Abstract 2219: Cancer prevention using a novel fatty acid synthase inhibitor
Authors: Neil L. Spector, Tim Haystead, Sumin Zhao, Yazan Alwarawrah, David Alcorta, William Kim, Jose R. Roques, Michael Trinkler, David B. Darr
Journal: Cancer Research (2017)

Abstract Tumor growth and survival is dependent upon de novo fatty acid synthesis regulated via preferential upregulation of fatty acid synthase (FASN) in tumor cells. Here a novel FASN inhibitor that has shown antitumor activity in established tumor models (Alwarawrah Y et al., 2016), now shows promise blocking oncogene-induced cell transformation and significantly delaying time to tumor development in a prevention study using a GEMM of triple negative breast cancer. Non-malignant, immortalized MCF10A human breast epithelial cells were infected with lentivirus encoding for the highly oncogenic 110 kDa truncated form of HER2, herein referred to as p110, under a doxycycline inducible promoter. Lentivirus containing a sham insert served as a control. Forty-eight hours after lentiviral infection, p110 was induced by dox and cells treated with FASN (2 and 4 μM) or vehicle alone for 21 days, and then assessed for cell growth and evidence of senescence. The C3TAg GEMM model of triple negative breast cancer was used to study FASN in the prevention setting. The mice (FVB/N background) express C(3)SV40 T-antigen resulting in the inactivation of p53 and Rb. Eighteen mice were randomized to receive FASN treatment (15mg/kg/ 5 days per week) or control (non-treatment [NT]). The mice were randomized and started treatment at 6 weeks of age, and continued until tumors reached an average size of 87.5mm3. All mice were monitored (5 times/week) for weight loss and time to tumor development. Expression of p110 led to the transformation of MCF10A cells, as evidenced by the formation of plaques in cell culture. Treatment with FASN blocked transformation in p110 expressing MCF10A cells and instead induced growth arrest, expression of senescence associated β-gal, and morphologic appearance consistent with cell senescence. Analysis of viable p110 expressing MCF10A cells that were maintained in the continuous presence of FASN for 60 days led to the identification of a potential mechanism of therapeutic resistance. In the C3TAg in vivo prevention study, FASN resulted in a significant prolongation in time to tumor development (Log-rank (Mantel-Cox); p &amp;lt;0.0056). The median days of tumor onset between the NT and treated groups were 111 and 145 with a range of 84-130 and 85-163, respectively. No gross toxicity or weight loss was observed in FASN treated animals. A novel small molecule FASN inhibitor blocked oncogenic cell transformation and induced a state of senescence. Moreover, FASN significantly delayed the onset of mammary tumors in a GEMM model of aggressive triple negative breast cancer. Identification of a mechanism(s) enabling tumor cells to survive long term FASN inhibition will provide rationale combination strategies to induce permanent senescence or apoptosis, and improve the efficacy of FASN inhibitors as preventative agents. Citation Format: Neil L. Spector, Tim Haystead, Sumin Zhao, Yazan Alwarawrah, David Alcorta, William Kim, Jose R. Roques, Michael Trinkler, David B. Darr. Cancer prevention using a novel fatty acid synthase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2219. doi:10.1158/1538-7445.AM2017-2219