL). In drug combination experiments, PF05175157 added to iniparib, or to the PKM2 activator, TEPP46, decreased cell viability compared to single agent therapies in several cell lines. PF05175157 significantly delayed tumor growth compared to vehicle, when administered orally (20mg/kg gavage BID) in a TNBC PDX model (median tumor volume after 33 days: 334.1 mm3 in PF05175157-treated vs. 490.5 mm3 in methylcellulose-treated mice; p=3.39e-7) and intraperitoneally (20 mg/kg in DMSO) in an MDAMB468 xenograft model (median tumor volume after 40 days: 244.5 mm3 in PF05175157-treated vs. 303.3 mm3 in DMSO-treated mice; p<0.05). Transcriptomic and metabolic profiling of MDAMB468 and BT474 cells treated with 10 ug/ml PF05175157 for 6 and 24 hours revealed activation of immune signaling, epigenetic regulation and DNA damage repair pathways along with down-regulation of a broad range of metabolic pathways. Conclusions: The small molecule ACC inhibitor, PF05175157, has significant single agent in vitro and in vivo growth inhibitory effect on a range of breast cancer cell lines at concentrations that can be achieved in human serum. It showed synergy with iniparib and another metabolic inhibitor (TEPP46). Targeting de novo fatty acid synthesis by inhibiting ACC is a promising therapeutic strategy. Citation Format: Julia Foldi, Michal Marczyk, Vignesh Gunasekharan, Tao Qing, Raghav Sehgal, Naing Lin Shan, Viswanathan Muthusamy, Sheila Umlau, Yulia V. Surovtseva, Richard Kibbey, Lajos Pusztai. Targeting Acetyl-CoA carboxylase in pre-clinical breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-01.

A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques.

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease and has become a leading indication for liver transplantation in the United States. The development of effective therapies for NASH is a major unmet need. Here, we identified a small molecule, IMA-1, that can treat NASH by interrupting the arachidonate 12-lipoxygenase (ALOX12)–acetyl-CoA carboxylase 1 (ACC1) interaction. IMA-1 markedly blocked diet-induced NASH progression in both male mice and Cynomolgus macaque therapeutic models. The anti-NASH efficacy of IMA-1 was comparable to ACC inhibitor in both species. Protein docking simulations and following functional experiments suggested that the anti-NASH effects of IMA-1 were largely dependent on its direct binding to a pocket in ALOX12 proximal to its ACC1-interacting surface instead of inhibiting ALOX12 lipoxygenase activity. IMA-1 treatment did not elicit hyperlipidemia, a known side effect of direct inhibition of ACC enzymatic activity, in both mice and macaques. These findings provide proof of concept across multiple species for the use of small molecule–based therapies for NASH.

Metabolic Targets in Nonalcoholic Steatohepatitis: Treating the Disease at the Metabolic Root

Nonalcoholic fatty liver disease (NAFLD) and its more aggressive form nonalcoholic steatohepatitis (NASH) are a leading cause of chronic liver disease worldwide. Thus far, there are no FDA-approved therapeutic options for NASH. This review discusses relevant and recent findings in the development of pharmacotherapy that targets the metabolic processes implicated in NASH. Several key drugs have been identified across various drug classes. Among inhibitors of de novo lipogenesis, the SCD-1 inhibitor aramchol and the ACC inhibitor firsocostat are the most advanced. Within nuclear hormone receptor agonists, PPARα/δ agonist elafibranor and PPARα/γ agonist saroglitazar show promise with respect to improvement in NASH histology and hepatic steatosis. Additionally, THR-β agonist resmetirom showed significant reduction in hepatic steatosis and NASH resolution. Larger studies with longer treatment duration are needed to establish safety and efficacy of these metabolic drugs. Significant progress has been made over the past decade in testing drugs that modulate the metabolic targets responsible for NASH progression.

Pyridoxal 5′-phosphate enhances the growth and morpho-physiological characteristics of rice cultivars by mitigating the ethylene accumulation under salinity stress

Salinity-induced ethylene accumulation caused by high production of 1-aminocyclopropane-1-carboxylic acid (ACC) hinders rice plant growth and development. Nevertheless, ACC deaminase may alleviate salt stress and high ethylene production in rice cultivars under salinity stress. Pyridoxal 5′-phosphate (PLP), an ACC deaminase co-factor, could be a useful ACC inhibitor in plants; however, it has not been studied before. In the present study, the effects of PLP on the growth and morphophysiological characteristics of rice cultivars (Jinyuan 85 (JY85) and Nipponbare (NPBA) were investigated under salinity stress (control (CK), low salinity (LS), and high salinity (HS) in hydroponic conditions. The experiment was laid out in a completely randomized design (CRD) under factorial arrangement of treatments. The results showed that, compared with no PLP, exogenous application of PLP significantly inhibited ACC and ethylene production in the roots, leaves and panicles of both cultivars under salinity, and PLP was more effective at improving the physiological characteristics of both cultivars under salinity stress. Further, root morphophysiological traits and pollen viability were triggered in the PLP treatment compared to the no-PLP treatment under various salinity levels. ACC production inhibited by PLP was useful for improving the 1000-grain weight, grain yield per plant, and total plant biomass under the CK, LS and HS treatments in both rice cultivars. These results revealed that PLP, as an ACC deaminase cofactor, is a key tool for mitigating ethylene-induced effects under salinity stress and for enhancing the agronomic and morphophysiological traits of rice under saline conditions.

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

SummaryFibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-β signaling and fibrosis.

1813-P: Coadministration of a GLP-1/Glucagon Receptor Agonist with an FXR Agonist and ACC Inhibitor Reverses Nonalcoholic Steatohepatitis (NASH) in Diet-Induced and Biopsy-Confirmed Mice

Combination approaches for the treatment of NASH are being actively pursued. We examined the effects of administration of a dual GLP-1 and glucagon receptor agonist (GLP-1:GCG, 0.015 mg/kg, s.c., q.d.) alone and combined with an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analog, ACCi; 5 mg/kg, both p.o., q.d) on NASH endpoints in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, GLP-1:GCG reduced body weight 15%, being slightly greater in the GLP-1:GCG + CILO group (22%). Liver triglyceride was reduced by GLP-1:GCG (by 76% vs. vehicle, p<0.001). Addition of CILO, ACCi or both to GLP-1:GCG further reduced liver lipid (by 82%, 88% and 91%, respectively). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 7/16 (44%) of vehicle controls and in all mice (100%) in the GLP-1:GCG-containing groups. In vehicle controls, 0/16 mice had a final NAS of 0-1 whereas this increased to 5/15 mice (33%) with GLP-1:GCG, and was not significantly improved by addition of CILO (7/15, 47%) or ACCi (6/16, 38%). Triple therapy increased number of mice with NAS of 0-1 to 11/16 (69%). GLP-1:GCG was associated with 1/15 mice (7%) improving pre-to-post fibrosis stage which was not altered by addition of CILO or ACCi, but increased to 7/16 (44%) with triple therapy. Collagen-1a and α-SMA immunoreactivity (% area) revealed no significant effect of GLP-1:GCG for collagen (5.7%), but reduction in α-SMA (1.4%, p<0.001) vs. vehicle (6.8% and 4.9%, respectively). Triple therapy reduced both collagen and α-SMA area (3.8% and 1.5%, respectively, both p<0.001 vs. vehicle). In conclusion, GLP-1:GCG effectively reduced hepatic lipid and the addition of an FXR agonist and ACC inhibitor further improved pre-to-post NAS and fibrosis stage in DIO-NASH mice, supporting development of combination approaches for NASH. Disclosure J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. M. Latta: Employee; Self; Novo Nordisk A/S.

Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors

Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC50 values 3–10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC50 values 9–17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.

Abstract 1276: Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion

Abstract Primary and acquired EGFR-TKIs resistance restricts the benefit of EGFR-TKIs to EGFR mutant NSLCLC patients. Recent studies found that metabolic reprogramming might contribute to develop metastasis and drug resistance of tumor cells. Therefore, illustrating the metabolism change is meaningful and targeting the peculiar metabolic pathways might be considered as potential therapeutic strategies for EGFR-TKIs resistant NSCLC. We separated single clones from gefitnib resistant NSCLC cells, by exposing EGFR-mutant EGFR-TKIs sensitive PC-9 cells into increasing concentrations of gefitnib. Among the numerous clones, clone 5 was resistant to gefitinib or AZD9291 and named as PC-9GR-FGF because of high level of bFGF secretion. We found that bFGF promote the transcription of SREBP-1 and its downstream genes, acetyl-CoA carboxylase alpha (ACC), ATP citrate lyase (ACLY) and fatty acid synthase (FASN) in PC-9 cells. Compared to PC-9 cells, higher ACC expression was detected in PC-9GR-FGF cells. Basing on TCGA database (lung Adenocarcinoma, provisional), patients with high ACC expression showed significant shorter PFS (progression-free survival) and OS (overall survival) compared to those with low ACC expression in the EGFR-mutant NSCLC (p<0.05, N=32). Down-regulation of ACC by siRNA or TOFA, a small molecular ACC inhibitor, mederately decreased the proliferation of PC-9 cells whereas strongly decreased proliferation of PC-9GR-FGF cells in vitro and in vivo. Moreover, Reactive oxygen species (ROS) and oxidative stress scavenger, NAC and ferrostatin-1, failed to reverse the effect of ACC inhibition in PC-9 and PC-9GR-FGF cells. Furthermore, after down-regulation or inhibition of ACC, stronger G2/M arrest and more accumulation of DNA damage marker, γH2AX, were found in PC-9GR-FGF cells compared with PC-9 cells. In addition, ACC expression were increased after irradiation of X-ray in PC-9GR-FGF cells, and inhibition of ACC increased accumulation of γH2AX induced by X-rays in PC-9GR-FGF cells. Our research gives a view sight into lipid metabolism changes in EGFR-mutant NSCLC cells before and after acquired EGFR-TKIs resistance, and explores the possibility of combination strategy with radiotherapy and anti-cancer lipid metabolism therapy. Citation Format: Wei Wang, Shunli Peng, Rong Wang, yueyun Ma, Longhui Zhong. Inhibition of lipid metabolism decreases proliferation and increases radiosensitvity in EGFR-TKI resistant NSCLC cells with bFGF secretion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1276.

SAT-352-A combination of the ACC inhibitor GS-0976 and the nonsteroidal FXR agonist GS-9674 improves hepatic steatosis, biochemistry, and stiffness in patients with non-alcoholic steatohepatitis

SAT-352-A combination of the ACC inhibitor GS-0976 and the nonsteroidal FXR agonist GS-9674 improves hepatic steatosis, biochemistry, and stiffness in patients with non-alcoholic steatohepatitis

SAT-283-Plasma acylcarnitines are biomarkers of magnetic resonance imaging-proton density fat fraction response in NASH patients treated with the ACC inhibitor GS-0976

SAT-283-Plasma acylcarnitines are biomarkers of magnetic resonance imaging-proton density fat fraction response in NASH patients treated with the ACC inhibitor GS-0976

A combined drug discovery strategy based on machine learning and molecular docking

Data mining methods based on machine learning play an increasingly important role in drug design and discovery. In the current work, eight machine learning methods including decision trees, k-Nearest neighbor, support vector machines, random forests, extremely randomized trees, AdaBoost, gradient boosting trees, and XGBoost were evaluated comprehensively through a case study of ACC inhibitor data sets. Internal and external data sets were employed for cross-validation of the eight machine learning methods. Results showed that the extremely randomized trees model performed best and was adopted as the first step of virtual screening. Together with structure-based virtual screening in the second step, this combined strategy obtained desirable results. This work indicates that the combination of machine learning methods with traditional structure-based virtual screening can effectively strengthen the ability in finding potential hits from large compound database for a given target.

Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma

The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.

FRI-485 - Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304) following single and multiple oral doses

FRI-485 - Safety, tolerability, pharmacokinetics and pharmacodynamics of a liver-targeting ACC inhibitor (PF-05221304) following single and multiple oral doses

FRI-077 - Combination of an FXR agonist and an ACC inhibitor increases anti-fibrotic efficacy in rodent models of NASH

FRI-077 - Combination of an FXR agonist and an ACC inhibitor increases anti-fibrotic efficacy in rodent models of NASH

FRI-087 - ACC inhibitor demonstrates potent anti-fibrotic activity in vitro and in vivo

FRI-087 - ACC inhibitor demonstrates potent anti-fibrotic activity in vitro and in vivo

Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway

Background/Aims: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling pathway. Methods: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- γ/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT-qPCR) and Westernblot. Besides, PPAR-γ antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-γ and AMPK. Results: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-γ mediated the activation of AMPK and subsequent inhibition of ACC expression. Conclusion: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-γ/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN.

Abstract 3781: 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

Abstract Background: Hepatocellular carcinoma (HCC) is increasing in incidence worldwide. Current treatment options for HCC are limited, and as such, prognosis is extremely poor with a 5-year survival less than 12%. Sorafenib is the only FDA-approved drug for the treatment of HCC but its effects are marginal as it only extends survival by a few months. Therefore, new treatment options are urgently needed. Metabolic attenuation is a promising approach to cancer therapy, and rate-limiting steps in key biosynthetic pathways are particularly attractive targets. We recently identified ND-654, a hepatoselective (∼3000:1 liver to muscle exposure), allosteric ACC inhibitor that binds to the ACC subunit dimerization site and inhibits the enzymatic activity of both ACC1 (IC50 = 3 nM) and ACC2 (IC50 = 8 nM). Daily oral administration of 10 mg/kg ND-654 reduced tumor incidence by 55% and significantly improved median survival time in a rat model of cirrhosis and HCC. Here, we examine the effects of ND-654 alone and in combination with sorafenib on HCC development in cirrhotic rats. Methods: Male Wistar rats were treated once weekly with 50 mg/kg diethylnitrosamine (DEN) for 18 weeks to induce sequential development of fibrosis, cirrhosis and HCC. After establishment of cirrhosis and when HCCs are first developing (13 weeks), rats were treated daily by oral gavage with either 1) vehicle control, 2) 10 mg/kg ND-654, 3) 10 mg/kg sorafenib, or 4) 10 mg/kg ND-654 and 10 mg/kg sorafenib. After 18 weeks, tumor nodules were counted and liver and tumor tissue was harvested for analysis. Results: Similar to our previous study, simultaneous inhibition of ACC1 and ACC2 significantly reduced HCC incidence by 41% (p < 0.05) which was comparable to results with sorafenib (57% reduction, p < 0.01). Remarkably, the combination of ND-654 and sorafenib significantly reduced HCC incidence by 81% (p < 0.001). We are currently examining the effects of combining ND-654 and sorafenib on markers of tumor proliferation and apoptosis. Conclusions: These results provide further evidence that de novo lipogenesis is an important mediator of hepatic carcinogenesis and that selective inhibition of hepatic ACC is a viable cancer metabolism therapeutic strategy for treating HCC that could be combined with sorafenib. Citation Format: Lan Wei, Geraldine Harriman, Sarani Ghoshal, Omeed Moaven, Jeremy Greenwood, Sathesh Bhat, William F. Westlin, H. James Harwood, Rosana Kapeller, Kenneth K. Tanabe, Bryan C. Fuchs. 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. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3781.