Combination of Polymeric Micelle Formulation of TGFβ Receptor Inhibitors and Paclitaxel Produce Consistent Response Across Different Mouse Models of TNBC

Abstract

Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor-beta (TGF{beta}) family of proteins and their receptors (TGFR) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here we evaluated combination treatments using experimental TGFR inhibitors (TGF{beta}i), SB525334 (SB), and LY2109761 (LY) with Paclitaxel (PTX) chemotherapy. These TGF{beta}i target TGFR-I (SB) or both TGFR-I&II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2-oxazoline) (POx) high-capacity polymeric micelles (SB-POx and LY-POx). We assessed their anti-cancer effect as single agents and in combination with micellar Paclitaxel (PTX-POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11-Apobec and T11-UV). While either TGF{beta}i or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGF{beta}, EMT, TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGF{beta}i and PTX combination therapy using high-capacity POx micelle delivery provides a robust anti-tumor response in multiple TNBC subtype mouse models. Translational Impact StatementPaclitaxel is a widely used chemotherapy in breast cancer. However, response to single-agent chemotherapy is short-lived in a metastatic setting. This study shows the broad applicability of the therapeutic combination of TGF{beta} inhibitors with Paclitaxel across different TNBC subtypes.