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Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.

Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS - EBioMedicine (2015)

Bottom Line: Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays.Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific.Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: 3-V Biosciences, Menlo Park, CA, United States.

ABSTRACT

Unlabelled: Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.

Research in context: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

No MeSH data available.


Related in: MedlinePlus

TVB-3166 inhibits growth of patient-derived non-small-cell lung cancer xenograft tumors: (A) CTG-0165, (B) CTG-0160 and (C) CTG-0743. TVB-3166 was dosed once daily by oral gavage at 60 mg/kg. Animals were randomized according to tumor size and drug treatment was started when the mean tumor size was 150–200 mm3. The in-life phase for all studies was performed at Champions, Oncology (Baltimore, MD).
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f0040: TVB-3166 inhibits growth of patient-derived non-small-cell lung cancer xenograft tumors: (A) CTG-0165, (B) CTG-0160 and (C) CTG-0743. TVB-3166 was dosed once daily by oral gavage at 60 mg/kg. Animals were randomized according to tumor size and drug treatment was started when the mean tumor size was 150–200 mm3. The in-life phase for all studies was performed at Champions, Oncology (Baltimore, MD).

Mentions: In vivo efficacy of FASN inhibition on tumor growth was investigated in tumor cell line and patient-derived xenograft tumor models. Dose responsive tumor growth inhibition was observed in multiple tumor models (Fig. 6, Fig. 7). In the PANC-1 tumor cell line xenograft (Fig. 6A), once-daily, oral dosing of TVB-3166 at 100 mg/kg for 18 days resulted in statistically significant 57% tumor growth inhibition compared to vehicle (p = 0.04). A once-daily dose of 30 mg/kg TVB-3166 showed non-significant 19% tumor growth inhibition. Tumor growth inhibition was associated with dose-dependent inhibition of Akt phosphorylation (S473) and induction of FASN expression (Fig. 6C). Inhibition of Akt phosphorylation in FASN inhibitor-treated tumors, relative to vehicle treatment, was 53% and 0% in the 100 and 30 mg/kg treatment groups, respectively. FASN protein expression was increased 5.4 fold and 4-fold in the high and low dose groups, respectively. Pharmacokinetic analysis of plasma and tumor samples collected 6 h post-dosing showed the concentration of TVB-3166 to be approximately 3-fold higher in plasma than tumor. The 100 and 30 mg/kg groups had plasma and tumor concentrations of 7 and 2.9 μM, respectively. Following normalization for free, non-protein-bound drug, the TVB-3166 plasma concentration in the 100 mg/kg group at 6 h post-dosing was equivalent to the FASN IC50. The overall PK of TVB-3166 in mice predicts that most of the drug is cleared by 12 h after dosing. Body weight loss was not significant in the TVB-3166-treated mice and was similar to changes observed in the vehicle-treated mice. Together, the results demonstrated that TVB-3166 has excellent oral bioavailability and manageable pharmacokinetic properties, which resulted in well-tolerated dose-dependent inhibition of Akt phosphorylation and tumor growth.


Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.

Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS - EBioMedicine (2015)

TVB-3166 inhibits growth of patient-derived non-small-cell lung cancer xenograft tumors: (A) CTG-0165, (B) CTG-0160 and (C) CTG-0743. TVB-3166 was dosed once daily by oral gavage at 60 mg/kg. Animals were randomized according to tumor size and drug treatment was started when the mean tumor size was 150–200 mm3. The in-life phase for all studies was performed at Champions, Oncology (Baltimore, MD).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563160&req=5

f0040: TVB-3166 inhibits growth of patient-derived non-small-cell lung cancer xenograft tumors: (A) CTG-0165, (B) CTG-0160 and (C) CTG-0743. TVB-3166 was dosed once daily by oral gavage at 60 mg/kg. Animals were randomized according to tumor size and drug treatment was started when the mean tumor size was 150–200 mm3. The in-life phase for all studies was performed at Champions, Oncology (Baltimore, MD).
Mentions: In vivo efficacy of FASN inhibition on tumor growth was investigated in tumor cell line and patient-derived xenograft tumor models. Dose responsive tumor growth inhibition was observed in multiple tumor models (Fig. 6, Fig. 7). In the PANC-1 tumor cell line xenograft (Fig. 6A), once-daily, oral dosing of TVB-3166 at 100 mg/kg for 18 days resulted in statistically significant 57% tumor growth inhibition compared to vehicle (p = 0.04). A once-daily dose of 30 mg/kg TVB-3166 showed non-significant 19% tumor growth inhibition. Tumor growth inhibition was associated with dose-dependent inhibition of Akt phosphorylation (S473) and induction of FASN expression (Fig. 6C). Inhibition of Akt phosphorylation in FASN inhibitor-treated tumors, relative to vehicle treatment, was 53% and 0% in the 100 and 30 mg/kg treatment groups, respectively. FASN protein expression was increased 5.4 fold and 4-fold in the high and low dose groups, respectively. Pharmacokinetic analysis of plasma and tumor samples collected 6 h post-dosing showed the concentration of TVB-3166 to be approximately 3-fold higher in plasma than tumor. The 100 and 30 mg/kg groups had plasma and tumor concentrations of 7 and 2.9 μM, respectively. Following normalization for free, non-protein-bound drug, the TVB-3166 plasma concentration in the 100 mg/kg group at 6 h post-dosing was equivalent to the FASN IC50. The overall PK of TVB-3166 in mice predicts that most of the drug is cleared by 12 h after dosing. Body weight loss was not significant in the TVB-3166-treated mice and was similar to changes observed in the vehicle-treated mice. Together, the results demonstrated that TVB-3166 has excellent oral bioavailability and manageable pharmacokinetic properties, which resulted in well-tolerated dose-dependent inhibition of Akt phosphorylation and tumor growth.

Bottom Line: Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays.Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific.Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: 3-V Biosciences, Menlo Park, CA, United States.

ABSTRACT

Unlabelled: Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.

Research in context: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

No MeSH data available.


Related in: MedlinePlus