Abstract 5767: LPA1 antagonist, Debio 0719, acts as a metastasis suppressor in breast cancer
Authors: Marshall Jean-Claude A. , Collins Joshua , Murone Maximilien , Barbier Maryse , Steinberg Seth , Steeg Patricia 
Published: February 2011

The control of micrometastatic cancer is vital to clinical success in the adjuvant or post-treatment (minimal residual disease) settings. Over twenty metastasis suppressor genes (MSGs) have been validated; when over-expressed, they exert no significant effect on primary tumor growth but significantly reduce metastasis. Translation of this basic research to the clinic is difficult, as it is virtually impossible to re-express a gene in every tumor cell. An alternate approach is to identify genes whose expression is inversely correlated with MSGs that can be used as potential therapeutic targets. We identified LPA1, a G-Protein Coupled Receptor (GPCR) for the bioactive lipid lysophosphatidic acid (LPA), as a being inversely correlated with the Nm23-H1 MSG levels in multiple cell lines and a panel of human primary breast carcinomas. These data suggest a novel hypothesis that LPA1 inhibitors may be effective in halting micrometastatic disease in breast cancer patients with low Nm23-H1 expressing, aggressive tumors. To test this we used the 4T1 murine mammary carcinoma model system due to its highly aggressive nature and low Nm23 expression levels. Stably transfected murine or human Nm23 expressing 4T1 clones significantly decreased the motility of the 4T1 cells and expressed lower levels of LPA1. Treatment of the cells with a small molecule LPA1 specific inhibitor, Debio 0719, at an IC50 of 50nM significantly reduced the migration of all 4T1 parental cells towards both 1% FBS and LPA (10uM), while having minimal effects on tumor cell growth as measured by MTT assay. To assess the effects of this LPA1 inhibitor in vivo, 4T1 parental, vector control and Nm23-M1 expressing clones were orthotopically injected into the mammary fat pad of Balb/c mice at day 0. On day two after injection the mice receiving the 4T1 parental cells were randomized between vehicle control and treatment group. The treated group received Debio 0719 which was administered subcutaneously (twice daily, 15 mg/kg). Primary tumors were resected from all mice at day 10 and mice were subsequently allowed to continue until day 70 before sacrifice. The compound had no significant effect on primary tumor sizes and, as such, would have been a no-go for traditional drug development. However, mice treated with Debio 0719 had significantly decreased lung and liver metastasis, 84% and 86% respectively (P &lt; 0.0001 for both). This reduction in metastasis is similar to that seen in the 4T1 Nm23-M1 expressing clones. Subsequent immunohistochemical studies have revealed that while there is no change in proliferative index in the primary tumors between treated and non-treated mice, there was a significant difference in Ki67 staining between the untreated liver metastasis (19%) and treated (5%). The data indicate that Debio 0719 acts as a metastasis suppressor, reducing metastatic foci and can induce dormancy in the metastatic site. As such, it represents a new class of potential therapeutics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5767.