Author: Pniewski, Katherine ; Dessain, Jena ; Patel, Jeet ; O'Connor, Seamus ; Bertolazzi, Fabrizio ; Mullins, Mary ; Schug, Zachary T ; Mukha, Dzmitry

Proliferating cancer cells actively utilize anabolic processes for biomass production, includingde novobiosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions1,2. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors3,4. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.

Scientific Reports

FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models

Article

Author: Buckley, Douglas ; Bhattacharya, Dipankar ; Crowley, Richard ; Duke, Greg ; O'Farrell, Marie ; Kemble, George ; Martins, Eduardo B ; Friedman, Scott L

AbstractFatty acid synthase (FASN) is an attractive therapeutic target in non-alcoholic steatohepatitis (NASH) because it drives de novo lipogenesis and mediates pro-inflammatory and fibrogenic signaling. We therefore tested pharmacological inhibition of FASN in human cell culture and in three diet induced mouse models of NASH. Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). In human primary liver microtissues, FASN inhibiton (FASNi) decreased triglyceride (TG) content, consistent with direct anti-steatotic activity. In human hepatic stellate cells, FASNi reduced markers of fibrosis including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). In CD4+ T cells exposed to NASH-related cytokines, FASNi decreased production of Th17 cells, and reduced IL-1β release in LPS-stimulated PBMCs. In mice with diet induced NASH l, FASNi prevented development of hepatic steatosis and fibrosis, and reduced circulating IL-1β. In mice with established diet-induced NASH, FASNi reduced NAFLD activity score, fibrosis score, ALT and TG levels. In the CCl4-induced FAT-NASH mouse model, FASN inhibition decreased hepatic fibrosis and fibrosis markers, and development of hepatocellular carcinoma (HCC) tumors by 85%. These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH.

Oral Diseases

Isolation and phenotypic characterization of cancer stem cells from metastatic oral cancer cells

Article

Author: Cuadra-Zelaya, Florence Juana Maria ; Coletta, Ricardo Della ; Aquino, Iara Gonçalves ; Bastos, Débora Campanella ; Graner, Edgard ; Salo, Tuula ; Palma, Patricia Vianna Bonini ; Bizeli, Ana Laura Valença ; Mariano, Fernanda Viviane

AbstractObjectivesTo isolate cancer stem cells (CSC) from a metastatic oral squamous cell carcinoma (OSCC) cell line and investigate their in vitro and in vivo phenotypic characteristics.Materials and MethodsSubpopulations with individual staining intensities for CD44 and CD326 were isolated from the OSCC cell line LN‐1A by FACS: CD44Low/CD326− (CSC‐M1), CD44Low/CD326High (CSC‐E), and CD44High/CD326− (CSC‐M2). Proliferation, clonogenic potential, adhesion, migration, epithelial‐mesenchymal transition markers, and sensitivity to cisplatin and TVB‐3166 were analyzed in vitro. Tumor formation and metastasis were assessed by subcutaneous and orthotopic inoculations into BALB/c mice.ResultsE‐cadherin levels were higher in CSC‐E cells while vimentin and Slug more produced by CSC‐M2 cells. CSC‐M1 and CSC‐M2 subpopulations showed higher proliferation, produced more colonies, and have stronger adhesion to the extracellular matrix. All cell lines established tumors; however, CSC‐E and CSC‐M2 formed larger masses and produced more metastases.ConclusionThe CSC subpopulations here described show increased cancer capabilities in vitro, tumorigenic and metastatic potential in vivo, and may be exploited in the search for novel therapeutic targets for OSCC.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Sagimet Biosciences, Inc.	01 Aug 2015

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