Abstract 4457: Novel fatty-acid synthase inhibitor in combination with platinum-based therapy provides increased tumor killing efficacy in luminal breast murine model
Authors: Darr David , Alwarawrah Yazan , Hunter Lucas , Loiselle David , Hughes Philip , Haystead Timothy 
Published: August 2015

While targeted therapies exist for Her2 and Luminal breast cancers there remains a subset of patients that would benefit from additional therapeutic options when refractory disease emerges. Independent previous studies have shown that Fatty acid synthase (FAS) can inhibit Her2 oncogene expression and has been shown to be effective as a therapeutic target in xenografts. In this abstract we provide evidence for the anti-tumor activity of a novel FAS inhibitor HS-106 in the Mouse mammary tumor virus (MMTV) driven transgenic mice expressing the Her2 rat analog Neu when combined with platinum-based chemotherapeutic agent Carboplatin.

Single parous female MMTV-Neu mice (Jackson Labs Strain 002376) were used to test the efficacy of HS106 (15mpk, IP twice weekly) alone and in combination with Carboplatin (50mpk IP once weekly). Mice were monitored for tumor development by palpating them weekly as per UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U) protocol. Once tumors were observed, the mice were placed on treatment. The tumor-bearing mice were injected weekly with HS106 and/or Carboplatin. HS106 is dosed at 15 milligrams (mg) per 1 kilogram (kg) of mouse weight, using a solution of 5mg per 1 milliliter (ml) of solvent. The solvent for HS106 consists of 50% dimethyl sulfoxide (DMSO)and 50% saline (0.9% sodium chloride solution). Clinical grade Carboplatin was purchased from the UNC Hospital pharmacy. Tumor volume was measured at the time of injection by caliper and width (short diameter) and length (long diameter) in millimeters (mm) were recorded. The volume was calculated using the formula: length x width2 × 0.5. Body composition was assessed and weight measurements (in grams) were taken weekly at the time of injection were recorded and used to determine toxicity. After three weeks, tumor progression was calculated using the formula: (21 day volume - initial volume)/initial volume x 100. This percent change in tumor volume, at 21 days, was used to assess the objective response rate of the therapies.

Objective Response Rate (Stable Disease, Partial Responses and Complete Responses) were noted in 7 of 8 mice treated with the combination of HS106 and Carboplatin (Mean tumor regression of 4.5%) compared to 3 of 9 in Carboplatin alone (Mean tumor progression of 103%). The combination was well tolerated with no deaths associated with toxicity The FAS inhibitor HS-106 provides a novel means to homogenize and increase the therapeutic response to Platinum-based therapeutic agents. Additional analyses are underway however pharmacokinetic data suggests that a more frequent dosing schedule could provide additional benefit. Further refinement of the dosing schedule for HS-106 may permit the reduction of Carboplatin dose, leading to lowering Carboplatin related toxicity and adverse effects.

Citation Format: David Darr, Yazan Alwarawrah, Lucas Hunter, David Loiselle, Philip Hughes, Timothy Haystead. Novel fatty-acid synthase inhibitor in combination with platinum-based therapy provides increased tumor killing efficacy in luminal breast murine model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4457. doi:10.1158/1538-7445.AM2015-4457