Abstract 715: TGF-beta blockade improves the distribution and efficacy of chemotherapeutic agents in breast carcinoma

Although the role of TGF-β has been studied extensively, its impact upon drug delivery within tumors remains poorly understood. In this study, we blocked the TGF-β pathway in mouse models of breast cancer and studied the effect on delivery and efficacy of chemotherapeutics. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmaceutical (1D11, a TGF-β antibody) approaches to block the TGF-β signaling in two orthotopic breast cancer models (human MDA-MB-231 cells and murine 4T1 cells). TGF-β blockade significantly decreased the growth and metastasis of orthotopic human breast carcinoma xenografts. In addition, TGF-β blockade increased the recruitment and incorporation of myofibroblasts into tumor blood vessels and restored vascular perfusion. Moreover, TGF-β blockade normalized the tumor extracellular matrix (ECM) by decreasing collagen I content. As a result of this vessel and ECM normalization, TGF-β blockade improved the transvascular and interstitial transport of both small and large molecular weight chemotherapeutic agents, and consequently enhanced their efficacy. In conclusion, our study shows that TGF-β blockade might represent a new approach to improve delivery of both low molecular weight conventional drugs as well as nanomedicines in order to maximize therapeutic outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 715. doi:10.1158/1538-7445.AM2011-715