Abstract P2-16-24: Folate targeted SMDC’s: A possible new treatment alternative for folate receptor expressing TNBC patients

Abstract

Triple negative breast cancer (TNBC) is a subtype characterized by lack of gene expression for the estrogen receptor, progesterone receptor and the Her2/neu protein. Hence, the lack of hormonal or Her2 targeted therapy options makes TNBC difficult to treat, resulting in a death rate which is disproportionately higher than for other breast cancer subtypes. Recently, the folate receptor (FR) was shown to be highly expressed in TNBC, and expression significantly correlated with the higher grades of malignancy as well as poor outcomes. These observations suggest that TNBC patients may benefit from treatment with an FR-targeted therapy. To address this question, an established FR-positive subcutaneous TNBC pre-clinical model (MDA-MB-231) was chosen to evaluate a panel of FR-targeted small molecule drug conjugates (SMDC) with high potencies and varying mechanisms of action. Thus, EC1456 (folate-tubulysin B; IC50 ∼ 1 nM) and EC1744 (a folate-DNA cross-linking agent; IC50 ∼0.1 nM) were dosed intravenously at 2 μmol/kg following a three times per week, two week schedule in tumor-bearing mice. Both FR-targeted agents were found to be highly active against the MDA-MB-231 tumors, with 80-100% cure rates. In all cases, the observed anti-tumor activity was not accompanied by any significant weight loss in the test animals. These findings suggest that folate-targeted SMDCs may be active against TNBC and that further preclinical studies are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-24.